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Durvalumab - Celgene/MedImmune

Drug Profile

Durvalumab - Celgene/MedImmune

Alternative Names: Anti-PD-L1 monoclonal antibody; Anti-PD-LI mAb; Anti-programmed cell death 1 ligand 1 monoclonal antibody; Imfinzi; MEDI-4736

Latest Information Update: 17 Jan 2019

At a glance

  • Originator MedImmune
  • Developer Advaxis; AIO Studien gGmbH; AstraZeneca; Big Ten Cancer Research Consortium; Canadian Cancer Trials Group; Case Comprehensive Cancer Center; Celgene International SARL; Centre hospitalier de l'Universite de Montreal; Centre Leon Berard; Charite - Universitatsmedizin Berlin; Childrens Hospital Los Angeles; Dana-Farber Cancer Institute; Eli Lilly; Fondazione IRCCS Istituto Nazionale dei Tumori; GlaxoSmithKline; Gradalis; Grand Hopital de Charleroi; Grupo Espanol de Tumores Neuroendocrinos; Gustave Roussy; Immunocore; Innate Pharma; Institut Claudius Regaud; Juno Therapeutics; Kyoto Breast Cancer Research Network; Ludwig Institute for Cancer Research; M. D. Anderson Cancer Center; MedImmune; Memorial Sloan-Kettering Cancer Center; Mirati Therapeutics; National Cancer Institute (USA); National Health and Medical Research Council; Northwestern University; Pharmacyclics; Plexxikon; Samsung Medical Center; Seoul National University Hospital; Swiss Group for Clinical Cancer Research; UNC Lineberger Comprehensive Cancer Center; UNICANCER; University College London; University of Colorado at Denver; University of Kansas Medical Center; University of Maryland Greenbaum Cancer Center; University of Southern California; University of Sydney; University of Texas M. D. Anderson Cancer Center; VentiRx Pharmaceuticals; Washington University School of Medicine; Yale University; Yonsei University College of Medicine
  • Class Antineoplastics; Monoclonal antibodies
  • Mechanism of Action Programmed cell death-1 ligand-1 inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Urogenital cancer
  • Registered Non-small cell lung cancer
  • Phase III Bladder cancer; Head and neck cancer; Liver cancer; Renal cell carcinoma; Small cell lung cancer; Solid tumours
  • Phase II/III Breast cancer; Gynaecological cancer; Pancreatic cancer
  • Phase II Acute myeloid leukaemia; Biliary cancer; Brain metastases; Cholangiocarcinoma; Colorectal cancer; Diffuse large B cell lymphoma; Endometrial cancer; Fallopian tube cancer; Gallbladder cancer; Gastric cancer; Germ cell and embryonal neoplasms; Glioblastoma; Mesothelioma; Multiple myeloma; Myelodysplastic syndromes; Neuroendocrine tumours; Oesophageal cancer; Oropharyngeal cancer; Ovarian cancer; Peritoneal cancer; Prostate cancer; Sarcoma; Soft tissue sarcoma
  • Phase I/II Cervical cancer; Chronic lymphocytic leukaemia; Cutaneous T-cell lymphoma; Lung cancer; Lymphoma; Malignant melanoma; Non-Hodgkin's lymphoma; Peripheral T-cell lymphoma; Renal cancer
  • Phase I CNS cancer; Gastrointestinal cancer; Lymphoproliferative disorders; Myelofibrosis; Thyroid cancer; Vulvovaginal cancer

Most Recent Events

  • 11 Jan 2019 MedImmune plans a phase II trial for Non-small cell lung cancer (Combination therapy) in USA, Canada, France, Italy, Portugal, Spain and Switzerland (NCT03794544)
  • 07 Jan 2019 AstraZeneca initiates enrolment in a phase III trial for Non-small cell lung cancer (Second-line therapy or greater) in USA (EudraCT2018-002997-29)
  • 19 Dec 2018 Samsung Medical Center plans a phase II trial for Solid tumour (Metastatic disease; Combination therapy) in January 2019, (NCT03780608)

Development Overview

Introduction

Durvalumab (MEDI 4736), developed by MedImmune (a subsidiary of AstraZeneca), is a fully human monoclonal antibody directed against programmed death ligand-1 (PD-L1), for the treatment of various cancers. Durvalumab is an immunoglobulin G1 kappa (IgG1κ) antibody that blocks the interaction of PD-L1 (CD274 or B7 homolog 1) with PD-1 and CD80 (B7.1) on T cells thus reducing self-tolerance and immunosuppression, which allows the immune cells to find and destroy the cancerous tissue. Durvalumab is launched in the US, and approved in Canada and Brazil, for urogenital cancer. The drug is also approved in the US, Japan, Canada, Switzerland, Brazil, India and European Union for non-small cell lung cancer. Clinical development is ongoing worldwide for acute myeloid leukaemia, biliary cancer, bladder cancer, brain metastases, breast cancer, CNS cancer, cervical cancer, chronic lymphocytic leukaemia, colorectal cancer, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, endometrial cancer, fallopian tube cancer, gastric cancer, gastrointestinal cancer, glioblastoma, gynaecological cancer, head and neck cancer, hepatocellular carcinoma, lung cancer, lymphoma, lymphoproliferative disorders, malignant melanoma, mesothelioma, multiple myeloma, myelodysplastic syndromes, myelofibrosis, neuroendocrine tumours, non-Hodgkin's lymphoma, oesophageal cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, peripheral T-cell lymphoma, peritoneal cancer, prostate cancer, renal cancer, renal cell carcinoma, sarcoma, small cell lung cancer, soft tissue sarcoma, solid tumours, thyroid cancer, urogenital cancer, gallbladder cancer, vulvovaginal cancer and germ cell cancer.

Durvalumab emerged from MedImmune's research into anticancer monoclonal antibodies [see AdisInsight drug profile 800034274].

MedImmune, in collaboration with Ventana Medical Systems, is developing a personalised PD-L1 immuno-histochemistry assay [see AdisInsight drug profile 800040741] to screen patients that enrol in clinical trials of durvalumab. This includes the ATLANTIC trial for NSCLC that will enrol only patients that express PD-L1 as determined by the VENTANA assay. The companion diagnostic is approved in the US for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue.

Company Agreements

In July 2018, MedPacto and AstraZeneca entered into a clinical collaboration to evaluate the safety and efficacy of MedPacto’s vactosertib (TEW-7197) in combination with durvalumab in patients with metastatic non-small cell lung cancer. Under the terms of the agreement, MedPacto and AstraZeneca will collaborate on a non-exclusive basis to evaluate the combination of the two drugs in NSCLC. MedPacto will sponsor and fund the study and AstraZeneca will supply durvalumab for the study. [1]

Immunomedics and AstraZeneca entered into a collaboration in July 2018, to conduct a phase I/II trial for sacituzumab govitecan in combination with durvalumab in patients with triple negative breast cancer and urothelial cancer. [2]

In February 2018, Syndax Pharmaceuticals entered into a non-exclusive clinical trial collaboration with AstraZeneca, to evaluate the safety and efficacy of the former's SNDX 6352 (also known as UCB 6352), in combination with the latter's durvalumab, for the treatment of solid tumours. Under the terms of the agreement, in the first half of 2018, Syndax will initiate a phase Ib trial to establish the safety and recommended dose regimen of the combination therapy. Both the companies can use the data from the phase Ib trial to sponsor, design and initiate subsequent phase II studies, aimed at assessing the safety and efficacy of the combination therapy in different types of solid tumours. [3]

In January 2018, Innate Pharma entered into a non-exclusive clinical trial collaboration with MedImmune to conduct the phase I/II STELLAR-001 trial. Innate Pharma will conduct the trial to assess the safety and efficacy of durvalumab plus IPH 5401 for the treatment of patients with selected solid tumours. Both the companies will equally share the expenses of the trial [4]

In September 2017, NewLink Genetics Corporation signed a clinical collaboration agreement with AstraZeneca to evaluate the combination of indoximod and durvalumab along with standard of care chemotherapy for patients with metastatic pancreatic cancer. [5]

In July 2017, Merck entered into a global strategic oncology collaboration with AstraZeneca to co-develop and co-commercialise AstraZeneca’s olaparib (Lynparza) and selumetinib as monotherapy and in combination treatments for multiple cancer types. Merck and AstraZeneca will independently develop and commercialise olaparib and selumetinib in combinations with the companies’ respective PD-1 and PD-L1 immuno-oncology medicines pembrolizumab and durvalumab. Merck will fund all development and commercialization costs of pembrolizumab in combination with olaparib or selumetinib. AstraZeneca will fund all development and commercialization costs of durvalumab in combination with olaparib or selumetinib. AstraZeneca will receive up to $US8.5 billion in total consideration, including $US1.6 billion upfront, $US750 million for certain license options and up to an additional $US6.15 billion upon successful achievement of future regulatory and sales milestones. Under their agreement, gross profits from selumetinib product sales generated through monotherapy or combination therapies will be shared equally. AstraZeneca will book all product sales of selumetinib and gross profits due to Merck under the collaboration will be recorded by AstraZeneca under cost of sales. [6] [7] [8]

In June 2017, Eleven Biotherapeutics signed a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI) on the development of Eleven's oportuzumab monatox (ViciniumTM) in combination with AstraZeneca's durvalumab (ImfinziTM; [see Adis Insight Drug profile 800037095]), for the treatment of non-muscle invasive bladder cancer. Under the terms of CRADA, NCI Center for Cancer Research, Urologic Oncology Branch, will conduct a phase I clinical trial in patients with high-grade NMIBC to evaluate the safety, efficacy, and biological correlates of the vicinium and durvalumab combination therapeutic strategy [9]

In August 2015, MedImmune and Mirati Therapeutics entered into an exclusive clinical trial collaboration to evaluate the safety and efficacy of MedImmune’s, durvalumab, in combination with Mirati’s, mocetinostat, in patients with non-small cell lung cancer (NSCLC) during a phase I/II trial [see AdisInsight drug profile 800020983]. Under the agreement, Mirati will conduct and fund the initial phase I/II trial, which will be overseen by a Joint Steering Committee. MedImmune will have an exclusive period of time to negotiate a commercial license for the of the combination therapy in NSCLC indication following the positive results from the initial clinical trial [10] .

In August 2015, AstraZeneca entered into a non-exclusive clinical trial collaboration with Peregrine (now Avid Bioservices) to conduct a phase I/Ib trial of the former's durvalumab latter's in combination with bavituximab [see AdisInsight drug profile 800022616] in multiple solid tumours. Pursuant to the terms of the agreement, Peregrine will conduct the initial phase I part of the trial [11] .

In October 2015, Peregrine Pharmaceuticals announced that it has expanded its clinical collaboration with AstraZeneca to include a global phase II trial of durvalumab in combination with bavituximab in patients with previously treated squamous or non-squamous non-small cell lung cancer (NSCLC). Patients will be evaluated retrospectively for the correlation between their PD-L1 levels and clinical outcomes. The randomised trial will be conducted by Peregrine [12] [13] .

In May 2015, AstraZeneca entered into a clinical trial collaboration with Eli Lilly to investigate the safety and preliminary efficacy of the combination therapy of durvalumab with the latter’s vascular endothelial growth factor receptor 2 antagonist, ramucirumab [see AdisInsight drug profile 800021478]. As per the agreement, Eli Lilly will sponsor the phase I study of the combination therapy for the treatment of patients with advanced solid tumours. Further details of the agreement, including tumours to be studied and financial terms, were undisclosed [14] . The companies' collaboration was expanded in October 2015, to also explore the combination of durvalumab with galunisertib, LY 2510924, or IMC CS4 in patients with solid tumours [see AdisInsight drug profiles 800028406, 800034546 and 800034411] [15] . Under the expanded agreement, Lilly and AstraZeneca will evaluate the safety and efficacy of the said combinations, with Lilly leading the execution of the studies. Both companies will contribute resources. As with the initial agreement, other details of the expanded agreement were not disclosed [16] .

In April 2015, MedImmune and Celgene International II Sarl entered into an exclusive collaboration to develop and commercialise durvalumab as a monotherapy and in combination with other anticancer drugs for haematologic malignancies including non-Hodgkin’s lymphoma, myelodysplastic syndromes and multiple myeloma. Under the agreement, Celgene will make an upfront payment of US$450 million, lead clinical development across all clinical trials and be responsible for all research and development costs until the end of 2016, following which Celgene will undertake 75% of these costs. MedImmune will continue to manufacture and book all sales of the drug and will pay royalty to Celgene on worldwide commercialisation of approved durvalumab indications in haematology. The royalty rates will begin with 70% and will decrease to 50% of the global sales of durvalumab in haematological indications over a period of four years. The collaboration agreement is expected to become effective in the second quarter of 2015, following the expiration or termination of applicable waiting periods under all applicable antitrust laws [17] . Initially, the collaboration will focus on the development of combination therapy of durvalumab with Celgene’s pipeline products and other drugs for haematological disorders. The collaboration will also explore combination therapies with AstraZeneca’s anticancer drugs and could expand to include other assets [18] .

During first quarter of 2015, AstraZeneca and Gilead entered into a clinical trial collaboration to investigate durvalumab in combination with idelalisib [see AdisInsight drug profile 800025920] for the treatment of haematological cancers/solid tumours including diffuse large B-cell lymphoma, and triple negative breast cancer [19] .

AstraZeneca and Innate Pharma signed an agreement in April 2015, for the co-development of durvalumab in combination with IPH 2201 for the treatment of cancer [20] [21] [22] .

In November 2014, AstraZeneca and Pharmacyclics (a subsidiary of AbbVie) entered into a clinical trial collaboration to investigate combination therapies for solid tumours. The collaboration will investigate the safety and efficacy of durvalumab in combination with ibrutinib [see AdisInsight drug profile 800022023]. Preclinical data suggested that combining these compounds may result in enhanced effects compared with the treatment alone. Both Pharmacyclics and AstraZeneca will collaborate on a non-exclusive basis and may consider and conduct multiple studies. The studies will be led by Pharmacyclics. Data from these studies will determine the feasibility of further clinical development of different combinations. Financial terms of the agreement were not disclosed [23] .

In May 2015, Pharmacyclics was acquired by AbbVie [24] .

In April 2015, MedImmune and Immunocore entered into a collaboration agreement. Under the terms of which, Immunocore will conduct a phase Ib/II study of IMC gp100 [see AdisInsight drug profile 800033036] in combination with durvalumab and/or tremelimumab [see AdisInsight drug profile 800020650], for the potential treatment of metastatic melanoma. MedImmune will have the first right of negotiation for the future development of these combinations for tumours expressing gp100. Immunocore and MedImmune will collaborate to establish a dosing regimen for IMC gp100 combined with durvalumab and/or tremelimumab within the phase Ib study while the phase II study will assess the safety and efficacy of the different combinations [25] [26] .

Also in November 2014, AstraZeneca, Pharmacyclics and Janssen Research & Development entered into a clinical trial collaboration to investigate durvalumab in combination with ibrutinib for the treatment of haematological malignancies, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma [see AdisInsight drug profile 800022023]. Preclinical data suggested that combining these compounds may result in enhanced effects compared with the treatment alone. Under the terms of the agreement, the studies will be led by Pharmacyclics. Phase I stage of the study will establish the recommended and tolerable dose and dosing schedule for the combination and the phase II stage will evaluate the safety and efficacy of the combination. Financial terms of the agreement were not disclosed [27] .

In July 2014, Advaxis and MedImmune, the development and research arm of AstraZeneca, entered into a collaboration for an immuno-oncology combination trial. Under the terms of the collaboration, both companies will team up on a phase I/II trial to evaluate the safety and efficacy of durvalumab in combination with Advaxis' axalimogene filolisbac for the treatment of advanced, recurrent or refractory HPV-associated cervical cancer and HPV-associated squamous cell carcinoma of the head and neck cancer. Advaxis will fund the study. MedImmune has a non-exclusive relationship for HPV-associated tumour types and has the first right to negotiate future development of combinations comprising axalimogene filolisbac and durvalumab [28] . [see AdisInsight drug profile 800025081].

AstraZeneca entered into a collaboration agreement with Kyowa Hakko Kirin in August 2014 to co-fund a clinical study of durvalumab in combination with Kyowa Hakko Kirin's anti CCR4 antibody, mogamulizumab [see AdisInsight drug profile 800025071] [29] .

In January 2018, Peregrine Pharmaceuticals changed its name to Avid Bioservices [30] .

Key Development Milestones

As of September 2017, the US FDA placed partial clinical hold on five trials and full clinical hold on one trial of FUSION programme, based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents [31] . Celgene has not discerned, at this time, an imbalance in the risk benefit profile in the Fusion programme; however, the clinical holds allow for additional information to be collected to further understand the risk benefit profile of the programme [32] . In December 2015, Celgene initiated the FUSION clinical programme which includes four trials for durvalumab, in collaboration with AstraZeneca. The FUSION programme consists of six clinical trials for newly diagnosed multiple myeloma, chronic lymphocytic leukaemia, relapsed/refractory multiple myeloma, non-Hodgkin's lymphoma, myelodysplastic syndromes and acute myeloid leukaemia. In July 2016, Celgene reported that it has initiated enrolment in these trials [33] [34] .

Urogenital cancer

In November 2018, AstraZeneca announced that durvalumab is approved in Israel, India, United Arab Emirates, Australia and Hong Kong as for previously-treated patients with advanced urothelial cancer [35] .

In November 2018, AstraZeneca initiated the NIAGARA phase III trial to valuate the efficacy and safety of durvalumab in combination with gemcitabine and cisplatin for neoadjuvant treatment followed by durvalumab alone for adjuvant treatment in patients with muscle-invasive bladder cancer (EudraCT2018-001811-59; D933RC00001; NCT03732677). The open-label, randomised study intends to enrol approximately 1050 patients. Enrolment is on-going at South Korea and is planned at the US, the UK, Vietnam, Turkey, Taiwan, Russia, Poland, Philippines, Japan, Israel, Germany, Czech Republic, Chile, Canada, Brazil and Australia [36] .

AstraZeneca, in September 2018 initiated a phase III NILE study to to determine the efficacy and safety of durvalumab in combination with standard of care (SoC) chemotherapy followed by durvalumab in combination with tremelimumab and standard of care chemotherapy versus standard of care chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (D933SC00001; NCT03682068; EudraCT 2018-001883-48; JapicCTI184160). The primary end point of the trial is to determine progression free survival (PFS) in a time frame of approximately four years. The randomized, open-label trial intends to enrol approximately 885 patients in Australia, Hungary and Russia [37] .

In May 2018, AstraZeneca initiated the POTOMAC phase III trial to evaluate the efficacy and safety of durvalumab plus BCG combination therapy, in the patients with non-muscle-invasive bladder cancer (D419JC00001; JapicCTI183968; NCT03528694). The open label trial intends to enrol approximately 975 patients in Russia, Australia, Japan, Netherlands, Spain, and the UK [38] .

In February 2018, AstraZeneca reported that the Brazil Health Regulatory Agency approved durvalumab (IMFINZI®) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC), who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery. The approval was granted within ten months of submission [39] .

In May 2017, the US FDA granted accelerated approval to durvalumab (IMFINZI®) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC), who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery [40] . In December 2016, the US FDA granted priority review status to the Biologics License Application (BLA) for durvalumab. The PDUFA date was set for the second quarter of 2017. The BLA was filed based on the bladder cancer cohort of study 1108 [see above] [41] .

In May 2017, AstraZeneca reported that durvalumab (IMFINZI®) will be immediately available at Biologics, a McKesson Specialty Health oncology pharmacy services company, which has been selected by AstraZeneca to be a speciality pharmacy provider in the limited distribution network for durvalumab [42] .

In November 2017, Health Canada issued a notice of compliance with conditions and granted an accelerated approval to durvalumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma (bladder cancer) who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before or after surgery. The approval was based on results of study 1108 [see below] [43] .

In February 2016, the US FDA granted breakthrough therapy designation to durvalumab for the treatment of patients with PD-L1 positive inoperable or metastatic urothelial cancer of the bladder, whose tumour has progressed during or after one standard platinum-based regimen. The special designation was granted, based on the clinical data from a phase I/II trial (study 1108) [see below] in patients with advanced metastatic urothelial bladder cancer [44] .

In November 2015, AstraZeneca initiated the phase III DANUBE trial to investigate the safety and efficacy of durvalumab first-line monotherapy and in combination with tremelimumab versus standard of care chemotherapy, in patients with stage IV urothelial bladder cancer (NCT02516241; EudraCT2015-001633-24; D419BC00001). Enrolment of 1200 patients has been completed in the randomised, open-label study in South Korea, the Netherlands, Spain, Germany, Greece, Israel, Belgium, Poland, Denmark, Brazil, Canada, Italy, Mexico, the US, Australia, Austria, China, Portugal, Japan, Taiwan, Belgium, France, Israel, Russia, Turkey, and the UK. The first patient was enrolled in the final quarter of 2015 [39] [45] .

In November 2018, Spanish Oncology Genito-Urinary Group and AstraZeneca initiated the phase II IMMUNOPRESERVE trial to evaluate the efficacy of durvalumab plus tremelimumab [see ADIS insight drug profile800020650] with concurrent radiotherapy, in terms of pathological response rate, in patients with localised muscle invasive bladder cancer treated with bladder preservation intent (SOGUG2017A-IEC-VEJ1; EudraCT2017-003159-44; NCT03702179). The open label trial intends to enrol approximately 32 patients in Spain [46] .

In January 2018, Memorial Sloan Kettering Cancer Center in collaboration with AstraZeneca initiated a phase II study to test the safety and effectiveness of durvalumab combined with tremelimumab in patients urinary tract cancer (NCT03430895). The single arm, open-label study intends to enrol approximately 27 patients in the US [47] .

In March 2017, M.D. Anderson Cancer Center initiated a pilot pre-surgical clinical trial to assess safety and tolerability of durvalumab in combination with tremelimumab [see AdisInsight drug profile 800020650] in patients with urogenital cancer (2016-0033; NCT02812420). The open-label trial is enrolling approximately 15 patients in the US [48] .

AstraZeneca and H. Lee Moffitt Cancer Center and Research Institute, in February 2017, initiated a phase II trial to assess the efficacy of durvalumab in Bacillus Calmette-Guérin refractory patients with urothelial carcinoma in situ of the bladder (MCC-18788; ESR-15-11326; NCT02901548). The open-label, single-group trial will enrol approximately 34 patients in the US [49] .

University of California, San Francisco, in collaboration with MedImmune, planned to initiate a phase II trial evaluating safety and efficacy of durvalumab, with or without tremelimumab [see AdisInsight drug profile 800020650], in combination with stereotactic body radiation therapy (SBRT), in patients with unresectable, muscle-invasive or metastatic bladder cancer that are ineligible or refusing chemotherapy (16529; NCT03150836). The randomised, sequential, open-label study will enrol approximately 74 patients, in the US. However, the trial was withdrawn prior to enrolment due to organisational change of the principal investigator [50] .

In November 2016, AstraZeneca initiated a phase Ib/II trial, to evaluate safety and efficacy of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab, in patients with urothelial cancer (BTCRC-GU15-023; NCT02891161). The non-randomised, open-label trial will enrol approximately 42 patients in the US [51] .

In March 2018, AstraZeneca initiated the phase II BAYOU trial to determine the efficacy and safety of durvalumab in combination with olaparib [See ADIS Insight Drug Profile 800024096] for first-line treatment in cisplatin-ineligible patients with unresectable stage IV urothelial cancer (NCT03459846; D933IC00003). The double-blind, parallel, prospective, randomised trial is enrolling approximately 256 patients in Taiwan, Spain, Vietnam, Russia, South Korea, the US and Canada [52] .

Acute myeloid leukaemia

Celgene initiated a phase II trial in June 2016, to evaluate the safety and efficacy of azacitidine in combination with subcutaneous durvalumab, in patients with acute myeloid leukaemia and those who are at a high risk myelodysplastic syndrome (MEDI4736MDS001; NCT02775903; EudraCT2015-003596-30). The randomised, open-labelled trial intends to enrol approximately 182 patients in Austria, Portugal, Poland, Netherlands, Italy, France, Canada, Belgium, USA, Germany, Spain and the UK. The primary endpoint will be overall response rate in both myelodysplastic syndrome and acute myeloid leukaemia cohorts [34] [53] .

Biliary tract cancer

In November 2018, Multidisciplinary Oncology Cooperative Group in collaboration with AstraZeneca initiated a phase II trial of durvalumab in combination with tremelimumab [see Adis Insight Drug profile 800020650] with or without weekly paclitaxel in patients with advanced biliary tract cancer patients after failure of platinum-based chemotherapy (IMMUNO-BIL; IMMUNO-BIL-D18-1PRODIGE57; NCT03704480). The open-label, randomised trial intends to enrol approximately 102 patients in France [54] .

In February 2017, Seoul National University Hospital initiated a phase II trial biomarker-oriented study of durvalumab and tremelimumab [see Adis Insight drug profile 800020650] in combination with gemcitabine/cisplatin in chemotherapy-naïve biliary tract cancer patients (BTC-1st MEDITREME; NCT03046862). The trial intends to enrol 31 patients in South Korea [55] .

Brain metastases

A phase II trial was terminated due to low accrual, withdrawal of funding by AstraZeneca and change in clinical practice (201602169; NCT02669914; 16-x001). In September 2016, the Washington University School of Medicine and AstraZeneca initiated the trial to investigate the safety and efficacy of durvalumab in patients with brain metastases from epithelial-derived tumours. The parallel, non-randomised, open-label trial recruited four patients in the US [56] .

Breast cancer

In June 2016, AstraZeneca, Gradalis and Mary Crowley Medical Research Center (sponsor) initiated a phase II/III trial to assess the safety and efficacy of durvalumab 1 500mg IV plus autologous tumour cell vaccine [see AdisInsight drug profile 800029621] in patients with PD-L1 negative locally advanced or metastatic breast cancer (16-06; CL-PTL 124; ESR-15-11306; NCT02725489). The open-label, parallel, non-randomised trial will enrol approximately 33 patients in the US [57] . In August 2016, Gradalis announced that the first patient has been dosed in the study [58] .

In August 2018, AstraZeneca in collaboration with Kyoto Breast Cancer Research Network terminated a phase II trial that was designed to evaluate the safety and efficacy of durvalumab plus tremelimumab (anti-CTLA-4 antibody drug) [see AdisInsight drug profile 800020650] in combination with hormone therapy (fulvestrant) [see AdisInsight drug profile 800000789] in patients with inoperable or recurrent hormone-receptor-positive and HER2-negative breast cancer with distant metastasis (KBCRN-B-001; R000029938; UMIN000026050; NCT03430466). The trial also intended to investigate immunological biomarkers affecting the therapeutic effect. The trial was initiated in December 2017 and intended to enrol approximately 33 patients in Japan. Response rate based on RECIST criteria was to be evaluated as the primary endpoint [59] .

In September 2018, AstraZeneca, Celgene and German Breast Group completed the phase II GeparNuevo trial which was initiated in March 2016, to evaluate the addition of durvalumab 1.5g IV to chemotherapy(paclitaxel 125 mg/m², epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²) in patients with early triple negative breast cancer (GBG89; DRKS00011286; NCT02685059; EudraCT2015-002714-72). The primary endpoint was to compare the pathological complete response (pCR = ypT0 ypN0) rates of neoadjuvant treatment of sequential, nab-paclitaxel followed by EC +/- durvalumab. The randomised, parallel, double-blind, placebo-controlled trial will enrolled 174 patients in Germany [60] .

In July 2018, MedImmune and the Northwestern University re-initiated participant recruitment in a phase II trial that was designed to assess the efficacy of durvalumab in combination with tremelimumab [see AdisInsight drug profile 800020650] for the treatment of patients with metastatic HER2-negative breast cancer. In September 2017, the recruitment in the trial was suspended (NU 15B01; NCI-2015-01445; ESR-14-10694; D4190C00030; STU00200984; P30CA060553; NCT02536794). The response rate evaluated as stable disease for ≥12 weeks, partial response or complete response as evaluated by the RECIST version 1.1 were to be evaluated as primary endpoint measure in the trial. The open-label, single-group assignment trial was initiated in December 2015 and intended to enrol approximately 30 patients in the US [61] .

In July 2016, AstraZeneca in collaboration with King Faisal Specialist Hospital and Research Center initiated a phase I/II trial to assess the safety, tolerability and efficacy of durvalumab in combination with paclitaxel in patients with metastatic triple negative PD-L1 positive breast cancer (2151-169; ESR-14-10649; NCT02628132). The phase I dose de-escalation portion will include three doses of paclitaxel administered to 3 patients followed by phase II dose expansion phase in 25 patients. Paclitaxel will be administered weekly for 2 cycles followed by combination of paclitaxel and durvalumab. After completion of 6 cycles of paclitaxel, durvalumab alone will be administered until disease progression or unacceptable toxicity. Primary endpoint will be toxicity and tolerability of the two combinations, efficacy will be a secondary end point. The open-label trial intends to enrol 34 patients in Saudi Arabia [62] .

Grand Hopital de Charleroi initiated the B-IMMUNE phase I/II trial to assess the safety and tolerability of durvalumab in combination with a dose-dense EC regimen in a neoadjuvant setting for early breast cancer (ONCOGHdC2015-01; EudraCT2016-003998-17). This open, prospective, randomised is enrolling 57 patients in Belgium [63] .

In November 2015, Yale university initiated a phase I/II neoadjuvant trial to assess the safety of durvalumab combined with chemotherapy and determine if full dose of durvalumab can be administered concomitantly with full dose weekly nab-paclitaxel followed by dose-dense AC chemotherapies (ddAC), respectively, for the treatment of breast cancer (1409014537; NCT02489448). The phase II portion will evaluate the pathologic complete response (pCR) rate with durvalumab in combination with weekly nab-paclitaxel x 12 treatments followed by durvalumab in combination with ddAC x 4 treatments for estrogen receptor (ER), progesterone receptor (PR) and HER2 negative (triple negative, TNBC) breast cancer. The open-label, single-group assignment trial will enrol 61 patients in the US. In June 2017, Yale university presented safety data of the trial at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO-2017) [64] [65] .

In May 2018, AstraZeneca in collaboration with Icahn School of Medicine at Mount Sinai initiated a phase I trial to evaluate the safety and tolerability of durvalumab in combination with eribulin [see ADIS Insight Drug profile 800015511] in patients with HER2-negative metastatic breast cancer and recurrent ovarian cancer (GCO17-2320; NCT03430518). The open-label trial is enrolling approximately 12 patients in the US [66] .

In April 2018, Washington University School of Medicine in collaboration with MedImmune LLC initiated a phase I trial to compare the safety and efficacy of neoantigen DNA vaccine alone [see ADIS insight drug profile800049779] and neoantigen DNA vaccine plus durvalumab, in triple negative breast cancer (TNBC) patients following standard of care therapy (201710109; NCT03199040). The open label trial intends to enrol approximately 24 patients in the US [67] .

In June 2017, University of Texas M.D. Anderson Cancer Center in collaboration with AstraZeneca, initiated a pilot, pre-surgical, phase I trial to evaluate the highest dose combination of durvalumab and tremelimumab in patients with HR+, HER2- breast cancer. The open-label trial is designed to enrol approximately 15 patients in the US [68] .

In August 2016, Massachusetts General Hospital in collaboration with OncoPep and AstraZeneca, initiated a phase Ib trial to assess the safety, tolerability and immune response of intramuscularly administered PVX 410 vaccine [see AdisInsight drug profile 800035618] (mixed with poly-ICLC adjuvant) alone and in combination with durvalumab intravenous infusion, in human leukocyte antigen (HLA)-A2+ patients following standard treatment of stage II or III triple negative breast cancer (16-132; NCT02826434). The open-label, single-group trial will enrol approximately 20 patients in the US [69] [70] .

In April 2016, The Canadian Cancer Trials Group in collaboration with AstraZeneca initiated a phase Ib, pharmacodynamic study of durvalumab in adjunction with trastuzumab in patients with advanced/metastatic/recurrent or unresectable HER-2 positive metastatic breast (I229; NCT02649686). The primary endpoint of the study is to establish the recommended phase II dose. The trial enrolled 15 patients in Canada [71] . In June 2018, the company presented safety and efficacy data of the combination therapy at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [72] .

Cervical and vulvovaginal cancer

In April 2015, MedImmune and Advaxis initiated a phase I/II trial to evaluate durvalumab alone and in combination with axalimogene filolisbac [see AdisInsight drug profile 800025081] in patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer (ADXS001-04; NCT02291055). The phase I portion is designed to identify a recommended dose regimen for the combination therapy, and the phase II portion will evaluate the safety and efficacy of the combination. The open-label, randomised study enrolled 66 patients in the US [73] . In July 2016, dosing of patients in second-dose escalation cohort was completed and commenced enrolment in the the part A expansion and part B portion of the trial. The part A expansion portion of the trial intends to enrol approximately 20 patients with HPV associated head and neck cancer, who will receive 1x109 cfu in combination with durvalumab (10 mg/kg). The part B portion of the trial intends to enrol approximately 45 patients, who will receive same dosage of the combination [74] . In March 2016, Advaxis and MedImmune completed the first dose-escalation cohort of 1x109 cfu with 3 mg/kg durvalumab and commenced the second dose-escalation cohort of 1x109 cfu in combination with 10 mg/kg durvalumab in the study [75] . In November 2014, Advaxis submitted an IND to the US FDA for the phase I/II trial of axalimogene filolisbac alone or in combination with MedImmune's durvalumab for the treatment of advanced, recurrent or refractory HPV-associated cervical cancer and HPV-associated head and neck cancer. Preclinical data suggested that the combination of these two products will enhance overall anti-tumour response. The US FDA will notify Advaxis within 30 calendar days of any questions relates to the trial protocol. The two companies entered into a collaboration in July 2014 to conduct the trial [76] [28] .

In July 2018, M. D. Anderson Cancer Center and AstraZeneca initiated a phase I trial to evaluate durvalumab and tremelimumab in combination with radiotherapy for treatment of patients with recurrent or metastatic advanced cervical, vaginal or vulvar cancer (2017-0548; NCI-2018-00627; NCT03452332). The open-label trial is designed to enrol approximately 18 patients in the US [77] .

In December 2017, AstraZeneca initiated the phase I DURVIT study of durvalumab in cervical cancer patients who are scheduled for lymph node dissection or lymph node debulking in the context of a radical hysterectomy or chemo-radiation (ESR16-11856Astra-Zeneca; NTR6119; NL59122-018-16ABR; 25490). The non-randomised, single-arm, open-label study is enrolling approximately 24 patients in the Netherlands [78] .

Chronic lymphocytic leukaemia

In September 2017, the US FDA placed a partial clinical hold on a phase I/II trial which was evaluating efficacy, pharmacokinetics, pharmacodynamics, safety and tolerability of durvalumab 1 500mg IV infusion both alone and as a combination therapy in patients with chronic lymphocytic leukaemia and certain lymphoma subtypes (FUSION NHL 001; MEDI4736-NHL-001; NCT02733042). The hold was based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents [32] . The study had 3 parts: dose finding, dose confirmation and dose expansion. The open-label, non-randomised trial initiated in May 2016, intended to enrol approximately 265 patients in France, Italy, Japan, the Netherlands, the US, the UK, and will expand recruitment sites in Germany [31] [34] [79] .

Colorectal cancer

In March 2018, M.D. Anderson Cancer Center in collaboration with MedImmune, AstraZeneca and Novartis initiated a phase II trial to evaluate the efficacy and safety of trametinib [see ADIS insight drug profile800024261] and durvalumab, in patients with metastatic colorectal cancer (2017-0514; NCT03428126). Evaluation of the maximum tolerated dose and best overall response are the defined primary endpoints of the trial. The open label trial intends to enrol approximately 56 patients in the US [80] .

In August 2017, AstraZeneca initiated a phase I/IIa trial to evalute the safety, tolerability and immunological activity of durvalumab, in combination with tremelimumab and FOLFOX, in patients with metastatic colorectal cancer (NCT03202758; MEDI-TREME-COLON). The open-label study is enrolling approximately 48 patients in France [81] .
In April 2017, Memorial Sloan Kettering Cancer Center, MedImmune and AstraZeneca initiated a phase II trial to evaluate the safety and efficacy of durvalumab and tremelimumab [see AdisInsight drug profile 800020650] given in combination with radiation therapy or ablation (17-139; NCT03122509). This non-randomised, parallel trail is enrolling 33 patients in the US [82] .

In August 2016, AstraZeneca and Canadian Cancer Trials Group initiated a phase II trial to assess the safety and efficacy of tremelimumab [see AdisInsight drug profile 800020650] in combination with durvalumab and best supportive care (BSC) versus BSC alone in patients with refractory, advanced and unresectable colorectal adenocarcinoma (CO26; NCT02870920). The randomised, open-label, parallel trial will enrol approximately 180 patients in Canada [83] .

In October 2014, MedImmune and Memorial Sloan-Kettering Cancer Center initiated a phase II trial of durvalumab for the treatment of colorectal cancer (14-109; NCT02227667). The trial will evaluate the efficacy of durvalumab in immunological subsets of refractory metastatic colorectal cancer. The open-label, single-arm study is recruiting 48 patients in the US [84] .

NSABP Foundation plans to initiate a phase II trial to evaluate the safety and efficacy of tremelimumab and durvalumab following hypofractionated palliative radiation in patients with microsatellite stable metastatic colorectal cancer (NSABP FC-9; ESR-15-11514; NCT03007407). The open-label, single-group trial will enrol approximately 21 patients in the US [85] .

MedImmune and M.D. Anderson Cancer Center, in July 2016, initiated a pilot phase I trial to evaluate the safety and efficacy of neoadjuvant use of tremelimumab [see AdisInsight drug profile 800020650] in combination with durvalumab, FOLFOX (fluorouracil, leucovorin, and oxaliplatin) and bevacizumab in patients with resectable colorectal cancer with liver metastases (2015-0828; NCT02754856). The open-label, single-group trial will enrol approximately 35 patients in the US [86] .

Diffuse large B cell lymphoma

In September 2017, the US FDA placed a partial clinical hold on a phase II trial which was investigating the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma (NCT03003520; MEDI4736-DLBCL-001; EudraCT2015-005173-20). The hold was based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents [32] . The open-label trial initiated in December 2016, intended to enrol approximately 120 patients and is enrolling in Estonia, Austria, Denmark, the US and in the UK. The trial is expected to expand to France, Germany, Poland, Portugal, Slovakia and Sweden [31] [87] .

Pharmacyclics and AstraZeneca initiated a phase I/II trial to evaluate safety and tolerability of ibrutinib in combination with durvalumab, in patients with relapsed or refractory diffuse large B cell lymphoma, in May 2015 (PCYC1136CA; NCT02401048) [see AdisInsight drug profile 800037095]. The phase I portion of the study is designed to determine the appropriate dose of ibrutinib when administered in combination with durvalumab. The phase II portion is expected to assess the safety and effectiveness of the combination treatment. The open-label study is intended to enrol 109 patients in the US [88] [89] .

AstraZeneca and Gilead are planning to initiate a phase I/II study to investigate the safety and efficacy of durvalumab in combination with idelalisib [see AdisInsight drug profile 800025920] in patients with haematological cancers/solid tumours including diffuse large B-cell lymphoma and triple negative breast cancer [19] [90] .

In July 2016, MedImmune (a subsidiary of AstraZeneca) initiated a phase I trial to determine the maximum tolerated dose, identify dose-limiting toxicities, and assess the safety, tolerability and efficacy of durvalumab alone and in combination with either tremelimumab [see AdisInsight drug profile 800020650] or AZD 9150 [see AdisInsight drug profile 800021483] in adult patients with relapsed or refractory diffuse large B-cell lymphoma, previously treated with ≤ two prior lines of therapy, including at least 1 rituximab-containing chemotherapy regimen (D4190C00023; NCT02549651). The randomised, open-label, parallel trial will recruit 180 patients in the US, Italy, Ireland, France and the UK [91] .

Endometrial cancer

In February 2017, AstraZeneca and University of Sydney initiated the phase II PHAEDRA trial to evaluate the safety and efficacy of durvalumab in patients with advanced endometrial cancer (371527; U1111-1186-8932; ANZGOG1601Australia-New-Zealand-Gynaecological-Oncology-Group; X16-0346amp-HREC16RPAH472; ACTRN12617000106336). Evaluation of the objective tumour response rate is the defined primary endpoint of the trial. The open-label, non-randomised trial intends to enrol approximately 70 patients in Australia [92] .

Gastric cancer

In November 2018, AstraZeneca and Seoul National University Hospital initiated a biomarker-oriented phase II trial to investigate the safety and efficacy of durvalumab in combination with olaparib and paclitaxel in patients with advanced, unresectable or recurrent gastric cancer (NCT03579784; ESR-15-11655). The open-label, single-group trial is recruiting approximately 40 patients in South Korea [93] .

In November 2016, AstraZeneca and Memorial Sloan Kettering Cancer Center initiated a pilot phase Ib/II trial to investigate the safety and efficacy of durvalumab addition to chemoradiation (carboplatin and paclitaxel) in patients with adenocarcinoma of the oesophagus or gastroesophageal junction (16-1405; NCT02962063). The open-label, single-group trial is recruiting 35 patients in the US [94] .

In March 2015, MedImmune initiated a randomised, open-label phase Ib/II trial of durvalumab in combination with tremelimumab, versus durvalumab monotherapy and tremelimumab monotherapy, as second- or third-line therapy in patients with metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma (D4190C00021; NCT02340975). The trial will enrol approximately 136 patients in the US, Japan, South Korea, Singapore and Taiwan. In June 2018, results from the trial were presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [95] [96] .

Head and neck cancer

AstraZeneca, in November 2016, announced that the US FDA had lifted the partial clinical hold on the enrolment of new patients with head and neck squamous cell carcinoma (HNSCC) for clinical trials of durvalumab as a monotherapy and in combination with tremelimumab or other potential medicines. Consequently, AstraZeneca resumed enrolment for all head and neck cancer trials globally. The US FDA placed a partial hold on the enrolment of new patients with head and neck cancer in October 2016. AstraZeneca submitted a detailed analysis of adverse events related to bleeding observed during phase III KESTREL and EAGLE trials to FDA to facilitate the re-initiation of patient enrolment [97] [98] .

AstraZeneca intends to file durvalumab for approval for the second-line treatment of PD-L1-positive head and neck cancer in the US, in the first half of 2017. The product has received fast track designation from the US FDA. Filings in the EU and Japan are planned in 2019, in this indication. The filings will be supported by the results of the pivotal HAWK trial [99] .

AstraZeneca initiated the randomised, open-label phase III EAGLE trial in September 2015 to evaluate the safety and efficacy of durvalumab in combination with tremelimumab, compared with the standard of care, in patients with recurrent or metastatic, PD-L1-positive or negative squamous cell head and neck cancer (D4193C00002; NCT02369874; EudraCT2014-003863-40). The primary endpoint was progression-free survival and overall survival up to 2 years. Enrolment of 736 patients has been completed in the US, Hungary, France, Poland, Belgium, Bulgaria, Czech Republic, Italy, Ukraine, Serbia, Croatia, Brazil, Argentina Japan, South Korea, Romania, Russia, Spain, Germany, Australia, Chile, Israel and Taiwan. The enrolment was suspended in October 2016, and was re-initiated subsequently. In December 2018, Astrazeneca reported that the phase III EAGLE trial did not meet the primary endpoints of improving overall survival (OS) compared to standard-of-care (SoC) chemotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma and safety and tolerability profiles for durvalumab monotherapy and durvalumab in combination with tremelimumab were consistent with previous studies [100] [39] [101] .

AstraZeneca initiated the phase III KESTREL trial in October 2015, to determine the safety and efficacy of durvalumab alone or in combination with tremelimumab [see AdisInsight drug profile 800020650], compared with the standard of care in patients with recurrent or metastatic squamous cell head and neck cancer (NCT02551159; EudraCT2015-003589-10). The primary endpoint of the trial is progression-free survival and overall survival up to 3 years of therapy. Enrolment of 823 patients has been completed in in Vietnam, Ukraine, Thailand, Taiwan, Spain, Slovakia, Russia, Romania, Portugal, Poland, Philippines, South Korea, Japan, Italy, India, Greece, Germany, Canada, Austria, France, Belgium, Brazil and Bulgaria, the US, and the UK. The enrolment was suspended in October 2016, which was then re-initiated [39] [102] .

In August 2018, Charite Universitätsmedizin Berlin and AstraZeneca initiated the phase II DuTRe-raD trial to evaluate the feasibility and efficacy of durvalumab plus tremelimumab in combination with radiotherapy and durvalumab in combination with radiotherapy as first-line therapy for patients with non-resectable locally advanced HPV negative HNSCC- A COMPARISON WITH A HISTORICAL CONTROL GROUP (CCCC-H&N-IRT-1; EudraCT2016-003175-22; NCT03624231). The two-arm, randomised trial is recruiting 120 patients in Germany [103] .

In December 2017, AstraZeneca and Celgene in collaboration with UNC Lineberger Comprehensive Cancer Center initiated a phase II trial to evaluate the multimodality therapy with induction carboplatin/nab-paclitaxel/durvalumab followed by surgical resection and risk-adapted adjuvant therapy for the treatment of locally-advanced and surgically resectable squamous cell carcinoma of the head and neck (NCT03174275; LCCC1621). The open, parallel trial is enrolling approximately 39 patients in the US [104] .

In October 2014, AstraZeneca, in collaboration with a CRO, PRA Health Sciences, initiated the phase II HAWK trial to evalute the efficacy of durvalumab monotherapy as second-line therapy in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck (D4193C00001; NCT02207530; EudraCT014-003295-23). The open-label, single-arm study enrolled 112 patients in the US, Canada, the UK, Belgium, Czech Republic, France, Germany, Hungary, Israel, Georgia, South Korea, Malaysia, Taiwan and Spain (AstraZeneca pipeline, February 2017) [105] [99] [106] .

In April 2015, AstraZeneca, in collaboration with a CRO, PRA Health Sciences, initiated the phase II CONDOR trial to determine the efficacy and safety of durvalumab monotherapy, tremelimumab monotherapy and durvalumab + tremelimumab combination therapy, in patients with recurrent or metastatic PD-L1-negative squamous cell carcinoma of the head and neck and who have progressed during or after treatment with a platinum-containing regimen (D4193C00003; NCT02319044; EudraCT2014-003717-29). The open-label, randomised trial enrolled 267 patients in the US, the UK, Belgium, Canada, Czech Republic, France, Georgia, Germany, Hungary, South Korea, Malaysia, Taiwan, Australia, Israel and Spain (AstraZeneca pipeline, February 2017). Data from the study were anticipated in the first half of 2017. In February 2018, safety and efficacy data from the trial were released by the company [99] [105] [107] .

In July 2018, AstraZeneca in collaboration with Centre hospitalier de l'Université de Montréal and AstraZeneca initiated a phase I/II trial to evaluate durvalumab plus tremelimumab plus stereotactic body radiotherapy for metastatic head and neck carcinoma (NCT03283605; ESR16-12361). The open-label trial is enrolling approximately 45 patients in Canada [108] .

AstraZeneca, in collaboration with MedImmune, in August 2015, initiated a randomised, open-label, two-part phase Ib/II SCORES trial (D5660C00004; EudraCT2015-002525-19; NCT02499328). The dose-escalation phase Ib part will evaluate the safety, pharmacokinetics and preliminary anti-tumour activity of durvalumab, in combination with AZD 9150 or AZD 5069 [see AdisInsight drug profiles 800021483800030696], in patients with advanced solid malignancies. As of December 2016, enrolment was underway in dose-expansion phase II part, designed to evaluate the combinations as a second-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. The trial is designed to enrol approximately 465 patients in Belgium, Germany, Italy, Spain, United Kingdom, and the US [109] . Data from treatment-naive patients with head and neck cancer, administered with the combination of durvalumab and AZD 9150, were released by Ionis Pharmaceuticals in September 2017 [110] . Early results from the trial were presented at the 41st European Society for Medical Oncology Congress (ESMO-2016) [111] . Updated results from the trial were presented at 43rd European Society for Medical Oncology Congress (ESMO-2018) in October 2018 [112] [113] .

In March 2017, AstraZeneca and Massachusetts General Hospital initiated the phase Ib/II Rescue trial to assess the safety and efficacy of azacitidine, durvalumab and tremelimumab [see AdisInsight drug profiles 800019273 and 800020650] combination therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who have progressed on anti-PD-1, anti-PD-L1, or anti-CTLA-4 monotherapy (16-425; NCT03019003). The open-label, non-randomised, single-group trial will enrol approximately 59 patients in the US [114] .

In April 2015, MedImmune and Advaxis initiated a phase I/II trial to evaluate durvalumab alone and in combination with axalimogene filolisbac [see AdisInsight drug profile 800025081] in patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer (ADXS001-04; NCT02291055). The phase I portion is being designed to identify a recommended dose regimen for the combination therapy, and the phase II portion will evaluate the safety and efficacy of the combination. The open-label, randomised study is recruiting 66 patients in the US [73] . In November 2014, Advaxis submitted an IND to the US FDA for the phase I/II trial of axalimogene filolisbac alone or in combination with MedImmune's durvalumab for the treatment of advanced, recurrent or refractory HPV-associated cervical cancer and HPV-associated head and neck cancer. Preclinical data suggested that the combination of these two products will enhance overall anti-tumour response. The US FDA will notify Advaxis within 30 calendar days of any questions relates to the trial protocol. The two companies entered into a collaboration in July 2014 to conduct the trial [76] [28] .

In November 2018, University of Colorado, Denver and AstraZeneca initiated a phase I/Ib safety trial to assess the safety and efficacy of radiotherapy in combination with durvalumab in patients with non-metastatic, biopsy-proven p16-negative histology squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and must be eligible and amenable to surgical resection (18-0606cc; NCT03635164). The open-label, single-group trial is recruiting 60 patients in the US [115] .

In August 2018, AstraZeneca initiated a phase I trial of durvalumab and tremelimumab [see AdisInsight drug profile 800020650] with radiotherapy for the adjuvant treatment of intermediate risk head and neck squamous cell carcinoma (LCCC 1725; NCT03529422). The open, prospective trial will enrol approximately 24 patients in the US [116] .

In September 2017, MedImmune completed the randomised, open-label, phase I trial that evaluated the safety, tolerability, efficacy, pharmacokinetics, pharmacodynamics and immunogenicity of tremelimumab [see AdisInsight drug profile 800020650] alone or in combination with durvalumab, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (D4190C00011; NCT02262741). The dose-exploration and dose-expansion trial was initiated in October 2014 and enrolled 71 patients in Canada and the US [117] .

In December 2017, University Health Network, Toronto, AstraZeneca and Mirati Therapeutics withdrew a phase I trial due to a change in internal prioritisation and not due to any safety concerns, that was designed to evaluate the pharmacodynamics and immune effects of pre-operative therapy with mocetinostat [see AdisInsight drug profile 800020983] and durvalumab on patients with squamous cell carcinoma of the oral cavity (floor of mouth, anterior 2/3 tongue, buccal mucosa, upper and lower gingiva, and retromolar trigone) considered resectable by the head and neck surgical rounds (PRIMED-001; NCT02993991). The non-randomised, open-label, single-group trial intended to enrol 12 patients in Canada [118] .

Glioblastoma

In September 2016, MedImmune in collaboration with Northwestern University initiated a phase II study comparing tremelimumab and durvalumab monotherapy versus combination therapy administering both drugs, in patients with malignant glioma or recurrent glioblastoma (NU-15C03; STU00202283; P30CA060553; NCI-2016-00665; NCT02794883). The study will evaluate changes to T-cells in the blood, before, during and after treatment in all the three arms, as a primary outcome measure. The randomised, open-label study is designed to enrol 36 patients in the US [119] .

A phase II trial evaluating durvalumab for the treatment of glioblastoma is being conducted by Ludwig Institute for Cancer Research and MedImmune (LUD2013-006; NCT02336165). This non-randomised, open-label trial, which was initiated in February 2015, is evaluating the efficacy and safety of durvalumab in 159 patients in the US and Australia [120] . Enrolment was completed in February 2017. In June 2017, efficacy and safety data from the trial were presented at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO-2017) [121] .

Institut Claudius Regaud and AstraZeneca, in January 2017, initiated the phase I/II STERIMGLI trial, to evaluate the safety and efficacy of durvalumab plus hypofractionated stereotactic radiation therapy, versus radiation therapy alone, in patients with recurrent glioblastoma (NCT02866747; EudraCT2016-001614-16). Approximately 62 adult and elderly subjects are expected to be enrolled in France [122] .

Hepatocellular carcinoma

In October 2017, AstraZeneca initiated the phase III HIMALAYA trial to evaluate the efficacy and safety of durvalumab plus tremelimumab combination therapy and durvalumab monotherapy versus sorafenib in the treatment of patients with no prior systemic therapy for unresectable hepatocellular carcinoma (D419CC00002; NCT03298451; EudraCT2016-005126-11; JapicCTI183849). The trial intends to enrol 1200 patients; recruitment is underway in Italy, Spain, Japan, South Korea, Russia and Ukraine, and may expand to additional countries.

MedImmune, in October 2015, initiated a phase II trial to evaluate the safety, pharmacodynamics, pharmacokinetics, antitumour activity, and immunogenicity of durvalumab, in combination with tremelimumab [see AdisInsight drug profile 800020650], and both the drugs as a monotherapy, in patients with unresectable hepatocellular carcinoma (D4190C00022; NCT02519348; EudraCT2015-001663-39). The randomised, open-label trial is designed to enrol approximately 144 patients in the US, Hong Kong, Italy, Japan, Singapore, South Korea, Spain and Taiwan [123] .

In May 2018, Massachusetts General Hospital and AstraZeneca initiated a phase II trial to evaluate the efficacy of durvalumab and tremelimumab [see ADIS insight drug profile800020650] and radiation therapy, in patients with hepatocellular carcinoma and biliary tract cancer (17-517; NCT03482102). Evaluations of the overall response rate is the defined primary endpoint of the trial. The open label trial intends to enrol approximately 70 patients in the US [124]

National Cancer Institute initiated a phase I/II trial in June 2016, to evaluate the efficacy of tremelimumab [see AdisInsight drug profile 800020650] given in combination with durvalumab, in patients with hepatocellular carcinoma (160135; 16-C-0135; NCT02821754). The non-randomised, open-label trial intends to enrol approximately 90 patients in the US [125] .

Malignant melanoma

In April 2018, MedImmune completed a phase I/II trial that evaluated the safety, tolerability, pharmacokinetics and anti-tumour activity of durvalumab in combination with dabrafenib and/or trametinib [see AdisInsight drug profiles 800030525, 800024261] in patients with metastatic or unresectable melanoma (CD-ON-MEDI4736-1161; NCT02027961). Evaluation of the effect of cmaximum tolerated dose was the primary endpoint of the trial. The open label trial was initiated in December 2013, and enrolled 68 patients in the US, Canada, France, Italy. Preliminary results were presented in May 2015 [126] [127] [128] .

In January 2016, MedImmune, in collaboration with Immunocore, initiated a phase Ib/II study of IMC gp100 [see AdisInsight drug profile 800033036] in combination with durvalumab and/or tremelimumab [see AdisInsight drug profile 800020650], for the potential treatment of metastatic melanoma (IMCgp100-201; NCT02535078). The randomised, open-labelled trial intends to enrol approximately 225 patients in the US, Germany and the UK [26] [129] .

Multiple myeloma

In December 2017, Celgene completed the phase II FUSION-MM-005 trial that evaluated the safety and efficacy of durvalumab in combination with daratumumab [see AdisInsight drug profile 800022454], in patients with refractory multiple myeloma (MEDI4736-MM-005; NCT03000452). Evaluation of the objective response was the primary endpoint of the trial. The open-label, single-group trial was initiated in February 2017, and enrolled 18 patients in the US, Austria, Greece, the Netherlands, Spain, Sweden, Germany, and Italy [31] [130] . In September 2017, the US FDA placed a partial clinical hold on the trial. The hold was based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents [32] .

In September 2017, the US FDA placed a partial clinical hold on the phase II FUSIONMM-003 trial, which was investigating safety and efficacy of durvalumab given in combination with daratumumab [see AdisInsight drug profile 800022454], in patients with multiple myeloma (MEDI4736-MM-003; NCT02807454). The hold was based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents. The randomised, open-label trial initiated in July 2016, intended to enrol approximately 144 patients in the US, the UK, Canada, Germany, Italy, Spain, Belgium, Sweden and Denmark [32] [31] [131] .

In September 2017, the US FDA placed full clinical hold on a phase Ib trial which intended to determine the recommended dose and regimen of durvalumab 1500mg IV in combination with lenalidomide (25 mg/day or 10 mg/day) [see AdisInsight drug profile 800012854] with or without dexamethasone (40 mg/day or 20 mg/day) in patients with newly diagnosed multiple myeloma (MEDI4736-MM-002; NCT02685826; EudraCT2015-004831-11). The hold was based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents [32] . The randomised, open-label trial initiated in April 2016 intended to enrol approximately 120 patients in Spain, Finland, the US, Canada, Denmark, Italy, the Netherlands, France and Germany [31] [132] .

In September 2017, the US FDA placed a partial clinical hold on a phase Ib trial which was investigating the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide with or without low dose-dexamethasone in patients with relapsed and refractory multiple myeloma (NCT02616640; MEDI4736-MM-001). The hold was based on the risks identified in other trials for an anti-PD-1 agent, pembrolizumab, in patients with multiple myeloma in combination with immunomodulatory agents [32] . The open-label, randomised trial initiated in January 2016 intended to enrol approximately 121 patients in the Netherlands, the US, Canada, France, Germany, Italy and Spain [31] [34] [133] .

In May 2018, MedImmune and Ludwig Institute for Cancer Research terminated a phase I trial as FDA placed on partial hold due to additional data, that was designed to assess the safety and efficacy of tremelimumab and durvalumab combination therapy in patients with multiple myeloma (LUD2014-010; NCT02716805). Checkpoint therapy was to be administered prior to and for two cycles post autologous stem cell transplant. The open-label, parallel, non-randomised trial intended to enrol approximately 24 patients in the US [134] .

In June 2018, Celgene withdrawn a phase II trial prior to enrolment due to safety concerns (373200; U1111-1198-3556; ACTRN12617000958381). The trial was designed to evaluate efficacy of durvalumab rescue for inadequate response to lenalidomide and dexamethasone, in transplant ineligible patients with newly diagnosed multiple myeloma. The open label trial intended to enrol 137 patients in Australia [135] .

Mesothelioma

In April 2017, Dana-Farber Cancer Institute and AstraZeneca initiated a phase II trial to evaluate the efficacy of durvalumab in combination with tremelimumab [see AdisInsight drug profile 800020650] for the treatment of patients with malignant pleural mesothelioma (16-549; NCT03075527). This trial is enrolling 40 patients in the US [136] .

In December 2016, AstraZeneca initiated a phase I/II DREAM trial to assess the efficacy of durvalumab combined with cisplatin and pemetrexed as first line therapy in malignant pleural mesothelioma (370989; CTC0142ALTG15/003; X16-0234and-HREC16RPAH287; ACTRN12616001170415). The non-randomised trial intends to enrol approximately 54 patients in Australia. In June 2018, interim efficacy and safety data were presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [137] [138] .

In October 2015, AstraZeneca in collaboration with Italian Network for Tumor Biotherapy Foundation initiated the phase II NIBIT-MESO 1 trial to evaluate the efficacy of tremelimumab in combination with durvalumab in patients with unresectable malignant mesothelioma (NCT02588131; NIBIT-MESO-1). The open-label, single-arm trial is recruiting 40 patients in Italy [139] .

In May 2017, AstraZeneca and PrECOG initiated a phase II trial to assess the safety and efficacy of durvalumab in combination with standard chemotherapy of pemetrexed and cisplatin as first-line treatment for patients with unresectable malignant pleural mesothelioma (PrE0505; ESR-15-10792; NCT02899195). The open-label, non-randomised, parallel trial will recruit approximately 55 patients in the US [140] .

Baylor College of Medicine initiated a phase I trial in May 2016, to determine whether MEDI 4736 or combination therapy with MEDI 4736 + tremelimumab [see AdisInsight drug profile 800020650] are associated with favourable alterations of the intratumoural immunologic environment in patients undergoing resectional surgery for malignant pleural mesothelioma (MPM) (H-36952; NCT02592551). The open-label, randomised, parallel trial will recruit approximately 20 patients in the US [141] .

Myelodysplastic syndromes

Celgene initiated a phase II trial in June 2016, to evaluate the safety and efficacy of azacitidine in combination with subcutaneous durvalumab, in patients with acute myeloid leukaemia and those who are at a high risk myelodysplastic syndrome (MEDI4736-MDS-001; NCT02775903; EudraCT2015-003596-30). The randomised, open-labelled trial intends to enrol approximately 182 patients in Austria, Portugal, Poland, the Netherlands, Italy, France, Canada, Belgium, USA, Germany, Spain and the UK. The primary endpoint will be overall response rate in both myelodysplastic syndrome and acute myeloid leukaemia cohorts [34] [53] .

In June 2015, Celgene initiated a phase II trial to evaluate the safety and efficacy of oral azacitidine both alone and in combination with durvalumab for the treatment of myelodysplastic syndromes in patients who failed to reach objective response when treated with azacitidine or decitabine (CC-486-MDS-006; EudraCT2014-002675-29; NCT02281084). The randomised, open-labelled study intends to enrol approximately 194 patients in the US, Australia, Belgium, France, Germany, Poland, Spain and the UK [34] [142] .

MedImmune initiated a single-group phase I trial in April 2014 to assess the safety and tolerability of durvalumab in patients with myelodysplastic syndromes after treatment with hypomethylating agents (D4190C00007; NCT02117219). The dose-escalation and dose-expansion study is recruiting 70 patients in the US [143] .

Myelofibrosis

In September 2016, Celgene, in collaboration with Northwestern University (sponsor), The Leukemia and Lymphoma Society and National Cancer Institute, initiated a pilot phase I trial to assess the safety and efficacy of durvalumab in patients with myelofibrosis (STU00202833; NU 16H05; P30CA060553; NCI-2016-01024; NCT02871323). The single-group, open-label trial will enrol approximately 10 patients in the US [144] .

Non-small cell lung cancer (NSCLC)

In July 2018, Japan Ministry of Health approved durvalumab (Imfinzi®) as a maintenance therapy after definative chemoradiation therapy in locally advanced (stage III), unresectable non-small cell lung cancer (NSCL). The approval is based on positive data from the phase III PACIFIC trial [145] [146] .

In February 2018, AstraZeneca and MedImmune announced that the US FDA approved durvalumab (Imfinzi®) for the treatment of patients with unresectable Stage III non-small cell lung cancer whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy [147] [148] . The companies had, in October 2017, announced that the agency accepted their supplemental Biologics License Application (sBLA) and granted priority review status for durvalumab for the treatment of patients with locally advanced, unresectable NSCLC. The sBLA submission was based on positive progression-free survival data from the phase III PACIFIC trial [149] .

In May 2018, the Health Canada approved durvalumab for the treatment of patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation therapy. The drug, reviewed under an accelerated approval, was granted Notice of Compliance with Conditions (NOC/c) based on data from the phase III PACIFIC trial809240286.

In September 2018, AstraZeneca announced that the Brazil Health Regulatory Agency has approved durvalumab for the treatment of locally-advanced, unresectable NSCLC, who had not progressed after standard platinum-based chemotherapy concurrent with radiation therapy. In February 2018, AstraZeneca had reported that the Brazil Health Regulatory Agency granted expedited review to durvalumab. The submission was based on PACIFIC trial data [150] [39] .

In February 2018, AstraZeneca reported that the the Republic of Korea Ministry of Food and Drug Safety accepted the marketing authorisation application for durvalumab for the treatment of locally-advanced, unresectable NSCLC, who had not progressed after standard platinum-based chemotherapy concurrent with radiation therapy. The submission was based on PACIFIC trial data [39] .

In September 2018, the European Commission granted a marketing authorisation of durvalumab for the treatment of locally-advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥1% of tumour cells and whose disease has not progressed following platinum-based chemotherapy and radiation therapy (CRT) [150] . In July 2018, Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency had adopted a positive opinion, recommending a marketing authorisation of durvalumab for the treatment of locally-advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥1% of tumour cells and whose disease was not progressed following platinum-based chemotherapy and radiation therapy (CRT). The recommendation was based on the progression-free survival (PFS) and overall survival (OS) primary endpoints of the Phase III PACIFIC trial, and post-hoc subgroup analyses by PD-L1 expression requested by the CHMP [151] . In October 2017, AstraZeneca and MedImmune announced that the European Medicines Agency (EMA) accepted a Marketing Authorisation Application (MAA) for durvalumab for the treatment of patients with locally-advanced (Stage III), unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation therapy. The regulatory submission was based on data from the phase III PACIFIC trial [146] [152] .

In September 2017, the NCCN Clinical Practice Guidelines in Oncology were updated to include durvalumab for the treatment of patients with locally advanced, unresectable NSCLC with no disease progression after two or more cycles of definitive chemoradiation, based on the data from the phase III PACIFIC trial [149] .

In July 2017, the US FDA granted Breakthrough Therapy Designation for durvalumab (IMFINZI™), for the treatment of patients with locally advanced, unresectable non-small cell lung cancer, whose disease has not progressed following platinum-based chemoradiation therapy, based on the interim results from the phase III PACIFIC trial [see below] [153] .

In May 2015, the US FDA granted durvalumab fast track designation for the treatment of advanced NSCLC that has failed two prior systemic-treatment regimens and is EFGR and ALK negative and PD-L1 positive [154] .

The OCEANS clinical development programme is assessing durvalumab as monotherapy and in combination with tremelimumab, a CTLA-4 monoclonal antibody, in lung cancer [10] .

In December 2018, AstraZeneca initiated a phase III trial to evaluate the activity of durvalumab and chemotherapy administered prior to surgery compared with placebo and chemotherapy administered prior to surgery in terms of major pathological response (D9106C00001; NCT03800134). The randomised, double-blind trial intends to enrol approximately 300 patients in Taiwan and plans to extend enrolment to the US, Austria, Hungary, Japan, Korea, the Philippines, Russia and in Vietnam [155] .

In January 2019, AstraZeneca initiated a phase III trial, to evaluate efficacy of durvalumab along with chemotherapy given prior to surgery in patients with non-small cell lung cancer (EudraCT2018-002997-29). The double-blind, placebo-controlled trial intends to enrol approximately 300 patients in Hungary.

In November 2018, AstraZeneca initiated a phase III PACIFIC-5 trial to assess the safety and efficacy of durvalumab as consolidation therapy in patients with locally advanced unresectable, non-small cell lung cancer, who have not progressed following definitive, platinum-based, chemoradiation therapy (D933YC00001; NCT03706690). The randomised, placebo-controlled trial intends to enrol approximately 360 patients. Enrolment is underway in South Korea, and is expected to expand in China, Philippines, Poland, Russia, Taiwan and Turkey [156] .

In April 2018, AstraZeneca initiated a phase III study to assess the efficacy and safety of durvalumab given concurrently with platinum-based chemoradiation therapy in patients with locally advanced, unresectable non-small cell lung cancer (PACIFIC-2; D933KC00001; NCT03519971). The randomised, placebo-controlled, double-blind, multi-centre, international study intends to enrol approximately 300 patients. Enrolment is under way in Brazil, Hungary, India, Mexico, Philippines, Poland, Thailand, Turkey, Vietnam, Russia, South Korea and Japan, and will extend to other countries [157] .

In June 2017, AstraZeneca initiated the phase III POSEIDON trial to determine the efficacy and safety of durvalumab + tremelimumab combination therapy + standard of care (SoC) chemotherapy or durvalumab monotherapy + SoC chemotherapy versus SoC chemotherapy alone as first line treatment in patients with metastatic non-small cell lung cancer with tumours that lack activating EGFR mutations and anaplastic lymphoma kinase ALK fusions (D419MC00004; NCT03164616). This open-label trial is enrolling approximately 801 patients. Enrolment is underway in Germany, Japan, South Korea, Russia, Taiwan, Ukraine, the United Kingdom, and the US, and will extend to Brazil, Bulgaria, Hong Kong, Mexico, Peru, South Africa, and Thailand [158] .

AstraZeneca, in January 2017, initiated the phase III PEARL trial to determine the efficacy and safety of durvalumab monotherapy versus platinum-based SoC chemotherapy in the first-line treatment of advanced NSCLC in patients who are epidermal growth factor receptor and anaplastic lymphoma kinase wild-type and with PD-L1-high expression (D419AC00002; NCT030039l62). The randomised, open-label, parallel-group trial will enrol approximately 440 patients in China, South Korea, Thailand, Vietnam, Australia and Russia [159] [160] .

In July 2017, AstraZeneca reported initial results from the phase III MYSTIC trial demonstrating that the combination treatment of durvalumab and tremelimumab did not meet a primary endpoint of improvement in the progression free survival as compared with standard of care regimen, in patients with 25% or more PDL1 expression on cancer cells (D419AC00001; NCT02453282; EudraCT2015-001279-39). The assessment of other two primary endpoints of overall survival for durvalumab monotherapy and combination therapy with tremelimumab is ongoing. The trial is designed to compare the safety and efficacy of durvalumab as a single agent and in combination with tremelimumab [see AdisInsight drug profile 800020650] versus platinum-based chemotherapy (SoC) as first-line therapy in patients with late-stage or metastatic NSCLC. The trial was initially focused on PFS; however, in January 2017, the company refined endpoints, to include overall survival (OS) as a co-primary endpoint, based on data showing durvalumab’s strong efficacy as a monotherapy. The trial will now assess PFS and OS in patients with PDL1-expressing tumours for both durvalumab monotherapy and combination therapy, and also in ‘all comers’ for the combination therapy, as compared with SoC chemotherapy. The randomised, open-label trial, initiated in July 2015, enrolled 1 118 patients in the US, Australia, Belgium, Canada, France, Germany, Hungary, Italy, Switzerland, Japan, the Netherlands, Russia, Spain, South Korea, Taiwan, Thailand and Vietnam [161] [159] [99] [127] [162] . Final results from the trial were released in November 2018 [35] . In December 2018, AstraZeneca and MedImmune presented results for the trial at the European Society for Medical Oncology Immuno-Oncology Congress (ESMO-2018) [163] .

AstraZeneca, in November 2015, initiated the NEPTUNE phase III trial to determine the efficacy and safety of durvalumab in combination with tremelimumab versus platinum-based standard of care chemotherapy in the first-line treatment of patients advanced or metastatic NSCLC (D419AC00003; NCT02542293). Enrolment of 960 patients has been completed in South Korea, the US, Argentina, Brazil, Bulgaria, China, Chile, Denmark, Finland, Greece, Hong Kong, India, Israel, Japan, Malaysia, Mexico, Peru, Philippines, Poland, Portugal, Qatar, Romania, Russia, Saudi Arabia, Singapore, Sweden, Turkey, Ukraine and the UK [39] [159] [164] [165] .

AstraZeneca, as at March 2016, terminated the phase III CAURAL study due to safety/efficacy concerns (AstraZeneca first quarter results, April 2016); the trial was earlier suspended in October 2015. In July 2015, AstraZeneca initiated the study to evaluate the safety and efficacy of osimertinib as single agent and in combination with durvalumab in patients with late-stage, metastatic T790M mutation positive NSCLC who have received prior epidermal growth factor receptor tyrosine kinase inhibitor therapy (D5165C00001; NCT02454933). The randomised, open-label trial was intended to enrol 350 patients. Enrolment had commenced in South Korea, Taiwan, Switzerland and Canada [166] .

AstraZeneca is planning a phase III trial to investigate the combination of durvalumab and gefitinib [see AdisInsight drug profile 800007340] as first line treatment of EGFR mutation NSCLC [167] [168] .

As at June 2018, AstraZeneca terminated the randomised, open-label phase III ARCTIC trial, that was designed to investigate the efficacy and safety of durvalumab as monotherapy, or in combination with tremelimumab, in patients with locally advanced or metastatic NSCLC who have received at least two prior lines of therapy (D4191C00004; NCT02352948; EudraCT2014-000338-46). The trial was initiated in October 2014 and the enrolment of 597 patients has been completed in the US, Australia, Belgium, Bulgaria, Canada, Chile, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, South Korea, Netherlands, Poland, Russia, Romania, Serbia, Singapore, Spain, Taiwan, Thailand, and the UK (MedImmune pipeline, June 2018) [39] [169] [170] . In April 2018, the company released efficacy data which demonstrated that sub-study B failed to meet the primary endpoint and sub-study A was not powered for statistical significance [171] . In October 2018, AstraZeneca presented results from the trial at the 43rd European Society for Medical Oncology Congress (ESMO-2018) [172] [170] .

In May 2017, the interim data of the randomised, double-blind, placebo-controlled phase III PACIFIC trial demonstrated that the primary endpoint of statistically-significant and clinically-meaningful progression free survival was met in all-comer patients with locally-advanced, unresectable (Stage III) non-small cell lung cancer and the results demonstrated a favourable benefit/risk profile (D4191C00001; NCT02125461; EudraCT2014-000336-42). In May 2018, durvalumab met the second primary endpoint of statistically-significant overall survival benefit with clinically-meaningful improvement in patients receiving durvalumab compared to placebo, in the planned interim analysis conducted by an Independent Data Monitoring Committee. The safety and tolerability profile for durvalumab was consistent with that reported at the time of the progression-free survival (PFS) analysis [146] [173] . In May 2014, AstraZeneca initiated the trial to assess the effects of durvalumab following concurrent chemotherapy in NSCLC patients, whose disease has not progressed following platinum-based chemoradiation therapy. Enrolment of 983 patients has been completed in the US, Canada, Mexico, Chile, Peru, the UK, Belgium, Germany, Hungary, Italy, Spain, Poland, France, Netherlands, Slovakia, Greece, Turkey, South Africa, Australia, Japan, South Korea, Singapore, Taiwan, Israel, Thailand and Vietnam. Updated results from the trial were released in September 2017 and September 2018 [174] [175] [176] [177] [169] [99] .

In November 2014, NCIC Clinical Trials Group initiated the phase III ADJUVANT trial, to evaluate durvalumab in the adjuvant setting in completely resected NSCLC (BR31; IFCT1401; ACTRN12615000323527; NCT02273375). This double-blind, randomised trial will enrol 1100 patients in the US, Australia, Canada, France, Italy, Japan, South Korea, Netherlands, New Zealand, Singapore, Spain and Taiwan [127] [178] [179] .

In June 2014, the Lung Cancer Master Protocol (Lung-MAP) phase II/III trial was initiated by the Southwest Oncology Group in the US, in collaboration with the US National Cancer Institute, as well as MedImmune, AstraZeneca, Pfizer, Amgen and Genentech (S1400; NCI-2014-00627; S1400E; S1400A; S1400I; S1400C; S1400D; S1400B; U10CA180888; NCT02154490). The trial is investigating biomarker-driven targeted therapy to treat patients with stage IIIB or IV squamous NSCLC who have failed first-line therapy with a platinum-based regimen for metastatic disease. Docetaxel, erlotinib, nivolumab, palbociclib, ipilimumab, durvalumab, rilotumumab [see AdisInsight drug profile 800015060], taselisib [see AdisInsight drug profile 800033797], AZD-4547 [see AdisInsight drug profile 800030912] will be evaluated in the study. Approximately, 10000 patients will be enrolled and assigned to a treatment arm based on the cancer mutation genomic profile. This trial contains multiple sub-studies. In June 2014, National Cancer Institute and Southwest Oncology Group initiated the phase II Lung-Map Sub-Study trial to assess the efficacy of durvalumab in patients with stage IV, recurrent squamous cell lung cancer and no-matching biomarkers (NCI-2014-01378; S1400A; U10CA180888; NCT02766335). The open-label, parallel, non-randomised trial recruited 100 patients in the US [180] [181] .

In December 2017, Celgene and AstraZeneca in collaboration with AIO-Studien-gGmbH initiated the phase II DURATION trial to assess the safety and tolerability of sequential therapy consisting of standard of care mono- or combination chemotherapy followed by durvalumab in comparison to standard of care mono- or combination chemotherapy in frail/elderly patients (NCT03345810; AIO-YMO/TRK-0416; EudraCT 2016-003963-20; ESR-15-11003). The open, parallel, prospective, randomised trial is enrolling approximately 200 patients in Germany [182] .

In December 2017, AstraZeneca initiated the phase II HUDSON trial to evaluate the efficacy, safety, and tolerability of durvalumab, AZD 6738 [see AdisInsight drug profile 800039325], AZD 9150 [see AdisInsight drug profile 800021483], olaparib [see AdisInsight drug profile 800024096] and vistusertib [see AdisInsight drug profile 800031625] in patients with metastatic NSCLC who have progressed on an anti-PD-1/PD-L1 containing therapy (119833; D6185C00001; NCT03334617). The open, parallel, prospective trial is enrolling approximately 200 patients in Canada, South Korea and may extend to the US, Austria, France, Germany and Israel [183] .

In March 2017, Canadian Cancer Trials Group and AstraZeneca initiated a phase II trial to assess the efficacy of durvalumab, in combination with tremelinumab [see AdisInsight drug profile 800020650] in patients with advanced metastatic NSCLC (NCT03057106; BR34). Overall survival is the defined primary endpoint of the trial. The randomized trial is enrolling 300 patients in Canada [184] .

In March 2016, The Swiss Group for Clinical Cancer Research initiated a phase II trial to evaluate the efficacy and feasibility of adding neoadjuvant and adjuvant immunotherapy with durvalumab to standard neoadjuvant chemotherapy in primary resectable stage IIIA(N2) NSCLC (NCT02572843; SAKK 16/14; 000001480). The open-label trial is recruiting approximately 68 patients in Switzerland [185] .

University of Texas M.D. Anderson Cancer Center in collaboration with MedImmune and AstraZeneca planned to initiate a phase II trial to evaluate safety and efficacy of durvalumab in combination with selumetinib in patients with KRAS mutant NSCLC, however the trial was withdrawn prior to enrolment due to insufficient funding (2016-0060; NCT03004105). The randomised, parallel, open-labelled trial was designed to enrol approximately 76 patients in the US [186] .

In September 2016, IFCT initiated a prospective phase II trial of durvalumab, for the treatment of patients with early stage resectable NSCLC (IFCT-1601; EudraCT2016-001849-15). The trial intends to evaluate the impact of neo-adjuvant therapy with durvalumab, for one month on complete resection. The open label trial intends to enrol 81 patients in France [187] .

In October 2015, Peregrine Pharmaceuticals, in collaboration with AstraZeneca, a global phase II trial included durvalumab in combination with bavituximab [see AdisInsight drug profile 800022616] in patients with previously treated squamous or non-squamous non-small cell lung cancer (NSCLC) (NCT02673814). However, as of March 2016, the trial was suspended by the company. The randomised trial to be conducted by Peregrine planned to include approximately 198 patients [12] [13] .

In June 2016, AstraZeneca completed a randomised, open-label phase IIa trial, which investigated the efficacy of gefitinib, osimertinib, selumetinib plus docetaxel, and tremelimumab, with switch to durvalumab, in patients with locally advanced or metastatic NSCLC (D4191C00011; NCT02179671) [see AdisInsight drug profiles 800007340, 800037784, 800019504, 800020650]. The trial was initiated in July 2014 and enrolment of approximately 40 patients was completed in the US in October 2015 [188] .

In February 2014, AstraZeneca initiated a single-arm phase II ATLANTIC trial to evaluate the efficacy and safety of durvalumab in patients with locally advanced or metastatic PD-L1-positive NSCLC who have received at least two prior treatment regimens, including one platinum-based chemotherapy regimen (D4191C00003; NCT02087423; EudraCT2013-005427-16). The primary endpoint will be objective response rate, assessed over 2 years. Enrolment of 453 patients has begun in the US, Austria, Belgium, Canada, the Czech Republic, France, Germany, Hungary, Italy, Japan, South Korea, Philippines, Poland, Singapore, Spain, Taiwan, Thailand and the UK [189] . In June 2017, MedImmune presented pooled efficacy and safety data of ATLANTIC and 1108 (see below) trial at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO-2017) [190] [191] .

Weill Medical College of Cornell University and AstraZeneca, in November 2016, initiated a phase II trial to assess the safety and efficacy of durvalumab with or without stereotactic body radiation therapy in patients with stage IB and II NSCLC prior to surgery and one year following surgery (1501015795; NCT02904954). The open-label, parallel, randomised trial will enrol approximately 60 patients in the US [192] .

In February 2018, AstraZeneca initiated a phase Ib/II trial to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of AZD 9150 [see AdisInsight drug profile 800021483] plus durvalumab, alone or in combination with chemotherapy in patients with advanced solid tumours and subsequently in patients with non-small-cell lung cancer (D5660C00016; REFMAL 558; NCT03421353). The randomised, parallel, open-label trial is intended to enrol approximately 213 patients in the US [193] .

In October 2017, Jonsson Comprehensive Cancer Center, AstraZeneca and National Cancer Institute initiated the phase I/II ISABR trial of ablative radiotherapy plus durvalumab for medically inoperable early-stage non-small cell lung cancer (17-000004; NCT03148327). The open, parallel, prospective, randomised trial is enrolling approximately 105 patients in the US [194] .

In August 2017, Ludwig Institute for Cancer Research, MedImmune, Xcovery and Cancer Research Institute, New York completed a phase I/II trial that evaluated the safety and preliminary efficacy of ensartinib [see AdisInsight drug profile 800036425] monotherapy and combination therapy with durvalumab, in patients with with ALK-positive NSCLC (LUD2014-012-ALK; NCT02898116). Evaluation of the treatment emergent adverse events was the primary endpoint of the trial. The open-label, parallel, non-randomised trial was initiated in March 2017, and enrolled two patients in the US [195] .

In May 2016, MedImmune and Mirati Therapeutics initiated a phase I/II trial to assess the safety and efficacy of durvalumab in combination with the latter's histone deacetylase inhibitor, mocetinostat, in patients with NSCLC and advanced or metastatic solid tumours (0103-020, NCT02805660). The open-label, dose escalation trial intends to enrol approximately 119 patients in the US. The primary endpoints were defined as the dose limiting toxicity incidences up to 28 days, and number of patients with tumour size reduction up to one year [10] [196] .

In February 2018, AstraZeneca in collaboration with University of Wisconsin and National Cancer Institute initiated a phase Ib trial to evaluate safety and tolerability of durvalumab and tremelimumab [see AdisInsight drug profile 800020650] with SBRT in the treatment of oligometastatic NSCLC (NCT03275597; P30CA014520; UW17003). The open-label trial is enrolling approximately 21 patients in the US [197] .

Positive preclinical data involving the combination therapy of durvalumab and monalizumab [see Adis Insight Drug profile 800034739] were presented at the American Association for Cancer Research Annual Meeting (AACR-2018), in April 2018 [198] .

In August 2014, AstraZeneca initiated the phase Ib TATTON trial to determine the safety, tolerability and preliminary anti-tumour activity of mereletinib [see AdisInsight drug profile 800037784] in combination with durvalumab, savolitinib or selumetinib in patients with EGFR mutation positive advanced lung cancer (D5160C00006; NCT02143466). The open-label, non-randomised study is intended to enrol approximately 240 patients in the US, Japan, South Korea and Taiwan [199] . Preliminary data from the trial indicated that durvalumab and mereletinib were tolerated at their phase III doses in the combination arm [126] .

MedImmune initiated a non-randomised, open-label phase I trial in March 2014 to evaluate the safety, tolerability, pharmacokinetics and antitumour activity of durvalumab in combination with gefitinib, in patients with locally advanced or metastatic non-small cell lung cancer (NCT02088112). Trial will enrol approximately 36 patients in the US, Japan and and South Korea [200] [27] . Interim data from the trial showed that the combination was generally well tolerated and had early treatment activity in heavily pre-treated patients [126] .

In October 2013, MedImmune initiated a phase Ib/II trial to investigate the safety and tolerability of durvalumab, in combination with tremelimumab [see AdisInsight drug profile 800020650], in patients with advanced NSCLC (Study 006; D4190C00006; EudraCT2015-003715-38; NCT02000947). The open-label, dose-escalation trial enrolled 459 patients in the US, Australia, Belgium, France, Italy, South Korea, Spain, Taiwan and the United Kingdom [201] . Positive interim data from the dose-escalation part of the trial have been presented, and identified a range of doses to be used for phase III combination studies. A specific dose and schedule of durvalumab 20mg every four weeks (12 total doses) and tremelimumab 1mg/kg every four weeks (four total doses) were selected [126] . In February 2016 and April 2018, updated efficacy and safety results of the trial were released by AstraZeneca and MedImmune [202] [203] .

Non-Hodgkin lymphoma: In October 2017, Juno Therapeutics (a subsidiary of Celgene) in collaboration with Celgene Corporation initiated the exploratory phase I/II PLATFORM trial to evaluate the safety and efficacy of JCAR 017 [see AdisInsight drug profile 800041076] in combination with durvalumab in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (JCAR017-BCM-002; U1111-1201-2046; NCT03310619). The open-label, multi-center trial will enroll approximately 50 patients in the US [204] [205] .

Juno Therapeutics, in May 2016, initiated a Fred Hutchinson Cancer Research Center sponsored phase Ib trial for durvalumab in combination with JCAR 014 [see AdisInsight drug profile 800041075] for the treatment of relapsed/refractory non-Hodgkin lymphoma (9457; NCI-2015-02286; NCT02706405). The open-label, non-randomised trial is enrolling approximately 42 participants in the US. The IND application for the phase Ib trial was approved by the US FDA in late 2015 [206] [207] .

Oesophageal cancer

In October 2018, Cambridge University Hospitals NHS Foundation Trust and AstraZeneca initiated a phase II trial to evaluate whether early changes in circulating tumour DNA can predict tumour response, in patients with advanced oesophageal malignancies receiving durvalumab (CALIBRATION; NCT03653052). Evaluation of the clinical response to therapy is the defined primary endpoint of the trial. The open label trial intends to enrol approximately 19 patients in the UK [208] .

In June 2016, The Ludwig Institute for Cancer Research in collaboration with AstraZeneca initiated an open-label, phase I/II study to evaluate the safety of durvalumab in combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer and with neoadjuvant chemotherapy before surgery in operable oesophageal cancer (NCT02735239; EudraCT2015-005298-19; LUD2015-005). The trial is enrolling 75 patients in the UK [209] .
In February 2016, Samsung Medical Center initiated a phase II trial to evaluate durvalumab, as an adjuvant therapy, in patients with completely resected oesophageal cancer, previously treated with neoadjuvant concurrent chemoradiotherapy (2015-06-166; NCT02520453). The placebo-controlled, randomised, double-blind study is designed to enrol approximately 84 patients in South Korea [210] .

Oropharyngeal cancer

In January 2018, AstraZeneca in collaboration with Canadian Cancer Trials Group initiated a phase II study to study cisplatin plus radiotherapy versus durvalumab plus radiotherapy followed by adjuvant durvalumab versus durvalumab plus radiotherapy followed by adjuvant tremelimumab and durvalumab in patients with locoregionally advanced oropharyngeal squamous cell cancer (HN9; NCT03410615). The non-comparative, randomised study intends to enrol approximately 140 patients in Canada [211] .

In July 2017, AstraZeneca in collaboration with M.D. Anderson Cancer Center initiated the phase I CIAO trial to evaluate durvalumab alone or in combination with tremelimumab [see AdisInsight drug profile 800020650] to patients with oropharynx carcinoma before standard-of-care surgery can help to control the disease (NCT03144778; 2016-0805). The open, parallel, prospective, randomised trial is enrolling approximately 28 patients in the US [212] .

Ovarian cancer

Institut Bergonié, AstraZeneca and PharmaMar, in May 2017, initiated the TRAMUNE phase I trial to evaluate the safety and early efficacy of trabectedin and durvalumab therapy in patients with ovarian cancer and soft tissue sarcoma (NCT03085225). This open-label trial is designed to enrol approximately 50 patients in France [213] .

M.D. Anderson Cancer Center and AstraZeneca, in May 2017, initiated a phase II trial to evaluate the safety and efficacy of tremelimumab and durvalumab given in combination versus sequentially in patients with high-grade, recurrent, platinum-resistant epithelial ovarian, peritoneal or fallopian tube cancer (2016-0093; NCT03026062). The open-label, randomised, parallel trial intends to enrol approximately 100 patients in the US [214] .

In October 2017, ARCAGY/GINECO-Group and AstraZeneca initiated a phase I/II trial to assess the afety and feasibility in neo-adjuvant first-line ovarian cancer (including patients with primary peritoneal or fallopian tube adenocarcinoma) of various combinations of durvalumab with chemotherapy with or without tremelimumab (GINECO-OV127b; NCT03249142). the open label trial is recruiting 66 patients in France.

In November 2015, Ludwig Institute for Cancer Research in collaboration with MedImmune, VentiRx Pharmaceuticals (a subsidiary of Celgene) and Institute of Cancer Research, initiated a phase I/II trial to evaluate the safety and efficacy of durvalumab in combination with motolimod [see AdisInsight drug profile 800029322] in patients with recurrent, platinum-resistant ovarian cancer (LUD2014-001; NCT02431559). The open-label trial is recruiting 53 patients, who are scheduled to receive pegylated liposomal doxorubicin, in the US and Switzerland [215] . In October 2018, data from the study was presented at the 43rd European Society for Medical Oncology Congress (ESMO-2018) [216] .

AstraZeneca and M.D. Anderson Cancer Center, in July 2016, initiated a phase I/II trial to assess the safety and efficacy of the combination of durvalumab 750mg, carboplatin and paclitaxel 80mg in patients with high-grade epithelial non-mucinous ovarian, primary peritoneal or fallopian tube cancers (2015-0900; NCT02726997). The open-label, single-group trial will enrol approximately 30 patients in the US [217] .

The Roswell Park Cancer Institute, in collaboration with the National Cancer Institute (NCI), plans to initiate a phase I/II trial that will evaluate the efficacy of durvalumab, in combination with olaparib [see AdisInsight drug profile 800024096] and tremelimumab [see AdisInsight drug profile 800020650], in the treatment of recurrent platinum sensitive or resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in female adult patients with a BRCA1 or BRCA2 mutation (I 288216; NCI-2016-01598; P30CA016056; NCT02953457). The open label, single group study intends to recruit approximately 39 adult female patients in the US [218] .

Pancreatic cancer

In November 2018, AstraZeneca and Seoul National University Hospital initiate a phase II trial to evaluate combination of chemoradiation therapy (CCRT/gemcitabine) and durvalumab as neoaduvant treatment followed by adjuvant gemcitabine/durvalumab in resectable or borderline resectable pancreatic cancer patients (NCT03572400; ESR-16-12315). The trial intends to enrol 71 patients in South Korea [219] .

Prior to February 2017, AstraZeneca and MedImmune terminated the phase II/III ALPS registrational trial of durvalumab in combination with tremelimumab, for the treatment of metastatic pancreatic ductal carcinoma due to safety and efficacy reasons. The study was initiated in the fourth quarter of 2015. Based on the results of the study, filings are planned in the US, the EU and Japan in 2017 (AstraZeneca pipeline, February 2017) (Medimmune pipeline, September 2016).
In August 2018, Baptist Health South Florida in collaboration with AstraZeneca initiated a phase II trial of durvalumab combined with radiation therapy for metastatic pancreatic cancer patients who have progressed through first-line chemotherapy (NCT03490760; ESR 15 11078). The single group assignment intends to enrol 39 participants in the US [220] .

MedImmune in July 2018, initiated a phase Ib/II study to evaluate the safety, pharmacokinetics, and clinical activity of oleclumab with or without durvalumab in combination with chemotherapy in metastatic pancreatic ductal adenocarcinoma patients (D6070C00005; NCT03611556). The primary end point of the trial is to determine the incidence of adverse events in dose escalation phase within a time frame of informed consent through treatment period and including the follow-up period 12 weeks after last dose of investigational product, approximately 1 year. The randomised, open-label trial intends to enrol approximately 240 participants in USA and plans to extend in Australia, Norway and Spain [221] .

In June 2018, University of Colorado in collaboration with AstraZeneca suspended a phase II trial as PI has initiated the trial (16-0546cc; NCT03038477). The trial was initiated in June 2017 to evaluate efficacy of durvalumab as an adjuvant therapy in patients with borderline resectable pancreatic ductal adenocarcinoma. The randomised, open-label trial intended to enrol 114 patients in the US [222] .

University of Maryland is planning to initiate a phase II trial to evaluate combination of radiation therapy and durvalumab in metastatic pancreas cancer patients who have progressed through first-line chemotherapy (HP-00070528; NCT02885727). The trial intends to enrol 55 patients in the US [223] .

AstraZeneca and Canadian Cancer Trials Group, in August 2016, initiated a phase II trial to assess the safety and efficacy of gemcitabine plus nab-paclitaxel versus gemcitabine, nab-paclitaxel, tremelimumab and durvalumab, as a first-line therapy in patients with metastatic pancreatic ductal adenocarcinoma (PA7; NCT02879318). The randomised, parallel, open-label trial will enrol approximately 180 patients in Canada [224] .

AstraZeneca is planning to conduct a phase II trial to investigate durvalumab plus tremelimumab [see AdisInsight drug profile 800020650] in combination with targeted therapies (AZD 5069) for the treatment of patients with pancreatic ductal adenocarcinoma as a second-line therapy [225] .

In May 2017, AstraZeneca completed the phase II ALPS trial that assessed the efficacy of durvalumab, alone or in combination with tremelimumab, as second-line therapy in patients with metastatic pancreatic ductal adenocarcinoma (D4198C00001; NCT02558894; EudraCT2015-002001-11). The primary endpoint was objective response rate, assessed up to 3 years. The randomised, open-label trial was initiated in November 2015 and enrolled 95 patients in the US, Canada, Netherlands, South Korea, Germany and Spain [226] .

In August 2017, AstraZeneca in collaboration with Cedars-Sinai Medical Center initiated the phase I/II DurvaRad trial to evaluate the safety and tolerability of durvalumab in combination with stereotactive ablative radiotherapy (SABR), a standard radiation treatment, for patients with borderline resectable and locally advanced pancreatic cancer (NCT03245541; IIT2016_01Tuli-DURVARAD). The open-label trial is enrolling approximately 30 patients in the US [227] .

AstraZeneca completed phase Ib/II trial in July 2018, that evaluated. the safety, tolerability, pharmacodynamics and anti-tumour activity of durvalumab in combination with chemotherapy and novel anticancer agents in patients with pancreatic ductal adenocarcinoma (PDAC) (D4198C00003; NCT02583477; EudraCT2015-003639-37). This study consisted of two independent cohorts, which will involve the combination of durvalumab with nab-paclitaxel + gemcitabine [see AdisInsight drug profiles 800016962 and 800000811] chemotherapy regimen and durvalumab + AZD 5069 [see AdisInsight drug profile 800030696]. The non-randomised and open-labelled trial was initiated in March 2016 and enrolled 23 patients in the UK and the US [228] .

In June 2016, Eli Lilly and AstraZeneca initiated a phase Ib trial to assess the safety and efficacy of galunisertib [see AdisInsight drug profile 800028406] in combination with durvalumab in patients with recurrent or refractory metastatic pancreatic cancer (15784; H9H-MC-JBEG; EudraCT2015-005295-26; NCT02734160). The dose-escalation and cohort-expansion, single-group, open-label trial will enrol approximately 37 patients. Enrolment is underway in the US, France, Spain and South Korea and will expand to Italy [229] .

AstraZeneca and New York University School of Medicine, in August 2016, initiated a phase Ib study to determine the safety, recommended phase II dose (RP2D) and efficacy of (A) durvalumab alone, (B) tremelimumab alone or (C) the combination of durvalumab and tremelimumab along with Stereotactic Body Radiation Therapy (SBRT) in patients with unresectable locally advanced adenocarcinoma of pancreas (NYU S14-01317; NCT02868632). The non-randomised, parallel, open-label, three-cohort trial will enrol approximately 36 patients in the US [230] .

In May 2018, NewLink Genetics announced that pancreatic cancer was deprioritized and the company has mutually agreed with AstraZeneca not to proceed with the phase II trial [231] . NewLink Genetics Corporation and AstraZeneca had planned the Indigo201 phase II, randomised, double-blind, placebo-controlled trial of indoximod in combination with durvalumab [see AdisInsight drug profile 800027736] along with standard of care chemotherapy for patients with metastatic pancreatic cancer. The trial was to be funded by both the companies [5] [232] .

Lymphoproliferative disorders

Before September 2017, as per the FDA recommendation, Celgene in collaboration with Memorial Sloan Kettering Cancer Center terminated a phase I trial (NCT03196401; 17-269). The trial was initiated in July 2017 to evaluate the abscopal effect of durvalumab, in combination with definitive radiation therapy, in solitary bone plasmacytoma with limited clonal bone marrow plasmacytosis. The open-label trial was intended to enrol 20 patients in the US [233] .

Prostate cancer

In July 2017, M.D. Anderson Cancer Center, in collaboration with Medimmune, initiated a phase II trial to explore the link between immunological changes, efficacy, safety and tolerability of durvalumab plus tremelimumab [see AdisInsight drug profile 800020650] in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (NCT03204812). This open-label trial is designed to enrol approximately 27 patients in the US [234] .

In May 2016, AstraZeneca in collaboration with Canadian Cancer Trials Group initiated a phase II trial to evaluate the efficacy and safety of durvalumab alone or in combination with tremelimumab [see AdisInsight drug profile 800020650] in patients with metastatic castration resistant prostate cancer (NCT02788773; 1232). The open, parallel, prospective, randomised trial is recruiting approximately 74 patients in Canada [235] .

The University of Washinton and the National Cancer Institute plans to initiate a phase II trial to evalaute the efficacy of durvalumab in hypermutated metastatic, castration-resistatnt prostate cancer (9768, NCI-2016-01618, 9768, P30CA015704, NCT02966587). The response rate to durvalumab in terms of modified RECIST 1.1 criteria or a reduction in PSA level >= 50% will be evaluated as priamry endpoint measure in the trial. The open-label, single-group assignment trial will enrol 28 patients in the US [236] .

Pulmonary sarcomatoid carcinoma (lung cancer in development table)

Seoul National University Hospital is planning a phase II study to evaluate the efficacy and safety of durvalumab plus tremelimumab regimen in patients with pulmonary sarcomatoid carcinoma (NCT03022500). Approximately 18 subjects will be enrolled in South Korea [237] .

Renal cell carcinoma

In November 2017, University College, London in collaboration with AstraZeneca initiated the phase III RAMPART trial to assess the efficacy of durvalumab monotherapy and durvalumab/tremelimumab combination therapy compared with standard of care regimen, in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse, in adjuvant setting (MRC RE06; ISRCTN53348826; EudraCT2017-002329-39, NCT03288532). The randomised, open-label trail is designed to enrol approximately 1750 patients in the UK [238] .

In December 2017, AstraZeneca and Big Ten Cancer Research Consortium, initiated a phase Ib/II trial to investigate the efficacy and safety of durvalumab 1500 mg IV, in combination with guadecitabine (60 mg/m2 or 45 mg/m2) subcutaneously [see AdisInsight drug profile 800025573], in patients with advanced renal cancer, renal cell carcinoma (BTCRC-GU16-043; NCT03308396). The single arm study is enrolling approximately 58 patients in the US [239] .

In May 2016, AstraZeneca initiated a clinical trial to assess the safety and efficacy of durvalumab alone or in combination with savolitinib or tremelimumab in patients with metastatic renal cell carcinoma (178883; UKCRN30435). The trial is recruiting patients in the UK, France and Spain [240] .

Small cell lung cancer

In September 2018, AstraZeneca initiates the ADRIATIC phase III trial to assess the efficacy of durvalumab [see AdisInsight drug profile [500037095]] or durvalumab and tremelimumab as consolidation therapy in patients with small-cell lung cancer (D933QC00001; NCT03703297). Enrolment of approximately 600 patients in randomised, triple-blind study is on-going in Russia and will expand to the US, Belgium, Canada, Czech republic, Germany, Japan, South Korea, Netherlands, Russia, Taiwan and Turkey.

AstraZeneca initiated a phase III trial in March 2017, to assess the efficacy of durvalumab or durvalumab and tremelimumab [see AdisInsight drug profile 800020650] in combination with platinum-based chemotherapy for the first-line treatment in patients with extensive (stage IV) small-cell lung cancer (CASPIAN; D419QC00001; EudraCT2016-001203-23; NCT03043872). The open-label, parallel trial will enrol approximately 795 patients in Bulgaria, Czech Republic, Hungary, Russia, South Korea, Slovakia, Spain, the Netherlands, and plans to extend recruitment in Argentina, Austria, Brazil, France, Germany, Israel, Italy, Poland, Romania, Taiwan, Turkey Ukraine and the US [241] .

In November 2016, AstraZeneca initiated a phase II trial to assess the preliminary efficacy, safety, tolerability and immunogenicity of two combinations, A) AZD 1775 + carboplatin [see AdisInsight drug profile 800028808] B) durvalumab + tremelimumab followed by durvalumab monotherapy, in patients with platinum refractory or resistant extensive-stage SCLC (BALTIC; D419QC00002; EudraCT2016-001202-42; NCT02937818). The non-randomised, parallel, open-label, signal-searching study is enrolling approximately 80 patients in Germany, Hungary, Poland, Spain, Ukraine and will expand to the US [242] . In October 2018, preliminary efficacy and safety results from the trial were presented by AstraZeneca at the 43rd European Society for Medical Oncology Congress (ESMO-2018) [243] .

In April 2016, AstraZeneca and Emory University initiated a phase II trial to assess the efficacy of tremelimumab [see AdisInsight drug profile 800020650] and durvalumab combination therapy with or without radiation therapy in patients with relapsed small cell lung cancer (IRB00086004; NCI-2016-00026; ESR-14-10531; Winship3112-15; NCT02701400). The randomised, parallel, open-label trial is enrolling approximately 20 patients in the US [244] .

Solid tumours

In March 2016, Astra Zeneca initiated the phase I/II MEDIOLA trial to evaluate the effect of durvalumab 50 mg/ml IV infusion in combination with olaparib [see AdisInsight drug profile800024096] (100mg and 150mg) film-coated tablet on disease control rate in patients with advanced solid tumours (D081KC00001; EudraCT2015-004005-16; NCT02734004). The trial will also assess the anti-tumour activity, safety and tolerability of the combination therapy in patients with selected advanced solid tumours, including small cell lung cancer, breast cancer, ovarian cancer and gastric cancer. The open-label trial enrolled 148 patients in the US, France, Israel, South Korea, Netherlands, Switzerland, and the UK. Preliminary safety and efficacy data from the breast cancer cohort were presented at the 40th Annual San Antonio Breast Cancer Symposium (SABCS-2017) [167] [245] .

In May 2018, Innate Pharma released preliminary data from a phase I trial, designed to evaluate the safety, tolerability, anti-tumour activity, and immunogenicity of monalizumab in combination with durvalumab (MEDI 4736) in patients with advanced solid tumours (NCT02671435; EudraCT2016-000662-38; D419NC00001). The company had amended the trial protocol and included expansion cohort of patients with first and second-line, metastatic colorectal cancer, in March 2018. The dose-escalating part of the study has been completed. The trial was initiated by Innate Pharma, in collaboration with MedImmune, in February 2016. The open-label, dose-escalation, cohort-expansion study intends to enrol approximately 280 patients in Canada, France, Hungary, Italy, Spain, United Kingdom, the US and expected to expand in South Korea. Updated positive results released in June 2018 have prompted further expansion of the study with cohorts including patients with less heavily pre-treated disease [246] [247] [248] [249] [250] .

In April 2017, AstraZeneca initiated the phase III STRONG trial to evaluate the safety of durvalumab monotherapy or in combination with tremelimumab [see AdisInsight drug profile 800020650] in patients with advanced solid tumours (D4191C00068; NCT03084471). This open-label trial is enrolling 1 200 patients in Canada, South Korea and the US and will expand in France, Germany, Italy, the Netherlands, Switzerland and United Kingdom [251] .

In March 2017, M.D. Anderson Cancer Center in collaboration with AstraZeneca initiated a phase II trial to evaluate the efficacy and safety of AZD 9150 [see AdisInsight drug profile 800021483] in combination with durvalumab (MEDI 4736) in patients with advanced pancreatic cancer, non-small cell lung cancer mismatch repair deficient colorectal cancer (NCT02983578; 2016-0108). The open-label trial intends to enrol approximately 75 patients in the US [252] .

In September 2016, The University Health Network, Toronto, initiated the phase II METADUR trial, to assess anti-tumour activity of durvalumab in combination with azacitidine, in patients with solid tumour (METADUR-001; NCT02811497). The open-label trial intends to enrol approximately 60 patients in Canada [253] .

In August 2016, AstraZeneca and Canadian Cancer Trials Group initiated a phase II trial to assess the safety and efficacy of tremelimumab [see AdisInsight drug profile 800020650] in combination with durvalumab in patients with advanced rare tumours, which includes salivary carcinoma, carcinoma of unknown primary with tumour infiltrating lymphocytes (TILs) and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary and squamous cell carcinoma of the anal canal (I228; NCT02879162). The open-label, single-group trial intends to enrol approximately 160 patients in Canada [254] .

In January 2016, Astra Zeneca initiated a phase II trial to evaluate the effect of durvalumab 50 mg/ml IV infusion in combination with olaparib (100mg and 150mg) film-coated tablet [see AdisInsight drug profile 800024096] on disease control rate in patients with advanced solid tumours (D081KC00001; EudraCT2015-004005-16). The trial will also assess the anti-tumour activity, safety and tolerability of the combination therapy in patients with selected advanced solid tumours, including small cell lung cancer, breast cancer, ovarian cancer and gastric cancer. The open-label trial is recruiting 139 patients in the Netherlands, the UK and will extend to France, Israel, South Korea, Switzerland and the US [167] [245] .

In June 2015, AstraZeneca presented data on durvalumab in combination with tremelinumab [see AdisInsight drug profile 800020650]. The combination therapy demonstrated efficacy regardless of PD-L1 status, showing promise for patients who fail anti-PD-1/PD-L1 monotherapy because of their PD-L1 biomarker negative status. The combination also had a manageable safety profile, with a 7% discontinuation rate due to related adverse events. The company plans to explore the combination therapy in other tumour types, including gastric, pancreatic and bladder cancer. Additional data that was presented included durvalumab in combination with and BRAF and MEK inhibitors, durvalumab in combination with mereletinib [see AdisInsight drug profile 800037784] and durvalumab in combination with gefitinib [see AdisInsight drug profile 800007340].

MedImmune, AstraZeneca and Greenville Health System, in December 2016, initiated a phase II trial to assess the anti-tumour activity, safety and tolerability of tremelimumab in combination with durvalumab in patients with select advanced rare solid tumours (ESR-15-11633; NCT02938793). The open-label, single-group study will enrol approximately 50 patients in the US [255] .

In November 2015, AstraZeneca initiated a phase II trial to evaluate durvalumab as a monotherapy and in combination with tremelimumab [see AdisInsight drug profile 800020650] in patients with advanced solid tumours (D4884C00001; NCT02527434; 2015-002934-32). This open-label trial is enrolling 96 patients in South Korea, the US, Belgium, the Netherlands and Poland [256] .

MedImmune is planning to initiate a phase II trial for durvalumab in combination with IPH 2201 [see AdisInsight drug profile 800034739] in patients with solid tumours [20] [21] [22] [257] .

In June 2018, AstraZeneca in collaboration with UNICANCER initiated the phase I/II MOVIE trial to evaluate the safety and activity of metronomic oral vinorelbine associated with durvalumab plus tremelimumab combination immunotherapy for the treatment of advanced solid tumours (NCT03518606; UC-101-1709). The open-label trial is enrolling approximately 150 patients in France [258] .

In June 2017, Gustave Roussy initiated a phase I/II trial to evaluate the safety, and clinical activity of durvalumab + tremelimumab [see AdisInsight drug profile 800020650] antibodies administered in combination with Stereotactic Body Radiotherapy (SBRT) in patients with metastatic squamous cell carcinoma of head and neck, lung, or oesophagus (2016/2454; EudraCT2016-003293-40; NCT03212469). The open-label trial intends to enrol approximately 40 patients in France.

In November 2017, Eli Lilly and AstraZeneca terminated a phase Ia/Ib trial that was designed to assess the safety and tolerability of durvalumab and LY 2510924 SC [see AdisInsight drug profile 800034546] in patients with advanced refractory solid tumours (16387; I2V-MC-CXAD; NCT02737072). The open-label, parallel, non-randomised trial was initiated in September 2016 and intended to enrol approximately 45 patients in the US [259] .

In September 2018, Innate Pharma and MedImmune initiated the phase I STELLAR-001 trial to evaluate IPH 5401[see AdisInsight drug profile800036376], in combination with durvalumab in patients with solid tumours, including non-small-cell lung cancer with secondary resistance to prior immuno-oncology (IO) treatment and IO-naive liver cancer (IPH5401-101; NCT03665129). The two-part study design includes an initial dose escalation phase to explore three doses of IPH5401 in combination with durvalumab, followed by dose expansion part. The open label trial is enrolling 100 patients in the US and France [260] [261] . Preclinical data suggested that C5aR blockade increased immune-mediated tumour killing and efficacy of checkpoint inhibitors [4] .

AstraZeneca initiated a phase I trial to assess the safety, tolerability, pharmacokinetics, preliminary anti-tumour activity and to determine the maximum tolerated dose of AZD 4365 [see AdisInsight drug profile 800046147] oral nano-suspension, alone and in combination with durvalumab in patients with advanced solid malignancies (D8730C00001; REFMAL 435; NCT02740985). The open-label, non-randomised trial intends to enrol approximately 50 patients in the US [262] [263] .

AstraZeneca is planning to initiate another clinical trial of AZD 9150 with durvalumab [264] .

In December 2016, AstraZeneca initiated a phase I/II trial to assess the safety, tolerability, pharmacokinetics and anti-tumour activity of durvalumab alone and in combination with tremelimumab in patients with advanced solid malignancies (phase I cohort), including nasopharyngeal carcinoma (phase II cohort) (D419AC00006; NCT02978482). The open-label, parallel, non-randomised trial is recruiting 26 patients in China [265] .

In August 2017, Pharmacyclics completed a phase Ib/II trial that evaluated the safety and efficacy of durvalumab in combination with ibrutinib [see AdisInsight drug profile 800022023], in patients with relapsed or refractory solid tumours including breast cancer, NSCLC and pancreatic cancer (PCYC-1135-CA; NCT02403271). The open-label trial was initiated in March 2015, and enrolled 124 patients in the US. Ibrutinib (560 mg, daily) and durvalumab, 10 mg/kg every two-week was identified as the recommended phase II dose. Data from the trial were presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [266] [267] [268] .

In August 2015, NCIC and AstraZeneca initiated a phase Ib trial to assess the safety and efficacy of durvalumab alone and in combination with tremelimumab in patients with advanced and incurable solid malignancies undergoing standard chemotherapy regimens (I226; NCT02537418). This study will determine the recommended phase II dose and will enrol 150 patients in Canada [269] .

In August 2014, MedImmune initiated a phase Ib/II study to evaluate the safety and efficacy of MEDI 6469 in combination with tremelimumab, durvalumab or rituximab in patients with either advanced solid tumours or diffuse large B-cell lymphoma (NCT02205333). The study will also determine the maximum tolerated dose of MEDI 6469 when administered as a monotherapy and as a part of a combination regimen. MEDI 6469 will be assessed with tremelimumab and durvalumab in patients with advanced solid tumours, whereas the MEDI 6469 plus rituximab regimen will be evaluated in patients with diffuse large B-cell lymphoma. Recruitment of approximately 252 patients is underway in the US [270] . [see AdisInsight drug profiles 800020650, 800035174 and 800004275].

In December 2014, MedImmune in collaboration with Incyte Corporation initiated a phase I/II trial to evaluate durvalumab in combination with Incyte's IDO1 inhibitor epacadostat [see AdisInsight drug profile 800025047] in patients with solid tumours, including metastatic melanoma, NSCLC, squamous cell carcinoma of the head and neck and pancreatic cancer (NCT02318277). The phase I portion is designed to identify a recommended dose regimen, and the phase II portion will evaluate the safety and efficacy of the combination. This open-label, single-group assignment study will enrol 157 patients with advanced solid tumours in the US to evaluate the safety, tolerability and efficacy of the durvalumab in combination with epacadostat [271] [272] .

In August 2012, MedImmune initiated a phase I/II trial to examine the safety, tolerability and pharmacokinetics of durvalumab in patients with solid tumours (CD-ON-MEDI4736-1108; EudraCT2012-002206-52; NCT01693562). The study enrolled 2378 patients in the US, Belgium, Canada, France, Germany, Italy, South Korea, Taiwan and the UK [273] . In June 2016, AstraZeneca presented preliminary results of 61 patients with advanced urothelial bladder cancer from the trial at American Society of Clinical Oncology (ASCO) Annual Meeting [274] . In October 2016, positive preliminary results from the study were presented at the 41st European Society for Medical Oncology Congress (ESMO-2016). Updated results from the trial, displaying a durable response of durvalumab, were released by the company in February 2017. In June 2017, MedImmune presented pooled efficacy and safety data of the ATLANTIC (see above) and 1108 trial at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO-2017). In June 2018, safety and efficacy data from the trial was presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [275] [190] [191] [276] [277] [278] [111] [126] [279] .

In September 2017, Targovax and MedImmune, in collaboration with Ludwig Institute for Cancer Research initiated a phase I/II study to investigate the safety and efficacy of durvalumab in combination with ONCOS 102 [see AdisInsight drug profile 800033483] in patients with advanced peritoneal malignancies, who have failed prior standard chemotherapy and have histologically confirmed platinum-resistant or refractory epithelial ovarian cancer or colorectal cancer (LUD2015-008; NCT02963831). The trial intends to enrol approximately 78 patients in the US [280] . In July 2018, the safety evaluation for the first dose cohort [281] .

MedImmune, in collaboration with the Ludwig Institute for Cancer Research and Cancer Research Institute, initiated a phase I/II trial of in situ vaccination with tremelimumab [see AdisInsight drug profile 800020650] and IV durvalumab in combination with the tumour microenvironment (TME) modulator polyICLC, in patients with advanced, measurable, biopsy-accessible cancers, including head and neck cancer, breast cancer, sarcoma, Merkel cell carcinoma, cutaneous T-cell lymphoma, malignant melanoma, renal cancer, bladder cancer and prostate cancer (NCT02643303; LUD2014-011). The non-randomised, parallel-assignment trial intends to enrol approximately 102 patients in the US [282] .

In May 2018, AstraZeneca initiated the phase I CLOVER trial to evaluate the safety and tolerability of durvalumab ± tremelimumab in combination with chemoradiation in patients with advanced solid tumours (D933BC00001; NCT03509012). The open, parallel, prospective trial is enrolling approximately 300 patients in South Korea and may extend to the US [283] .

In March 2017, Medimmune initiated a phase I trial to evaluate the safety, pharmacokinetics and immunogenicity of MEDI 5083 [see AdisInsight drug profile 800049207 alone and in combination with durvalumab in selected advanced solid tumours (D6840C00001; NCT03089645). The trial plans to enrol 204 patients in the US and Australia [284] .

In August 2016, MedImmune initiated a phase I trial to assess the safety, tolerability, pharmacokinetics, immunogenicity and anti-tumour activity of MEDI 9090 [see AdisInsight drug profile 800047888] plus durvalumab in adult patients with advanced solid tumours (D4190C00055; NCT02900157). The trial is recruiting 30 patients in the US [285] .

In July 2016, the Children's Hospital Los Angeles initiated a phase I, open-label, single institution study to assess the safety, tolerability, and pharmacokinetics of durvalumab in paediatric patients with relapsed or refractory solid tumours, lymphoma, and central nervous system tumours (ESR-14-10488; NCT02793466). The study is enrolling approximately 36 patients in the US [286] [287] .

In February 2016, AstraZeneca and Eli Lilly (sponsor) initiated a phase I trial to evaluate the safety and preliminary efficacy of the combination therapy of durvalumab and ramucirumab [see AdisInsight drug profile 800021478] for the treatment of patients with advanced solid tumours (NCT02572687; EudraCT2015-003013-14; 16116; I4T-MC-JVDJ). The non-randomised, open-label trial is enrolling approximately 114 patients in the US, France, Germany, Israel, Italy, South Korea, Spain and Taiwan [288] . Preclinical data of the combination therapy of vascular endothelial growth receptor inhibitors with immune checkpoint blockades demonstrated the potential to enhance the anti-tumour activity [14] .

In April 2016, AstraZeneca initiated a phase I trial to investigate the safety and tolerability of durvalumab and tremelimumab [see AdisInsight drug profile 800020650], in combination with first-line chemotherapy in patients with advanced solid tumours (NCT02658214; D419SC00001). The open-label, non-randomised trial is enrolling approximately 60 patients in South Korea and will be extending to the US [289] .

AstraZeneca, in December 2015, initiated a phase I trial to evaluate the safety, tolerability and pharmacokinetics of MK 1775 capsule [see AdisInsight drug profile 800028808] in combination with durvalumab IV infusion in patients with advanced or refractory solid tumours (D6015C00002; REFMAL 412; NCT02617277). The immunogenicity, pharmacodynamics and preliminary anti-tumour activity will also be determined. The dose-escalation/expansion, open-label, single-group trial will enrol approximately 18 patients in the US [290] .

In collaboration with AstraZeneca, Kyowa Hakko Kirin initiated a phase I/Ib trial in November 2014 to investigate the safety, tolerability and efficacy of mogamulizumab in combination with durvalumab, and in combination with tremelimumab, in patients with advanced solid tumours (NCT02301130). The trial will enrol 108 patients in the US [291] . The trial is being funded by both companies [29] .

In December 2015, AstraZeneca initiated a phase I trial to investigate the safety, tolerability, pharmacokinetics and anti-tumour activity of durvalumab in combination with ascending doses of selumetinib [see AdisInsight drug profile 800019504] in patients with advanced solid tumour (D1345C00003; NCT02586987). The open-label, non-randomised trial will be enrolling approximately 40 patients in the US [292] .

MedImmune, in July 2015, initiated a phase I study to assess the safety, tolerability, pharmacokinetics, immunogenicity and anti-tumour activity of MEDI 9447 [see AdisInsight drug profile 800042969] alone and in combination with durvalumab in adult patients with select advanced solid tumours (D6070C00001; NCT02503774). The 52-week, dose-escalation, dose-expansion, open-label, parallel, non-randomised trial will recruit 108 patients in the US [293] .

In October 2014, MedImmune initiated a phase I study to assess the safety, tolerability and anti-tumour activity of durvalumab, in combination with tremelimumab [see AdisInsight drug profile 800020650], in patients with advanced solid tumour (D4190C00010; NCT02261220). This open-label trial intends to enrol approximately 380 patients in the US, Canada, France, Germany, Israel, South Korea, the Netherlands, Spain, the UK [294] . In June 2018, safety and efficacy data were presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [295] .

In September 2014, MedImmune initiated a non-randomised phase I trial to assess the safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics and anti-tumour activity of MEDI 6383 [see AdisInsight drug profile 800041453], alone or in combination with durvalumab, as a second-line or greater therapy in patients with recurrent or metastatic solid tumours (D6050C00001; NCT02221960). The trial will enrol approximately 212 patients in the US and Australia [296] [297] .

AstraZeneca completed a phase I trial in January 2017, assessed safety, tolerability, pharmacokinetics and preliminary efficacy of durvalumab in combination with tremelimumab, compared to tremelimumab alone, patients with advanced solid tumours (D4880C00010; JapicCTI142553; NCT02141347). The non-randomised trial initiated in May 2014, enrolled 73 patients in Japan [298] .

MedImmune initiated an uncontrolled phase I trial in May 2014, to assess the safety and tolerability of AMP 514 in combination with durvalumab [see AdisInsight drug profile 800037095] in patients with advanced cancers (D6020C00001; NCT02118337). The trial will enrol 196 patients in the US [299] . Interim efficacy, safety and immunogenicity data was presented at the 41st European Society for Medical Oncology Congress (ESMO-2016) in October 2016 [300] .

The Ludwig Institute for Cancer Research, in collaboration with MedImmune, initiated a phase I trial in December 2013, which is evaluating the safety and tolerability of durvalumab, in combination with tremelimumab, in patients with advanced solid tumours (NCT01975831). Enrolment of approximately 102 patients for this open-label trial is ongoing in the US [301] .

AstraZeneca initiated an open-label phase I trial in September 2013 to assess the safety, tolerability and pharmacokinetics of escalating doses of durvalumab in 24 Japanese patients with advanced solid tumours (NCT01938612) [302] .

In June 2016, Plexxikon and AstraZeneca initiated the MEDIPLEX phase I trial to evaluate the safety and efficacy of combination of durvalumab with plexidartinib [see AdisInsight drug profile 800031061] in patients with advanced/metastatic cancer including colorectal or pancreatic cancers (ET15-037; EudraCT2015-002438-31; NCT02777710). This dose escalation, open-label trial intends to enroll 58 patients in France. The study will be a 2-part study comprising a dose-finding escalation part (to determine maximum tolerated dose/recommended phase II dose, safety and PK) followed by an extension part at recommended phase II dose. In the dose-escalation part, successive cohorts of 3 patients will receive pexidartinib (given orally every day at escalating doses, five dose levels) in combination with durvalumab (given IV every 4 weeks at a fixed dose of 1500mg) [303] .

AstraZeneca in collaboration with Peregrine plans a phase I/Ib trial to investigate the safety and efficacy of durvalumab in combination with bavituximab in patients with multiple solid tumours. However, as of March 2016, the trial was suspended by the company. The phase I part of the trial was planned to establish a recommended dose regimen for the combination, while the phase Ib part was planned to assess the safety and efficacy of the combination [11] [304] .

Eli Lilly and AstraZeneca, in June 2016, initiated a phase Ia/Ib trial to assess the safety of IMC CS4 IV in combination with durvalumab IV or tremelimumab IV in patients with advanced solid tumours (16348; I5F-MC-JSCC; EudraCT2016-000427-11; NCT02718911). The dose-escalation/expansion, open-label, parallel, non-randomised trial is enrolling approximately 178 patients in the US, and will expand to France, Belgium, Germany, Israel, Italy, the Czech Republic [15] .

In August 2015, Peregrine entered into a non-exclusive clinical trial collaboration with AstraZeneca to conduct a phase I/Ib trial of bavituximab [see AdisInsight drug profile 800022616] in combination with AstraZeneca's durvalumab in multiple solid tumours. The phase I part of the trial will establish a recommended dose regimen for the combination, while the phase Ib part will assess the safety and efficacy of the combination. Pursuant to the terms of the agreement, Peregrine will conduct the initial phase I part of the trial [11] [304] .

MedImmune in collaboration with Juno Therapeutics is planning to initiate a phase Ib trial during late 2015, to investigate the safety, tolerability and preliminary efficacy of durvalumab (MEDI 4736) in combination with anti-CD19 chimeric antigen receptors (CAR) transduced T cells [see AdisInsight drug profile 800041081] in patients with non-Hodgkin's lymphoma [305] [306] [307] .

AstraZeneca is planning to initiate clinical studies of durvalumab + AZD 9150 [see AdisInsight drug profile 800021483], in the first half of 2015 [308] .

Multiple sarcoma subtypes

In December 2017, AstraZeneca initiated the phase II MEDISARC trial to assess the efficacy of durvalumab and tremelimumab [See ADIS Insight Drug Profile 800020650] in comparison to doxorubicin in treatment-naïve soft tissue sarcoma patients (NCT03317457; EudraCT2016-004750-15; AIO-STS0415). The open, parallel, prospective, randomised trial is enrolling approximately 100 patients in Germany [309] .

In August 2016, M.D. Anderson Cancer Center in collaboration with MedImmune initiated a phase II study to evaluate the efficacy of the combination of durvalumab and tremelimumab [see AdisInsight drug profile 800020650] in multiple metastatic sarcoma subtypes, including, epithelioid haemangioendothelioma, undifferentiated pleomorphic sarcoma, synovial sarcoma and osteosarcoma (2015-1071; NCI-2016-01178; NCT02815995). The trial intends to enrol approximately 150 patients in the US [310] .

In June 2017, University of Maryland and AstraZeneca initiated the NEXIS phase I/II trial to evaluate the efficacy of the combination of durvalumab and tremelimumab [see AdisInsight drug profile 800020650] soft tissue sarcoma (HP-00073356; NCT03116529). This trial is enrolling 35 patients in the US [311] .

Thyroid cancer

In April 2017, Memorial Sloan Kettering Cancer Center and AstraZeneca initiated a phase I trial to evaluate the safety of durvalumab and tremelimumab [see AdisInsight drug profile 800020650] in combination with radiation therapy for the treatment of thyroid cancer (17-108; NCT03122496). The trial is enrolling 12 patients in the US [312] .

Other NIO-sponsored trials

In September 2018, Exelixis in collaboration with University of Kansas Medical Center initiated the phase I CAMILLA trial to evaluate the safety, tolerability and efficacy of cabozantinib [See ADIS Insight Drug profile 800021701] in combination with durvalumab in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (IIT2017Cabozant-DurvaGI; NCT03539822). The open-label trial is enrolling approximately 30 patients in the US [313] .

In May 2018, AIO-Studien-gGmbH and AstraZeneca initiated a phase II trial to evaluate the objective response rate of the combination of durvalumab and tremelimumab [see ADIS insight drug profile800020650], in addition with gemcitabine or in addition with gemcitabine and cisplatin, in treatment-naive patients with advanced, unresectable and/or metastatic cholangio- and gallbladder carcinoma (AIO-HEP0117; EudraCT2017-001538-25; NCT03473574). The open label trial intends to enrol approximately 63 patients in Germany [314] .
In February 2018, University of Southern California and National Cancer Institute initiated a phase Ib trial to evaluate the efficacy and safety of guadecitabine and durvalumab, in patients with advanced hepatocellular carcinoma, pancreatic adenocarcinoma, and cholangiocarcinoma/gallbladder cancer (0S16-18; NCI2017-01432; P30CA014089; NCT03257761). Evaluation of the adverse events and tumour response are the defined primary endpoints of the trial. The open label trial intends to enrol approximately 90 patients in the US [315] .
In May 2017, Memorial Sloan Kettering Cancer Center initiated a phase II trial to evaluate the safety and effectiveness of durvalumab with tremelimumab [see AdisInsight drug profile 800020650], in patients with relapsed or refractory germ cell tumours (17-160; NCT03158064). Evaluation of overall response is the defined primary endpoint of the trial. The single arm open label trial intends to enrol approximately 29 patients in the US [316] .

In February 2017, Fondazione IRCCS Istituto Nazionale dei Tumori in collaboration with AstraZeneca initiated the phase II APACHE trial of durvalumab, alone or in combination with tremelimumab [see AdisInsight drug profile800020650], in patients with advanced and relapsed germ cell tumours (INT123-16; NCT03081923). The primary endpoint is the modified objective response-rate (mORR = RECIST 1.1 complete or partial response or stable disease +STM reduction > 10%). The open label, randomised trial will enrol approximately 120 patients in Italy [317] . In June 2018, the company presented efficacy data at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO-2018) [318] .

In March 2017, Grupo Espanol de Tumores Neuroendocrinos initiated the DUNE phase II trial to evaluate the safety and efficacy of durvalumab with tremelimumab for the treatment of patients with advanced neuroendocrine tumours (ESR15-11561-61DUNE; EudraCT2016-002858-20; NCT03095274). This prospective, open label, stratified, exploratory trial is enrolling 126 patients in Spain [319] .

Columbia University plans a phase II trial to evaluate durvalumab and tremelimumab [see AdisInsight drug profile 800020650] as adjuvant therapy for the treatment of patients with resected non-small cell lung cancer (AAAQ8535; NCT03130764). This trial intends to enrol 30 patients in the US [320] .

In January 2017, Memorial Sloan Kettering Cancer Center initiated a phase II trial to assess the safety and efficacy of durvalumab with or without tremelimumab [see AdisInsight drug profile 800020650] in endometrial cancer (16-1491; NCT03015129). The open-label, parallel, randomised trial is recruiting 80 patients in the US [321] .

Azienda Ospedaliero-Universitaria Careggi plans a phase II trial of durvalumab combined with cetuximab and radiotherapy in locally advanced squamous cell carcinoma of the Head and Neck (DUCRO-HN; EudraCT2016-004668-2; NCT03051906). This open-label trial intends to enrol 69 patients [322] .

City of Hope Medical Center and the National Cancer Institute plan to initiate a pilot feasibility study to evaluate the safety and efficacy of tremelimumab plus durvalumab regimen, following radioembolisation in patients with microsatellite stable colorectal cancer that has spread to the liver (16423; NCI-2016-02001; NCT03005002). Approximately 18 adult and elderly subjects will be enrolled in the US [323] .

In February 2017, Breast International Group and UNICANCER initiated the phase II ULTIMATE trial to assess the safety and efficacy of durvalumab combined with exemestane in patients with ER+/Her2- breast cancer eligible for neoadjuvant endocrine therapy and who present CD8+ T cell infiltration after 4-6 weeks exposure to immune-attractant (tremelimumab) (UC-0140/1606; UCBG-105; BIG-106; EudraCT2016-000764-42; NCT02997995). The open-label, single-group trial is enrolling 240 patients in France [324] .

In March 2017, Spanish Lung Cancer Group initiated a phase II trial to assess the efficacy of durvalumab as a monotherapy in HIV-1 patients with advanced solid tumours (EudraCT2016-004524-38; GECP16/04; NCT03094286). The open label trial is enrolling 20 patients in Spain [325] .

In February 2017, City of Hope Medical Center and the National Cancer Institute initiated a phase I/II trial to determine the maximum tolerated dose (recommended phase II dose, RP2D), safety and anti-tumour activity of durvalumab with or without lenalidomide [see AdisInsight drug profile 800012854] in patients with relapsed or refractory cutaneous T cell lymphoma (mycosis fungoides or Sezary syndrome) or peripheral T cell lymphoma (NCI-2016-02061; 16221; NCT03011814). The open-label, parallel, randomised trial will enrol approximately 62 patients in the US [326] .

In February 2018, Dana-Farber Cancer Institute and AstraZeneca initiated a phase I trial to evaluate the safety and effectiveness of durvalumab and tremelimumab in combination with radiation therapy as a possible treatment for recurrent or metastatic gynecologic cancer (NCT03277482; 17-382). The open-label trial is enrolling approximately 32 patients in the US [327] .

In December 2016, Yonsei University initiated a phase II trial of durvalumab (MEDI 4736) and tremelimumab [see ADIS Insight drug profile 800020650] in patients with receptor-positive, hypermutated metastatic breast cancer identified by whole exome sequencing (4-2016-0912; NCT03608865). The study intends to enrol 30 patients in Korea [328] .

In December 2016, Case Comprehensive Cancer Center initiated a phase Ib trial to assess the safety and efficacy of durvalumab with or without tremelimumab in patients with locally advanced renal cell carcinoma (CASE12815; NCT02762006). The open-label, single-group trial will enrol approximately 54 patients in the US [329] .

In December 2016, French National Cancer Institute and Gustave Roussy initiated the phase I MEDINDUCTION trial to evaluate the efficacy, feasibility and safety of the association of docetaxel, cisplatin, 5-fluorouracil (standard regimen for induction) and durvalumab, and determine the recommended phase II dose of the combination therapy in patients with locally advanced head and neck squamous cell carcinoma (EudraCT2015-004146-25; 2015/2316; NCT02997332). The open-label, single-group trial recruited 36 patients in France [330] .

In February 2017, VentiRx Pharmaceuticals was acquired by Celgene (VentiRx Pharmaceuticals website, February 2017).

In March 2018, Juno Therapeutics was acquired by Celgene [331] .

Drug Properties & Chemical Synopsis

  • Route of administration IV
  • Formulation Infusion, Injection, unspecified
  • Class Antineoplastics, Monoclonal antibodies
  • Mechanism of Action Programmed cell death-1 ligand-1 inhibitors
  • WHO ATC code

    L01X-C28 (Durvalumab)

  • EPhMRA code

    L1G (Monoclonal Antibody Antineoplastics)

  • Chemical name Immunoglobulin G1-kappa, anti-(human programmed cell death 1 ligand 1 (B7 homolog 1,CD274)); human monoclonal antibody; γ1 heavy chain (1-451) [human VH (IGHV3-7*01 (99%) –IGHJ4*01) [8.8.14] (1-121) –IGHG1*03 (CH1 (122-219), hinge (220-234), CH2 L4>F(238),L5>E(239),P101>S(335) (235-344), CH3 (345-451)) (122-451)] (224-215')-disulfide with κ light chain (1'-215') [human V-KAPPA (IGKV3-20*01 (97%) –IGKJ1*01) [7.3.9] (1'-108') –IGKC*01(109'-215')] dimer (230-230'':233-233'')-bisdisulfide
  • Molecular formula C6502 H10018 N1742 O2024 S42
  • CAS Registry Number 1428935-60-7

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

adenocarcinoma

not specified

Thyroid stimulating hormone, beta

SIL1 nucleotide exchange factor

immunoglobulin kappa variable 1-5

1

1

1

adenocarcinoma

Exclusion

PD-L1

PD-1

HER2

1

1

1

adenocarcinoma

Inclusion

SIL1 nucleotide exchange factor

PSA

HER2

1

2

1

adenocarcinoma

Outcome Measure

T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3

PSA

PD-L1

HER2

1

2

2

1

advanced breast cancer

Exclusion

PD-L1

3

advanced breast cancer

Inclusion

HER2

4

advanced breast cancer

Outcome Measure

VEGF-A

PD-L1

Kynurenine

IFN-gamma

HER2

CD8a

BRCA2

BRCA1

1

3

1

1

2

1

1

1

advanced breast cancer

Safety

PD-L1

1

B-cell lymphoma

Exclusion

PD-L1

1

B-cell lymphoma

Outcome Measure

PD-L1

bestrophin 1

1

1

biliary tract disorders

Inclusion

betacellulin

1

bladder cancer

not specified

bFGF

1

bladder cancer

Exclusion

PD-L1

FGFR4

FGFR3

FGFR2

FGFR1

1

1

1

1

1

bladder cancer

Inclusion

retinoblastoma 1

immunoglobulin kappa variable 1-5

FGFR4

FGFR3

FGFR2

FGFR1

c-Myc

1

1

1

1

1

1

1

bladder cancer

Outcome Measure

TNF-alpha

RPS6

PD-L1

immunoglobulin kappa variable 1-5

IL8

IL6

IL2

IL10

IFN-gamma

Histone H2AX

FGFR4

FGFR3

FGFR2

FGFR1

CD8a

1

1

2

1

1

1

1

1

1

1

1

1

1

1

1

breast cancer

Exclusion

PD-L1

PD-1

1

1

breast cancer

Inclusion

PGR

PD-L1

Ki67

HER2

ER alpha

CD8a

1

1

2

3

2

1

breast cancer

Outcome Measure

PD-L1

PD-1

mediator complex subunit 1

Ki67

HER2

ER alpha

EGFR

CD8a

2

1

1

2

2

1

1

1

carcinoma

Exclusion

PD-L1

PD-1

p16

iroquois homeobox 2

1

1

1

1

carcinoma

Inclusion

PD-L1

p16

Ki67

iroquois homeobox 2

3

2

1

1

carcinoma

Outcome Measure

PD-L1

PD-1

p16

mastermind like domain containing 1

Ki67

iroquois homeobox 2

immunoglobulin kappa variable 1-5

IFN-gamma

CD8a

3

1

1

1

1

1

1

1

1

cervical cancer

Outcome Measure

immunoglobulin kappa variable 1-5

IFN-gamma

1

1

cholangiocarcinoma

not specified

immunoglobulin kappa variable 1-5

1

cholangiocarcinoma

Exclusion

PD-L1

PD-1

1

1

cholangiocarcinoma

Inclusion

betacellulin

1

chronic lymphocytic leukaemia

Exclusion

PD-L1

1

chronic lymphocytic leukaemia

Outcome Measure

PD-L1

bestrophin 1

1

1

colorectal cancer

not specified

CD8a

1

colorectal cancer

Exclusion

PD-L1

1

colorectal cancer

Inclusion

SIL1 nucleotide exchange factor

PD-L1

2

1

colorectal cancer

Outcome Measure

PD-L1

mediator complex subunit 1

1

1

cutaneous T-cell lymphoma

not specified

CD4

1

cutaneous T-cell lymphoma

Inclusion

TSPY like 2

1

cutaneous T-cell lymphoma

Outcome Measure

TSPY like 2

1

diffuse large B cell lymphoma

not specified

tumor protein p53 inducible nuclear protein 2

1

diffuse large B cell lymphoma

Outcome Measure

STAT3

PD-L1

Hydrocortisone

1

2

1

early breast cancer

Exclusion

PD-L1

PD-1

1

1

early breast cancer

Inclusion

PD-L1

Ki67

1

1

early breast cancer

Outcome Measure

PD-L1

PD-1

Ki67

1

1

1

endometrial cancer

Outcome Measure

IFN-gamma

1

fallopian tube cancer

Exclusion

PD-L1

1

fallopian tube cancer

Inclusion

PD-L1

BRCA2

BRCA1

1

1

1

fallopian tube cancer

Outcome Measure

PD-L1

mediator complex subunit 1

immunoglobulin kappa variable 1-5

IFN-gamma

CA-125

1

1

1

1

1

gallbladder cancer

not specified

immunoglobulin kappa variable 1-5

1

gallbladder cancer

Exclusion

PD-L1

PD-1

1

1

gallbladder cancer

Inclusion

betacellulin

1

gastric cancer

Exclusion

HER2

1

gastric cancer

Inclusion

HER2

2

gastric cancer

Outcome Measure

VEGF-A

T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3

PD-L1

HER2

CD8a

BRCA2

BRCA1

1

1

2

1

1

1

1

gastric cancer

Safety

PD-L1

1

glioblastoma

Outcome Measure

PD-L1

1

glioma

Outcome Measure

PD-L1

1

head and neck cancer

not specified

PD-L1

CD8a

1

1

head and neck cancer

Outcome Measure

PD-L1

p16

mastermind like domain containing 1

iroquois homeobox 2

immunoglobulin kappa variable 1-5

hematological and neurological expressed 1

CD8a

2

1

1

1

1

1

1

head and neck cancer

Exclusion

p16

iroquois homeobox 2

hematological and neurological expressed 1

CDK4

2

1

1

1

head and neck cancer

Inclusion

PD-L1

p16

iroquois homeobox 2

CD8a

4

2

1

1

head and neck cancer

Safety

PD-L1

1

hepatitis B

Outcome Measure

PD-L1

1

hepatitis C

Outcome Measure

PD-L1

1

Hypopharyngeal cancer

Exclusion

p16

iroquois homeobox 2

1

1

Hypopharyngeal cancer

Inclusion

PD-L1

p16

iroquois homeobox 2

1

2

1

Hypopharyngeal cancer

Outcome Measure

PD-L1

p16

mastermind like domain containing 1

iroquois homeobox 2

immunoglobulin kappa variable 1-5

1

1

1

1

1

laryngeal cancer

Exclusion

p16

iroquois homeobox 2

1

1

laryngeal cancer

Inclusion

PD-L1

p16

iroquois homeobox 2

1

2

1

laryngeal cancer

Outcome Measure

PD-L1

p16

mastermind like domain containing 1

iroquois homeobox 2

immunoglobulin kappa variable 1-5

1

1

1

1

1

liver cancer

not specified

immunoglobulin kappa variable 1-5

1

liver cancer

Exclusion

PD-L1

PD-1

1

1

liver cancer

Inclusion

SIL1 nucleotide exchange factor

betacellulin

1

1

liver cancer

Outcome Measure

PD-L1

1

lung cancer

Inclusion

PD-L1

2

lung cancer

Outcome Measure

PD-L1

1

lymphoma

Exclusion

PD-L1

2

lymphoma

Outcome Measure

PD-L1

bestrophin 1

2

1

male breast cancer

Inclusion

PGR

HER2

ER alpha

1

1

1

mesothelioma

Exclusion

PD-L1

2

mesothelioma

Outcome Measure

PD-L1

CD8a

CD4

2

1

1

mycosis fungoides

not specified

CD4

1

mycosis fungoides

Inclusion

TSPY like 2

1

mycosis fungoides

Outcome Measure

TSPY like 2

1

myelofibrosis

not specified

L-selectin

interleukin 7 receptor

CD4

1

1

1

myelofibrosis

Exclusion

PD-L1

1

nasopharyngeal cancer

not specified

PD-L1

CD8a

1

1

nasopharyngeal cancer

Exclusion

p16

hematological and neurological expressed 1

CDK4

1

1

1

nasopharyngeal cancer

Inclusion

PD-L1

1

nasopharyngeal cancer

Outcome Measure

PD-L1

IFN-gamma

hematological and neurological expressed 1

CD8a

1

1

1

1

Nervous system neoplasms

Exclusion

PD-L1

1

Nervous system neoplasms

Outcome Measure

PD-L1

1

neuroendocrine tumours

Outcome Measure

NSE

CGA

1

1

non-Hodgkin's lymphoma

not specified

tumor protein p53 inducible nuclear protein 2

1

non-Hodgkin's lymphoma

Outcome Measure

PD-L1

Hydrocortisone

1

1

non-small cell lung cancer

not specified

TTF1

PIK3CA

Phosphatidylinositols

PD-L1

p63

MAPK1

Hepatocyte growth factor

FGFR3

FGFR2

FGFR1

EML4

EGFR

Cyclin D3

Cyclin D2

Cyclin D1

CDK6

CDK4

CD8a

c-Met

bFGF

ALK

1

1

1

1

1

1

1

1

1

1

1

2

1

1

1

1

1

1

1

1

2

non-small cell lung cancer

Outcome Measure

STAT3

PD-L1

mediator complex subunit 1

EGFR

CD8a

1

8

1

1

1

non-small cell lung cancer

Exclusion

PD-L1

EGFR

6

1

non-small cell lung cancer

Inclusion

PD-L1

EGFR

ALK

4

3

1

non-small cell lung cancer

Safety

EGFR

1

oesophageal cancer

not specified

PD-L1

CD8a

1

1

oesophageal cancer

Exclusion

p16

HER2

hematological and neurological expressed 1

CDK4

1

1

1

1

oesophageal cancer

Inclusion

HER2

1

oesophageal cancer

Outcome Measure

T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3

PD-L1

HER2

hematological and neurological expressed 1

1

1

1

1

oropharyngeal cancer

Exclusion

p16

iroquois homeobox 2

1

1

oropharyngeal cancer

Inclusion

PD-L1

p16

iroquois homeobox 2

1

2

1

oropharyngeal cancer

Outcome Measure

PD-L1

p16

mastermind like domain containing 1

iroquois homeobox 2

immunoglobulin kappa variable 1-5

CD8a

1

1

1

1

1

1

ovarian cancer

Exclusion

PD-L1

1

ovarian cancer

Inclusion

PD-L1

HER2

BRCA2

BRCA1

1

1

1

1

ovarian cancer

Outcome Measure

VEGF-A

PD-L1

mediator complex subunit 1

immunoglobulin kappa variable 1-5

IFN-gamma

CD8a

CA-125

BRCA2

BRCA1

1

2

1

1

1

1

1

1

1

ovarian cancer

Safety

PD-L1

1

pancreatic cancer

not specified

Thyroid stimulating hormone, beta

immunoglobulin kappa variable 1-5

1

1

pancreatic cancer

Exclusion

PD-L1

PD-1

1

1

pancreatic cancer

Outcome Measure

PD-L1

1

peripheral T-cell lymphoma

not specified

CD4

1

peripheral T-cell lymphoma

Inclusion

TSPY like 2

1

peripheral T-cell lymphoma

Outcome Measure

TSPY like 2

1

peritoneal cancer

Exclusion

PD-L1

1

peritoneal cancer

Inclusion

PD-L1

BRCA2

BRCA1

1

1

1

peritoneal cancer

Outcome Measure

PD-L1

mediator complex subunit 1

immunoglobulin kappa variable 1-5

IFN-gamma

CA-125

1

1

1

1

1

prostate cancer

Exclusion

PD-L1

1

prostate cancer

Inclusion

PSA

Microsatellite Instability

3

1

prostate cancer

Outcome Measure

PSA

PD-L1

mediator complex subunit 1

CD8a

CD3g

CD3e

CD3d

2

1

1

1

1

1

1

rectal cancer

not specified

SIL1 nucleotide exchange factor

1

renal cell carcinoma

Exclusion

PD-L1

c-Met

1

1

renal cell carcinoma

Inclusion

PD-L1

1

renal cell carcinoma

Outcome Measure

PD-L1

CD8a

c-Met

1

1

1

Sezary syndrome

not specified

CD4

1

Sezary syndrome

Inclusion

TSPY like 2

1

Sezary syndrome

Outcome Measure

TSPY like 2

1

small cell lung cancer

Exclusion

PD-L1

PD-1

1

1

small cell lung cancer

Inclusion

HER2

1

small cell lung cancer

Outcome Measure

VEGF-A

PD-L1

mediator complex subunit 1

CD8a

BRCA2

BRCA1

1

1

1

1

1

1

small cell lung cancer

Safety

PD-L1

1

solid tumours

not specified

SRC proto-oncogene, non-receptor tyrosine kinase

1

solid tumours

Outcome Measure

VEGF-A

STAT3

PD-L2

PD-L1

PD-1

mediator complex subunit 1

interleukin 34

IFN-gamma

colony stimulating factor 1 receptor

colony stimulating factor 1 (macrophage)

CD8a

BRCA2

BRCA1

1

1

1

5

1

1

1

1

1

1

2

1

1

solid tumours

Exclusion

PD-L1

PD-1

interleukin 34

colony stimulating factor 1 receptor

colony stimulating factor 1 (macrophage)

1

1

1

1

1

solid tumours

Inclusion

PD-L1

HER2

1

1

solid tumours

Safety

PD-L1

1

squamous cell cancer

not specified

TTF1

PIK3CA

Phosphatidylinositols

PD-L1

p63

MAPK1

Hepatocyte growth factor

FGFR3

FGFR2

FGFR1

EML4

EGFR

Cyclin D3

Cyclin D2

Cyclin D1

CDK6

CDK4

CD8a

c-Met

bFGF

ALK

1

1

1

2

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

squamous cell cancer

Outcome Measure

period circadian clock 1

PD-L1

p16

mastermind like domain containing 1

iroquois homeobox 2

immunoglobulin kappa variable 1-5

hematological and neurological expressed 1

CD8a

CD4

CD3g

CD3e

CD3d

1

4

1

1

1

1

1

3

1

1

1

1

squamous cell cancer

Exclusion

PD-L1

p16

iroquois homeobox 2

hematological and neurological expressed 1

CDK4

1

2

1

1

1

squamous cell cancer

Inclusion

PD-L1

p16

iroquois homeobox 2

EGFR

CD8a

ALK

6

2

1

1

1

1

squamous cell cancer

Safety

PD-L1

1

urogenital cancer

Exclusion

PD-L1

1

urogenital cancer

Inclusion

PD-L1

1

urogenital cancer

Outcome Measure

PD-L1

1

uterine cancer

Outcome Measure

IFN-gamma

1

vulvovaginal cancer

Outcome Measure

immunoglobulin kappa variable 1-5

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Durvalumab - Celgene/MedImmune ALK Inclusion
bestrophin 1 Outcome Measure
bFGF not specified
BRCA1 Outcome Measure
BRCA2 Outcome Measure
c-Met Exclusion, Outcome Measure
c-Myc Inclusion
CA-125 Outcome Measure
CD4 Outcome Measure
CD8a Inclusion, Outcome Measure
CDK4 Exclusion
CDK6 not specified
CGA Outcome Measure
Cyclin D1 not specified
Cyclin D2 not specified
Cyclin D3 not specified
EGFR Exclusion, Inclusion, Outcome Measure, Safety
EML4 not specified
ER alpha Inclusion, Outcome Measure
FGFR1 Exclusion, Inclusion, Outcome Measure
FGFR2 Exclusion, Inclusion, Outcome Measure
FGFR3 Exclusion, Inclusion, Outcome Measure
FGFR4 Exclusion, Inclusion, Outcome Measure
hematological and neurological expressed 1 Exclusion, Outcome Measure
Hepatocyte growth factor not specified
HER2 Exclusion, Inclusion, Outcome Measure
Histone H2AX Outcome Measure
IFN-gamma Outcome Measure
IL10 Outcome Measure
IL2 Outcome Measure
IL6 Outcome Measure
IL8 Outcome Measure
immunoglobulin kappa variable 1-5 Inclusion, Outcome Measure
iroquois homeobox 2 Exclusion, Inclusion, Outcome Measure
Ki67 Inclusion, Outcome Measure
Kynurenine Outcome Measure
MAPK1 not specified
mediator complex subunit 1 Outcome Measure
NSE Outcome Measure
p16 Exclusion, Inclusion
p63 not specified
PD-1 Exclusion, Outcome Measure
PD-L1 Exclusion, Inclusion, Outcome Measure, Safety
PGR Inclusion
Phosphatidylinositols not specified
PIK3CA not specified
PSA Inclusion, Outcome Measure
retinoblastoma 1 Inclusion
RPS6 Outcome Measure
SIL1 nucleotide exchange factor Inclusion
STAT3 Outcome Measure
T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3 Outcome Measure
Thyroid stimulating hormone, beta not specified
TNF-alpha Outcome Measure
TTF1 not specified
VEGF-A Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking over 460113 biomarker uses worldwide by over 930 companies

Development Status

Summary Table

Indication Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute myeloid leukaemia Combination therapy, Newly diagnosed Phase II Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, USA, United Kingdom IV / Infusion Celgene International SARL 01 Jun 2016
Biliary cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II USA IV / Infusion AstraZeneca 14 May 2018
Biliary cancer Combination therapy, Late-stage disease, Second-line therapy or greater Phase II France IV / Infusion AstraZeneca 09 Nov 2018
Biliary cancer Combination therapy, First-line therapy, Inoperable/Unresectable Phase II South Korea IV / Infusion Seoul National University Hospital 01 Feb 2017
Bladder cancer Adjuvant therapy, First-line therapy, Monotherapy Phase III South Korea IV / Infusion AstraZeneca 16 Nov 2018
Bladder cancer Combination therapy, First-line therapy, Neoadjuvant therapy Phase III South Korea IV / Infusion AstraZeneca 16 Nov 2018
Bladder cancer Combination therapy Phase III Australia, Japan, Netherlands, Russia, Spain, United Kingdom IV / Infusion AstraZeneca 14 May 2018
Bladder cancer Combination therapy, First-line therapy, In adults, In the elderly, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II Canada, Russia, South Korea, Spain, Taiwan, USA, Vietnam IV / Infusion AstraZeneca 16 Mar 2018
Brain metastases Second-line therapy or greater Phase II USA IV / Infusion Washington University School of Medicine 01 Sep 2016
Breast cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II/III USA IV / Infusion AstraZeneca, MedImmune, Gradalis 07 Sep 2016
Breast cancer Adjunctive treatment, Early-stage disease, Neoadjuvant therapy Phase II Germany IV / Infusion AstraZeneca, Celgene International SARL 08 Mar 2016
Breast cancer Combination therapy, Neoadjuvant therapy Phase II France IV / Infusion 15 Feb 2017
Breast cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II Japan IV / Infusion AstraZeneca, Kyoto Breast Cancer Research Network 04 Jan 2017
Breast cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase II South Korea IV / Infusion Yonsei University College of Medicine 07 Dec 2016
Breast cancer Combination therapy, Late-stage disease, Neoadjuvant therapy Phase I/II Belgium IV / Infusion Grand Hopital de Charleroi 01 Feb 2017
Breast cancer Combination therapy, Neoadjuvant therapy, Newly diagnosed Phase I/II USA IV / Infusion Yale University 01 Nov 2015
Breast cancer
Combination therapy, Second-line therapy or greater

in combination with paclitaxel, in patients with metastatic triple negative PD-L1 positive breast cancer

Phase I/II Saudi Arabia IV / Infusion AstraZeneca 01 Jul 2016
Breast cancer Combination therapy, Second-line therapy or greater Phase I USA IV / Infusion MedImmune, Washington University School of Medicine 20 Apr 2018
Breast cancer Adjunctive treatment, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater Phase I Canada IV / Infusion AstraZeneca 01 Apr 2016
Breast cancer Monotherapy, Second-line therapy or greater Phase I USA IV / Infusion MedImmune, Washington University School of Medicine 20 Apr 2018
CNS cancer In adolescents, In children, In infants, Second-line therapy or greater, Treatment-resistant Phase I USA IV / Infusion Childrens Hospital Los Angeles 17 Aug 2016
Cervical cancer
Combination therapy, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater

in combination with axalimogene filolisbac

Phase I/II USA IV / Infusion Advaxis, MedImmune 01 Apr 2015
Cervical cancer - Phase I Netherlands IV / Infusion AstraZeneca, MedImmune 30 Nov 2017
Cholangiocarcinoma Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II Germany IV / Infusion AIO Studien gGmbH, AstraZeneca 02 May 2018
Cholangiocarcinoma Combination therapy, Late-stage disease Phase I USA IV / Infusion National Cancer Institute (USA), University of Southern California 07 Feb 2018
Chronic lymphocytic leukaemia Combination therapy, Monotherapy, Second-line therapy or greater Phase I/II France, Italy, Japan, Netherlands, USA, United Kingdom IV / Infusion Celgene International SARL 01 May 2016
Colorectal cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II Canada IV / Infusion AstraZeneca, Canadian Cancer Trials Group 01 Aug 2016
Colorectal cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase II USA IV / Infusion MedImmune, University of Texas M. D. Anderson Cancer Center 02 Mar 2017
Colorectal cancer Late-stage disease Phase II USA IV / Infusion MedImmune 01 Oct 2014
Colorectal cancer Combination therapy, In adults, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I/II France IV / Infusion AstraZeneca, Plexxikon, Centre Leon Berard 29 Aug 2017
Cutaneous T-cell lymphoma Combination therapy, Monotherapy, Second-line therapy or greater Phase I/II USA IV / Infusion National Cancer Institute (USA) 01 Feb 2017
Diffuse large B cell lymphoma Combination therapy, First-line therapy, Late-stage disease Phase II Austria, Denmark, Estonia, USA, United Kingdom IV / Infusion Celgene International SARL 01 Feb 2017
Diffuse large B cell lymphoma Combination therapy, Second-line therapy or greater Phase I/II USA IV / Infusion Pharmacyclics 28 May 2015
Diffuse large B cell lymphoma Combination therapy, Second-line therapy or greater Phase I France, Ireland, Italy, United Kingdom IV / Infusion AstraZeneca 01 Jul 2016
Endometrial cancer Late-stage disease, Recurrent, Second-line therapy or greater Phase II Australia IV / Infusion AstraZeneca, University of Sydney 15 Feb 2017
Endometrial cancer Monotherapy, Recurrent, Second-line therapy or greater Phase II USA IV / Infusion Memorial Sloan-Kettering Cancer Center 01 Jan 2017
Endometrial cancer Combination therapy, Recurrent, Second-line therapy or greater Phase II USA IV / Infusion Memorial Sloan-Kettering Cancer Center 01 Jan 2017
Fallopian tube cancer Combination therapy, Recurrent, Second-line therapy or greater Phase II USA IV / Infusion AstraZeneca, University of Texas M. D. Anderson Cancer Center 18 May 2017
Fallopian tube cancer Chemotherapy-induced, First-line therapy, Neoadjuvant therapy Phase I/II France IV / Infusion AstraZeneca 18 Oct 2017
Fallopian tube cancer Combination therapy, First-line therapy Phase I/II USA IV / Infusion AstraZeneca, University of Texas M. D. Anderson Cancer Center 01 Jul 2016
Gallbladder cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II Germany IV / Infusion AIO Studien gGmbH, AstraZeneca 02 May 2018
Gastric cancer
Combination therapy, Late-stage disease, Second-line therapy or greater

In combination with tremelimumab

Phase II USA IV / Infusion MedImmune 08 Sep 2016
Gastric cancer
Combination therapy, Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater

In combination with olaparib and paclitaxel

Phase II South Korea IV / Infusion AstraZeneca 26 Nov 2018
Gastric cancer Combination therapy, Late-stage disease, Second-line therapy or greater Phase I/II Japan, Singapore, Taiwan IV / Infusion MedImmune 01 Mar 2015
Gastric cancer
Combination therapy, First-line therapy

oesophagael or gastroesophageal junction adenocarcinoma

Phase I/II USA IV / Infusion AstraZeneca, Memorial Sloan-Kettering Cancer Center 01 Nov 2016
Gastrointestinal cancer Combination therapy, Late-stage disease, Second-line therapy or greater Phase I USA IV / Infusion AstraZeneca, University of Kansas Medical Center 14 Sep 2018
Germ cell and embryonal neoplasms Combination therapy, Late-stage disease, Second-line therapy or greater Phase II Italy IV / Injection AstraZeneca, Fondazione IRCCS Istituto Nazionale dei Tumori 01 Feb 2017
Glioblastoma Late-stage disease, Monotherapy, Recurrent Phase II USA IV / Infusion AstraZeneca, National Cancer Institute (USA), MedImmune, GlaxoSmithKline 01 Sep 2016
Glioblastoma Combination therapy, Late-stage disease, Recurrent Phase II USA IV / Infusion AstraZeneca, Northwestern University, National Cancer Institute (USA), MedImmune 01 Sep 2016
Glioblastoma - Phase II Australia, USA IV / Infusion Ludwig Institute for Cancer Research, MedImmune 01 Feb 2015
Glioblastoma Late-stage disease, Recurrent Phase I/II France IV / Infusion AstraZeneca, Institut Claudius Regaud 27 Mar 2017
Gynaecological cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II/III USA IV / unspecified AstraZeneca, Dana-Farber Cancer Institute 03 Jun 2016
Head and neck cancer Combination therapy, First-line therapy, Late-stage disease Phase III Austria, Belgium, Brazil, Bulgaria, Canada, France, Germany, Greece, India, Italy, Japan, Philippines, Poland, Romania, Russia, Slovakia, South Korea, Spain, Taiwan, Thailand, USA, Ukraine, United Kingdom, Vietnam IV / Infusion AstraZeneca 01 Oct 2015
Head and neck cancer
Combination therapy, Second-line therapy or greater

PD-L1-positive/negative

Phase III Australia, Chile, Hungary, Israel, Spain, Taiwan, USA IV / Infusion MedImmune 18 Sep 2015
Head and neck cancer
Combination therapy, Metastatic disease, Recurrent, Second-line therapy or greater

PD-L1-positive/negative

Phase III Argentina, Belgium, Brazil, Bulgaria, Croatia, Czech Republic, France, Italy, Japan, Romania, Russia, Serbia, South Korea, Ukraine IV / Infusion AstraZeneca 10 Sep 2015
Head and neck cancer
Combination therapy, Second-line therapy or greater

PD-L1-positive/negative

PD-L1-negative

Phase III France, Poland IV / Infusion AstraZeneca 10 Sep 2015
Head and neck cancer First-line therapy, Late-stage disease, Monotherapy Phase III Austria, Belgium, Brazil, Bulgaria, Canada, France, Germany, Greece, India, Italy, Japan, Philippines, Poland, Portugal, Romania, Russia, Slovakia, South Korea, Spain, Taiwan, Thailand, USA, Ukraine, United Kingdom, Vietnam IV / Infusion AstraZeneca 01 Oct 2015
Head and neck cancer
Combination therapy, Metastatic disease, Recurrent, Second-line therapy or greater

PD-L1-positive/negative

Phase II Australia, Israel IV / Infusion AstraZeneca 01 Apr 2015
Head and neck cancer Combination therapy, First-line therapy, Late-stage disease, Metastatic disease, Neoadjuvant therapy Phase II USA IV / Infusion Celgene International SARL, UNC Lineberger Comprehensive Cancer Center 19 Dec 2017
Head and neck cancer
Metastatic disease, Recurrent, Second-line therapy or greater

PD-L1 positive/ PD-L1 ngative

Phase II Georgia IV / Infusion AstraZeneca 01 Apr 2015
Head and neck cancer
Metastatic disease, Recurrent, Second-line therapy or greater

PD-L1 positive/ PD-L1 ngative

Phase II Malaysia, South Korea, Taiwan IV / Infusion AstraZeneca, MedImmune 01 Apr 2015
Head and neck cancer
Combination therapy, Second-line therapy or greater

PD-L1-negative

Phase II Belgium, Canada, Germany, United Kingdom IV / Infusion MedImmune 14 Sep 2015
Head and neck cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase II USA IV / Infusion MedImmune 30 Sep 2015
Head and neck cancer Combination therapy, First-line therapy, Inoperable/Unresectable Phase II Germany IV / Infusion AstraZeneca, Charite - Universitatsmedizin Berlin 02 Aug 2018
Head and neck cancer
Metastatic disease, Recurrent, Second-line therapy or greater

PD-L1 positive

Phase II Belgium, Canada, Czech Republic, France, Germany, Hungary, Spain, USA (fast track), United Kingdom IV / Infusion MedImmune 10 Sep 2015
Head and neck cancer
Combination therapy, Recurrent, Second-line therapy or greater

in combination with axalimogene filolisbac

Phase I/II USA IV / Infusion Advaxis, MedImmune 01 Apr 2015
Head and neck cancer
Combination therapy, First-line therapy, Metastatic disease, Recurrent, Second-line therapy or greater

in combination with tremelimumab

Phase I Canada, USA IV / Infusion MedImmune 04 Nov 2017
Head and neck cancer Adjuvant therapy, Combination therapy Phase I USA IV / Infusion AstraZeneca 01 Aug 2018
Liver cancer Combination therapy, First-line therapy, Inoperable/Unresectable Phase III Italy, Japan, Russia, South Korea, Spain, Ukraine IV / Infusion AstraZeneca 11 Oct 2017
Liver cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase II USA IV / Infusion AstraZeneca 14 May 2018
Liver cancer Inoperable/Unresectable, Monotherapy Phase II Italy, Japan, South Korea, Spain IV / Infusion MedImmune 01 Oct 2015
Liver cancer Combination therapy, Inoperable/Unresectable, Monotherapy Phase II Hong Kong, Singapore, Taiwan, USA IV / Infusion MedImmune 01 Oct 2015
Liver cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I France, USA IV / Infusion Innate Pharma, MedImmune 01 Sep 2018
Liver cancer Combination therapy, Late-stage disease Phase I USA IV / Infusion National Cancer Institute (USA), University of Southern California 07 Feb 2018
Lung cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase I/II France IV / unspecified Gustave Roussy 20 Jun 2017
Lymphoma Combination therapy, Monotherapy, Second-line therapy or greater Phase I/II France IV / Infusion Celgene International SARL 01 May 2016
Lymphoma In adolescents, In children, In infants, Second-line therapy or greater, Treatment-resistant Phase I USA IV / Infusion Childrens Hospital Los Angeles 24 Aug 2016
Lymphoproliferative disorders

solitary bone plasmacytoma

- Phase I USA IV / unspecified Celgene International SARL, Memorial Sloan-Kettering Cancer Center 27 Jul 2017
Malignant melanoma
Combination therapy, Inoperable/Unresectable, Late-stage disease

in combination with IMC gp100 and tremelimumab

Phase I/II Germany, USA, United Kingdom IV / Infusion Immunocore, MedImmune 20 Jan 2016
Malignant melanoma Combination therapy Phase I/II Canada, France, Italy, USA IV / Infusion GlaxoSmithKline, MedImmune 01 Nov 2013
Mesothelioma Combination therapy, Inoperable/Unresectable Phase II Italy IV / Infusion MedImmune 01 Oct 2015
Mesothelioma Combination therapy Phase II USA IV / Infusion AstraZeneca 10 Apr 2017
Mesothelioma Combination therapy, First-line therapy, Inoperable/Unresectable Phase II USA IV / Infusion AstraZeneca 01 May 2017
Mesothelioma Combination therapy, First-line therapy Phase I/II Australia IV / Infusion AstraZeneca 28 Dec 2016
Multiple myeloma
Combination therapy, Second-line therapy or greater

in combination with daratumumab

Phase II Austria, Belgium, Canada, Denmark, Germany, Greece, Italy, Netherlands, Spain, Sweden, USA, United Kingdom IV / Infusion Celgene International SARL 01 Feb 2017
Multiple myeloma
Combination therapy, Second-line therapy or greater

in combination with pomalidomide

Phase I France IV / Infusion Celgene International SARL 11 Jan 2016
Multiple myeloma Monotherapy, Second-line therapy or greater Phase I Canada, France, Germany, Italy, Netherlands, Spain, USA IV / Infusion Celgene International SARL 11 Jan 2016
Multiple myeloma Combination therapy, Newly diagnosed Suspended (I) Canada, Denmark, Finland, Germany, Italy, Netherlands, Spain, USA IV / Infusion Celgene International SARL 07 Sep 2017
Myelodysplastic syndromes
Combination therapy, Second-line therapy or greater

in combination with azacitidine

Phase II Australia, Belgium, France, Germany, Poland, Spain, USA, United Kingdom IV / Infusion Celgene International SARL 01 Jul 2015
Myelodysplastic syndromes
Combination therapy, First-line therapy

in combination with azacitidine

Phase II Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Portugal, Spain, USA, United Kingdom IV / Infusion Celgene International SARL 01 Jun 2016
Myelofibrosis - Phase I USA IV / Infusion Celgene International SARL, Northwestern University 01 Sep 2016
Neuroendocrine tumours
Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater

Neuroendocrine Neoplasms of Gastroenteropancreatic or Lung Origin

Phase II Spain IV / Infusion Grupo Espanol de Tumores Neuroendocrinos 02 Mar 2017
Non-Hodgkin's lymphoma Combination therapy, Second-line therapy or greater Phase I/II USA IV / Infusion Celgene International SARL, Juno Therapeutics 30 Oct 2017
Non-Hodgkin's lymphoma Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I USA IV / unspecified Juno Therapeutics, MedImmune 09 May 2016
Non-small cell lung cancer Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Registered Brazil IV / Infusion AstraZeneca 24 Sep 2018
Non-small cell lung cancer Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Registered European Union, India, Switzerland, USA IV / Infusion AstraZeneca, MedImmune 24 Sep 2018
Non-small cell lung cancer Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Registered Canada, Japan IV / Infusion MedImmune 03 Jul 2018
Non-small cell lung cancer Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Preregistration South Korea IV / Infusion MedImmune 31 Dec 2017
Non-small cell lung cancer Combination therapy, First-line therapy, Late-stage disease Phase III Canada, South Korea, Taiwan IV / Infusion MedImmune 18 Aug 2015
Non-small cell lung cancer Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Phase III Australia, Chile, Mexico, Peru, Singapore, South Africa, Taiwan, Thailand, Turkey, Vietnam IV / Infusion MedImmune 01 May 2014
Non-small cell lung cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase III Australia, Chile, Greece, Hong Kong, Israel, Serbia, Thailand IV / Infusion AstraZeneca 13 Jan 2015
Non-small cell lung cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase III Belgium, Bulgaria, Canada, Czech Republic, France, Germany, Hungary, Italy, Japan, Netherlands, Poland, Romania, Russia, Singapore, South Korea, Spain, Taiwan, USA, United Kingdom IV / Infusion MedImmune 30 Sep 2015
Non-small cell lung cancer Combination therapy, First-line therapy, Late-stage disease Phase III Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, Peru, Philippines, Poland, Portugal, Qatar, Romania, Russia, Saudi Arabia, Singapore, Spain, Sweden, Switzerland, Thailand, Turkey, USA, Ukraine, United Kingdom, Vietnam IV / Infusion AstraZeneca 01 Nov 2015
Non-small cell lung cancer Adjuvant therapy Phase III Australia, Canada, France, Italy, Japan, Netherlands, New Zealand, Singapore, South Korea, Spain, Taiwan, USA IV / Infusion Canadian Cancer Trials Group 01 Nov 2014
Non-small cell lung cancer First-line therapy, Late-stage disease, Monotherapy Phase III Canada, South Korea, Taiwan IV / Infusion MedImmune 18 Aug 2015
Non-small cell lung cancer Inoperable/Unresectable, Late-stage disease, Second-line therapy or greater Phase III Israel IV / Infusion AstraZeneca 01 May 2014
Non-small cell lung cancer Combination therapy, Late-stage disease, Second-line therapy or greater Phase III Canada, South Korea IV / Infusion MedImmune 01 Aug 2015
Non-small cell lung cancer Combination therapy, First-line therapy, Late-stage disease, Metastatic disease Phase III Germany, Japan, United Kingdom IV / Infusion AstraZeneca 01 Jun 2017
Non-small cell lung cancer First-line therapy, Late-stage disease, Monotherapy Phase III Australia, Belgium, France, Germany, Hungary, Italy, Japan, Netherlands, Russia, Spain, Switzerland, Thailand, USA, Vietnam IV / Infusion AstraZeneca 01 Jul 2015
Non-small cell lung cancer First-line therapy, Late-stage disease, Metastatic disease, Monotherapy Phase III Australia, China, Russia, South Korea, Thailand, Vietnam IV / Infusion AstraZeneca 01 Jan 2017
Non-small cell lung cancer Late-stage disease, Second-line therapy or greater Phase II/III USA IV / Infusion AstraZeneca, MedImmune 14 Jun 2014
Non-small cell lung cancer Early-stage disease, In adults, In the elderly, Neoadjuvant therapy Phase II France IV / Infusion 22 Sep 2016
Non-small cell lung cancer In the elderly, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II Germany IV / Infusion AIO Studien gGmbH, Celgene International SARL, AstraZeneca 14 Dec 2017
Non-small cell lung cancer Late-stage disease, Neoadjuvant therapy Phase II Switzerland IV / Infusion Swiss Group for Clinical Cancer Research 01 Mar 2016
Non-small cell lung cancer Late-stage disease, Second-line therapy or greater Phase II Austria, Czech Republic, Philippines, Thailand IV / Infusion MedImmune 01 Feb 2014
Non-small cell lung cancer Combination therapy, Late-stage disease, Metastatic disease Phase II Canada IV / Infusion AstraZeneca, National Health and Medical Research Council, Fondazione IRCCS Istituto Nazionale dei Tumori, Canadian Cancer Trials Group 15 Feb 2017
Non-small cell lung cancer Adjuvant therapy, Late-stage disease Phase II Switzerland IV / Infusion Swiss Group for Clinical Cancer Research 01 Mar 2016
Non-small cell lung cancer Early-stage disease, First-line therapy Phase II USA IV / Infusion AstraZeneca 01 Nov 2016
Non-small cell lung cancer First-line therapy, In the elderly, Late-stage disease, Metastatic disease Phase II Germany IV / Infusion AIO Studien gGmbH, Celgene International SARL, AstraZeneca 14 Dec 2017
Non-small cell lung cancer Combination therapy, First-line therapy, Late-stage disease, Metastatic disease Phase I/II USA IV / Infusion AstraZeneca 07 Feb 2018
Non-small cell lung cancer Combination therapy Phase I/II USA IV / Infusion MedImmune, Mirati Therapeutics 01 May 2016
Oesophageal cancer Late-stage disease, Second-line therapy or greater Phase II United Kingdom IV / Infusion AstraZeneca 30 Oct 2018
Oesophageal cancer Adjuvant therapy Phase II South Korea IV / Infusion Samsung Medical Center 01 Feb 2016
Oesophageal cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase I/II France IV / Infusion Gustave Roussy 20 Jun 2017
Oesophageal cancer Late-stage disease, Neoadjuvant therapy, Second-line therapy or greater Phase I/II United Kingdom IV / Infusion AstraZeneca, Ludwig Institute for Cancer Research 01 Jun 2016
Oropharyngeal cancer Combination therapy, Late-stage disease Phase II Canada IV / unspecified AstraZeneca, Centre hospitalier de l'Universite de Montreal 31 Jan 2018
Oropharyngeal cancer Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater Phase I USA IV / unspecified AstraZeneca, M. D. Anderson Cancer Center 12 Jul 2017
Oropharyngeal cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I USA IV / unspecified AstraZeneca, M. D. Anderson Cancer Center 12 Jul 2017
Ovarian cancer Combination therapy, Metastatic disease, Recurrent, Second-line therapy or greater Phase II USA IV / Infusion AstraZeneca, University of Texas M. D. Anderson Cancer Center 18 May 2017
Ovarian cancer Combination therapy, First-line therapy Phase I/II USA IV / Infusion AstraZeneca, University of Texas M. D. Anderson Cancer Center 01 Jul 2016
Ovarian cancer Combination therapy, First-line therapy, Neoadjuvant therapy Phase I/II France IV / Infusion AstraZeneca 18 Oct 2017
Ovarian cancer Combination therapy, Recurrent, Second-line therapy or greater Phase I/II Switzerland IV / Infusion Ludwig Institute for Cancer Research, VentiRx Pharmaceuticals, MedImmune 01 Nov 2015
Ovarian cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I France IV / Infusion AstraZeneca 05 May 2017
Pancreatic cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase II/III USA IV / Infusion AstraZeneca 01 Oct 2015
Pancreatic cancer
Adjuvant therapy, Combination therapy, First-line therapy, Neoadjuvant therapy

In combination with chemoradiotherapy (CCRT/gemcitabine)

Phase II South Korea IV / Infusion AstraZeneca 29 Nov 2018
Pancreatic cancer Combination therapy, Metastatic disease Phase II United Kingdom IV / Infusion AstraZeneca 25 Mar 2016
Pancreatic cancer Combination therapy, First-line therapy, Metastatic disease Phase II Canada IV / Infusion AstraZeneca, Canadian Cancer Trials Group 01 Aug 2016
Pancreatic cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase II Canada, Germany, Netherlands, South Korea IV / Infusion AstraZeneca 01 Nov 2015
Pancreatic cancer Adjuvant therapy, Second-line therapy or greater Phase II USA IV / Infusion AstraZeneca, University of Colorado at Denver 12 Jun 2017
Pancreatic cancer Metastatic disease, Monotherapy, Second-line therapy or greater Phase II Canada, Germany, Netherlands, South Korea, USA IV / Infusion AstraZeneca 01 Nov 2015
Pancreatic cancer Combination therapy, First-line therapy, Metastatic disease Phase I/II USA IV / Infusion MedImmune 02 Aug 2018
Pancreatic cancer Combination therapy, Inoperable/Unresectable, Late-stage disease, Monotherapy Phase I USA IV / Infusion AstraZeneca 07 Aug 2016
Pancreatic cancer Combination therapy, Late-stage disease Phase I USA IV / Infusion National Cancer Institute (USA), University of Southern California 07 Feb 2018
Pancreatic cancer Combination therapy, Metastatic disease, Recurrent, Second-line therapy or greater Phase I France, USA IV / Infusion AstraZeneca, Eli Lilly 01 Jun 2016
Pancreatic cancer Combination therapy, Metastatic disease, Recurrent, Second-line therapy or greater Phase I South Korea, Spain IV / Infusion AstraZeneca 01 Jul 2016
Pancreatic cancer Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I France IV / Infusion AstraZeneca, Plexxikon, Centre Leon Berard 01 Jun 2016
Peripheral T-cell lymphoma Combination therapy, Monotherapy, Second-line therapy or greater Phase I/II USA IV / Infusion National Cancer Institute (USA) 01 Feb 2017
Peritoneal cancer Combination therapy, Recurrent, Second-line therapy or greater Phase II USA IV / Infusion AstraZeneca, University of Texas M. D. Anderson Cancer Center 18 May 2017
Peritoneal cancer Combination therapy, First-line therapy Phase I/II USA IV / Infusion AstraZeneca, University of Texas M. D. Anderson Cancer Center 01 Jul 2016
Peritoneal cancer Combination therapy, First-line therapy, Neoadjuvant therapy Phase I/II France IV / Infusion AstraZeneca 18 Oct 2017
Prostate cancer Combination therapy, Hormone refractory, Metastatic disease Phase II Canada IV / Infusion AstraZeneca 01 May 2016
Prostate cancer Combination therapy, First-line therapy, Hormone refractory, Metastatic disease Phase II USA IV / Infusion M. D. Anderson Cancer Center, MedImmune 14 Jul 2017
Prostate cancer Hormone refractory, Metastatic disease, Monotherapy Phase II Canada IV / Infusion AstraZeneca 01 May 2016
Renal cancer
Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater

in combination with guadecitabine

Phase I/II USA IV / unspecified AstraZeneca, Big Ten Cancer Research Consortium 19 Dec 2017
Renal cell carcinoma Adjuvant therapy, Combination therapy Phase III United Kingdom IV / Infusion AstraZeneca, University College London 22 Nov 2017
Renal cell carcinoma Adjuvant therapy, Monotherapy Phase III United Kingdom IV / Infusion AstraZeneca, University College London 22 Nov 2017
Renal cell carcinoma
Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater

in combination with guadecitabine

Phase I/II USA IV / Infusion AstraZeneca, Big Ten Cancer Research Consortium 19 Dec 2017
Renal cell carcinoma Late-stage disease, Neoadjuvant therapy Phase I USA IV / Infusion Case Comprehensive Cancer Center 01 Dec 2016
Renal cell carcinoma Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater Clinical Phase Unknown France, Spain IV / Infusion AstraZeneca 03 May 2016
Renal cell carcinoma Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Clinical Phase Unknown France, Spain IV / Infusion AstraZeneca 03 May 2016
Sarcoma
Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater

In combination with tremelimumab

Phase II USA IV / Infusion M. D. Anderson Cancer Center, MedImmune 01 Aug 2016
Small cell lung cancer
Combination therapy, First-line therapy

in combination with tremelimumab

Phase III Bulgaria, Czech Republic, Hungary, Netherlands, Russia, Slovakia, South Korea, Spain IV / Infusion AstraZeneca 27 Mar 2017
Small cell lung cancer Combination therapy, Early-stage disease, Mid-stage disease, Second-line therapy or greater Phase III Russia IV / Infusion AstraZeneca 27 Sep 2018
Small cell lung cancer Early-stage disease, Mid-stage disease, Monotherapy, Second-line therapy or greater Phase III Russia IV / Infusion AstraZeneca 27 Sep 2018
Small cell lung cancer Combination therapy, Metastatic disease, Second-line therapy or greater Phase II Germany, Hungary, Poland, Spain, Ukraine IV / Infusion AstraZeneca 24 Apr 2017
Small cell lung cancer Combination therapy, Second-line therapy or greater Phase II USA IV / Infusion AstraZeneca 01 Apr 2016
Soft tissue sarcoma Combination therapy, First-line therapy, Late-stage disease, Metastatic disease Phase II Germany IV / Infusion AstraZeneca 15 Dec 2017
Soft tissue sarcoma Combination therapy, Locally recurrent, Neoadjuvant therapy Phase I/II USA IV / Infusion AstraZeneca 21 Jun 2017
Soft tissue sarcoma Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I France IV / Infusion AstraZeneca, University of Maryland Greenbaum Cancer Center 05 May 2017
Solid tumours Late-stage disease, Monotherapy Phase III Canada, South Korea, USA IV / Infusion AstraZeneca 17 Apr 2017
Solid tumours
Combination therapy, Late-stage disease

in combination with tremelimumab

Phase III Canada, South Korea, USA IV / Infusion AstraZeneca 17 Apr 2017
Solid tumours Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II Belgium, Germany, Italy, Spain, USA IV / Infusion AstraZeneca, MedImmune 16 Dec 2016
Solid tumours
Combination therapy, Second-line therapy or greater

in combination with tremelimumab

Phase II Canada IV / Infusion AstraZeneca, Canadian Cancer Trials Group 01 Aug 2016
Solid tumours Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase II Netherlands, United Kingdom IV / Infusion AstraZeneca 25 Jan 2016
Solid tumours
Late-stage disease, Recurrent, Second-line therapy or greater

in combination with axalimogene filolisbac

Phase I/II USA IV / Infusion Advaxis, MedImmune 01 Apr 2015
Solid tumours
Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater

solid malignancies (phase I), nasopharyngeal carcinoma (phase II)

Phase I/II China IV / Infusion AstraZeneca 01 Dec 2016
Solid tumours Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I/II France IV / Infusion AstraZeneca, UNICANCER 20 Jun 2018
Solid tumours
Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater

solid malignancies (phase I), nasopharyngeal carcinoma (phase II)

Phase I/II China IV / Infusion AstraZeneca 01 Dec 2016
Solid tumours Adjuvant therapy, Monotherapy Phase I Canada IV / Infusion MedImmune 31 Aug 2015
Solid tumours Combination therapy, Late-stage disease, Second-line therapy or greater Phase I Australia IV / Infusion MedImmune 04 Nov 2017
Solid tumours In adolescents, In children, In infants, Second-line therapy or greater, Treatment-resistant Phase I USA IV / Infusion Childrens Hospital Los Angeles 17 Aug 2016
Solid tumours
Combination therapy, Late-stage disease

in combination with tremelimumab

Phase I France, Germany, Israel, Japan, Netherlands, Spain, United Kingdom IV / Infusion MedImmune 04 Nov 2017
Solid tumours Combination therapy, Late-stage disease, Second-line therapy or greater Phase I USA IV / Infusion AstraZeneca, Eli Lilly 01 Sep 2016
Solid tumours Combination therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease, Second-line therapy or greater Phase I Israel, South Korea, Taiwan, USA IV / Infusion AstraZeneca, Eli Lilly 01 Feb 2016
Solid tumours Combination therapy, First-line therapy, Inoperable/Unresectable, Late-stage disease, Metastatic disease Phase I South Korea IV / Infusion AstraZeneca 01 Apr 2016
Solid tumours Late-stage disease Phase I Japan IV / Infusion MedImmune 04 Nov 2017
Thyroid cancer Combination therapy, First-line therapy, Metastatic disease Phase I USA IV / Infusion AstraZeneca, Memorial Sloan-Kettering Cancer Center 25 Apr 2017
Urogenital cancer Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater Marketed USA IV / Infusion AstraZeneca 22 May 2017
Urogenital cancer Late-stage disease, Metastatic disease, Monotherapy, Second-line therapy or greater Registered Canada IV / Infusion AstraZeneca 06 Nov 2017
Urogenital cancer
Late-stage disease, Monotherapy, Second-line therapy or greater

urothelial cancer

Registered Australia, Hong Kong, India, Israel, United Arab Emirates IV / Infusion AstraZeneca 16 Nov 2018
Urogenital cancer Late-stage disease, Metastatic disease, Second-line therapy or greater Registered Brazil IV / Infusion AstraZeneca 31 Dec 2017
Urogenital cancer
Combination therapy, Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater

in combination with tremelimumab

Phase III Australia, Hungary, Russia IV / Infusion AstraZeneca 27 Sep 2018
Urogenital cancer Combination therapy, First-line therapy, Inoperable/Unresectable, Metastatic disease, Monotherapy Phase III Australia, Austria, Belgium, Brazil, Canada, China, Denmark, France, Germany, Greece, Israel, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Taiwan, Turkey, USA, United Kingdom IV / Infusion AstraZeneca 01 Nov 2015
Urogenital cancer
Combination therapy, First-line therapy, Inoperable/Unresectable, Metastatic disease

in combination with tremelimumab

Phase III Hungary IV / Infusion AstraZeneca 27 Sep 2018
Urogenital cancer Late-stage disease, Monotherapy, Second-line therapy or greater Phase I/II United Kingdom IV / Infusion AstraZeneca, MedImmune 05 Jun 2016
Vulvovaginal cancer Combination therapy, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater Phase I USA IV / Infusion AstraZeneca, M. D. Anderson Cancer Center 18 Jul 2018

Priority Development Status

Type Region Indication
Fastrack US Head and neck cancer

Commercial Information

Involved Organisations

Organisation Involvement Countries
MedImmune Originator USA
MedImmune Owner USA
Celgene International SARL Licensee World
Massachusetts General Hospital Collaborator USA
AstraZeneca Collaborator United-Kingdom
Pharmacyclics Collaborator USA
Incyte Corporation Collaborator USA
Icahn School of Medicine at Mount Sinai Collaborator USA
Grupo Espanol de Tumores Neuroendocrinos Collaborator Spain
Northwestern University Collaborator USA
GlaxoSmithKline Collaborator United-Kingdom
National Cancer Institute (USA) Collaborator USA
Yale University Collaborator USA
Grand Hopital de Charleroi Collaborator Belgium
Samsung Medical Center Collaborator South-Korea
Cancer Research Institute Collaborator USA
University of Colorado at Denver Collaborator USA
Targovax Collaborator Norway
Fondazione IRCCS Istituto Nazionale dei Tumori Collaborator Italy
Mirati Therapeutics Collaborator USA
UNC Lineberger Comprehensive Cancer Center Collaborator USA
Washington University School of Medicine Collaborator USA
Canadian Cancer Trials Group Collaborator Canada
Gilead Sciences Collaborator USA
Spanish Lung Cancer Group Collaborator Spain
National Health and Medical Research Council Collaborator Australia
UNICANCER Collaborator France
Cedars-Sinai Medical Center Collaborator USA
Institut Claudius Regaud Collaborator France
Syndax Pharmaceuticals Collaborator USA
Charite - Universitatsmedizin Berlin Collaborator Germany
MedPacto Collaborator South Korea
ARCAGY/GINECO Group Collaborator France
Big Ten Cancer Research Consortium Collaborator USA
Eli Lilly Collaborator USA
Childrens Hospital Los Angeles Collaborator USA
University of Wisconsin-Madison Collaborator USA
Bergonie Institute Collaborator France
Advaxis Collaborator USA
VentiRx Pharmaceuticals Collaborator USA
University of Southern California Collaborator USA
Janssen Research & Development Collaborator USA
Kyoto Breast Cancer Research Network Collaborator Japan
Seoul National University Hospital Collaborator South-Korea
Sesen Bio Collaborator USA
Case Comprehensive Cancer Center Collaborator USA
Baptist Health South Florida Collaborator USA
Centre hospitalier de l'Universite de Montreal Collaborator Canada
Xcovery Holdings Collaborator USA
Dana-Farber Cancer Institute Collaborator USA
M. D. Anderson Cancer Center Collaborator Usa
Baylor College of Medicine Collaborator USA
Intergroupe Francophone de Cancerologie Thoracique Collaborator France
Mary Crowley Cancer Research Center Collaborator USA
Avid Bioservices Collaborator USA
Novartis Collaborator Switzerland
New York University School of Medicine Collaborator USA
Plexxikon Collaborator USA
Immunocore Collaborator United-Kingdom
UCLAs Jonsson Comprehensive Cancer Center Collaborator USA
University College London Collaborator United-Kingdom
Innate Pharma Collaborator France
Gustave Roussy Collaborator France
Juno Therapeutics Collaborator USA
National Cancer Institute (France) Collaborator France
University of Texas M. D. Anderson Cancer Center Collaborator USA
University of Maryland Greenbaum Cancer Center Collaborator USA
University of Kansas Medical Center Collaborator USA
OncoPep Collaborator USA
NewLink Genetics Corporation Collaborator USA
Unknown Collaborator USA
Memorial Sloan-Kettering Cancer Center Collaborator USA
Ludwig Institute for Cancer Research Collaborator USA
Swiss Group for Clinical Cancer Research Collaborator Switzerland
Yonsei University College of Medicine Collaborator South-Korea
Kyowa Hakko Kirin Collaborator Japan
Centre Leon Berard Collaborator France
AIO Studien gGmbH Collaborator Germany
Gradalis Collaborator USA
University of Sydney Collaborator Australia
Weill Cornell Medical College Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
Imfinzi AstraZeneca Non-small cell lung cancer, Urogenital cancer Japan, USA

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Cancer - 1L bladder (DANUBE) Wrld (75% US) Amgen, AstraZeneca III 2020 50 - - 22 Oct 2018
Cancer - 2L bladder ex US Amgen, AstraZeneca III 2019 90 - - 22 Oct 2018
Cancer - 2L bladder US Amgen, AstraZeneca Marketed 2017 100 - - 22 Oct 2018
Cancer - Adjuvant NSCLC Wrld (50% US) Amgen, AstraZeneca III 2021 40 - - 22 Oct 2018
Cancer - other Wrld (50% US) Amgen, AstraZeneca III 2019 20 - - 22 Oct 2018
Cancer - unresectable lung (PACIFIC) ex US Amgen, AstraZeneca Marketed 2018 100 - - 22 Oct 2018
Cancer - unresectable lung (PACIFIC) US Amgen, AstraZeneca Marketed 2017 100 - - 22 Oct 2018
Cancer -last line lung (ARTIC) Wrld (50% US) - Development Stopped - - - - 22 Oct 2018
Cancer heamatology Wrld (50% US) - Development Stopped - - - - 22 Oct 2018

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Cancer - 1L bladder (DANUBE) Wrld (75% US) 0 5 0 0 50 150 250 300 330 356 22 Oct 2018
Cancer - 2L bladder ex US 0 0 0 50 75 80 90 100 100 100 22 Oct 2018
Cancer - 2L bladder US 0 4 45 75 100 100 100 100 100 100 22 Oct 2018
Cancer - Adjuvant NSCLC Wrld (50% US) 0 0 0 0 0 400 800 1250 1563 1766 22 Oct 2018
Cancer - other Wrld (50% US) 0 0 0 50 300 700 950 1093 1202 1298 22 Oct 2018
Cancer - unresectable lung (PACIFIC) ex US 0 0 60 200 450 750 850 950 988 1000 22 Oct 2018
Cancer - unresectable lung (PACIFIC) US 0 15 470 800 950 1100 1250 1400 1470 1500 22 Oct 2018
Total 0 24 575 1175 1925 3280 4290 5193 5753 6120

Scientific Summary

Pharmacokinetics

Dose-dependent durvalumab pharmacokinetic parameters were observed in patients with advanced solid tumours in a phase I 1108 study [279] [273] .

Pooled analysis

The pooled pharmacokinetic exposure-efficacy analysis of the phase I/II 1108 trial and phase II ATLANTIC trial in patients with urothelial carcinoma (UC) and other solid tumours demonstrated that durvalumab 10 mg/kg IV q2w regimen had no association of pharmacokinetic (PK) exposure with efficacy or safety, overall. Distribution of PK metrics were similar between responders and non-responders. A few inverse trends were observed, and the association of ECOG and albumin versus PK exposure were also observed in the population PK modeling [191] [273] [189] .

Adverse Events

Phase III:

In the phase III PACIFIC trial, treatment with durvalumab was generally safe and well tolerated in patients with non-small cell lung cancer (NSCL). Most frequent treatment-related adverse events (AEs) included cough (35.4% versus 25.2%), pneumonitis/radiation pneumonitis (33.9% versus 24.8%), fatigue (23.8% versus 20.5%), dyspnoea (22.3% versus 23.9%) and diarrhoea (18.3% versus 18.8%) as compared with placebo. Other most frequent adverse reactions reported were rash in 15.4% (n = 73), hypothyroidism in 10.5% (n = 50), diarrhoea 9.7% (n = 46) and interstitial lung disease 9.7% (n = 46) patients, respectively. Grade 3 or 4 AEs was reported in 29.9% versus 26.1% in placebo. In study group 15.4% of patients discontinued treatment due to AEs compared with 9.8% of placebo group, respectively. Treatment led to reduction in risk of death by 32% (HR 0.68, 99.73% CI 0.47-0.997; p = 0.0025). The results were reported from 713 patients recruited in a randomised, double-blind, placebo-controlled study [174] [145] [175] [176] .

Durvalumab monotherapy and durvalumab and tremelimumab combination therapy was well tolerated in the phase III MYSTIC trial, conducted in 1 118 patients with stage IV non-small cell lung cancer. The number of deaths observed in durvalumab monotherapy arm, standard-of-care (SoC) chemotherapy arm were 108 (66.3%) and 128 (79.0%), respectively [163] [35] [162] .

Results from the phase III ARCTIC trial showed that grade ≥3 treatment-emergent AEs were 46.8%durvalumab+tremelimumab and 54.5% standard of care in SSB; 45.2% D and 66.7% SoC in SSA (sub study A group: SoC (as SSA); durvalumab (as SSA); or tremelimumab 10 mg/kg IV q4w for 24 weeks then q12w for 24 weeks), median) [172] [170] .

Phase I/II

Updated results in 191 evaluable patients reported fatigue (19.4%), decreased appetite (9.4%), diarrhoea (8.4%), rash (7.3%), nausea (6.8%), arthralgia (5.8%), pyrexia (5.8%) and pruritus (5.2%), as the most common AEs in ≥5% of the patients. 6.8% of the patients showed occurrence of grade 3 or 4 adverse events, and treatment was discontinued by three patients due to AEs. Earlier, follow-up preliminary results from the phase I/II Study 1108 of durvalumab showed that the most frequent treatment-related adverse events (AEs) were fatigue (18%), decreased appetite (9%), nausea (8%), rash (8%) and diarrhoea (8%); 5% of patients discontinued treatment due to AEs. The most common adverse events reported in ≥5% in the cohort of patients with squamous cell carcinoma of the head and neck (n = 62) were fatigue (18%), diarrhoea and nausea (8% each), pruritus, rash and maculopapular rash (7% each). 25 pts (10%) had treatment-related Grade 3/4 AEs, most frequent: fatigue and hyponatremia (each 2%). 4% had treatment-related serious adverse events including colitis and pneumonitis (each 2%). No treatment related deaths were reported. Among 40 patients with hepatocellular carcinoma, 80% of patients experienced AEs, including fatigue (27.5%), pruritus (25.0%) and elevated aspartate aminotransferase (AST) (22.5%) as the most commonly observed AEs. Grade 3–4 treatment-related AEs were experienced by 20.0% of patients, most commonly observed AEs were elevated AST (7.5%) and elevated alanine aminotransferase (5.0%). Seven patients completed the initial 12-month treatment and 7 patients discontinued treatment because of an AE (none related to treatment). There were no deaths due to treatment-related AEs [275] [335] [334] [277] [278] [111] [273] .

Preliminary results from the phase I/II trial demonstrated that durvalumab (10mg/kg) had a manageable safety profile among all patients (n=61). The most common adverse events reported in 5% or more of patients were all grade 1 or 2: fatigue (13%), diarrhoea (10%), decreased appetite (8%), arthralgia (7%), asthenia (7%), nausea (7%) and pyrexia (7%). Treatment-related Grade 3 adverse events were experienced by 3 patients (1 acute kidney injury, 1 infusion-related reaction and 1 tumour flare) [274] .

Updated data from the phase Ib/IIa SCORES trial indicated that the safety profile of second line therapy with durvalumab, in combination with danvatirsen (AZD 9150) [see Adis Insight Drug Profile 800021483], in PD-L1 naive patients (n = 38), was consistent with previous results. Adverse events (AEs) included transaminase elevations and thrombocytopenia, which were manageable and reversible. Causally related AEs occurred in 76% PD-L1 naive patients (n = 20), on treatment with durvalumab in combination with AZD 5069 (CX2i) [see Adis Insight Drug Profile 800030696] [112] . Earlier results reported mild increase in a liver enzyme, mild decrease in platelet count and mild anaemia following treatment with AZD 9150 in combination with durvalumab, in treatment-naive patients (n = 28) with head and neck cancer. Thrombocytopenia (64%), neutropenia (45%) and ALT/AST increase (36%) were the most common drug related adverse events in patients with late-stage solid tumours on treatment with AZD 9150 in combination with durvalumab. There were no dose-limiting toxicities (DLT) or The open-label, randomized trial is designed to enrol a total of 465 patients [342] [111] [109] .

In a phase I/II study, treatment with durvalumab in combination MEDI 0680 in patients with cancer resulted in grade 3 dose-limiting toxicity in 1 patient of bladder cancer cohort. The most common drug-related adverse events were pruritus (17%); diarrhoea and fatigue (both 13%); and flushing, peripheral oedema, and pyrexia (each 10%). Immune-related adverse events were similar to those observed with other checkpoint blockade agents. Discontinuation of treatment was observed in 7% patients. No deaths were reported. The maximum tolerated dose was not reached. Results were reported from 30 patients enrolled in an open-label study [300] [299] .

Safety data from phase I/II neoadjuvant trial of durvalumab for the treatment of breast cancer showed that 3 patients completed therapy at the 3 mg/kg dose without any dose limiting toxicities (DLT), 1 patient refused further study medication because of recurrent gr 2 fatigue after 7 weeks of therapy. At the 10 mg/kg dose level, all 3 patients completed the nab-paclitaxel+durvalumab treatment without any DLT and 2 patients also completed 3 of the 4 planned treatments with dose dense doxorubicin/cyclophosphamide (ddAC) without DLT. Among all 7 patients who started therapy, 1 at the 3 mg/kg group experienced gr 3 dehydration and dyspnea without chest X ray abnormalities which resolved within 48 hours with hydration. There were no other gr 3 AEs. Among the 3 patients who have completed therapy as per protocol (not including the patient who withdraw consent), 1 achieved pCR, 1 had minimal, and 1 had extensive residual cancer. No surgical AE were seen [64] [65] .

In a phase I/II DREAM trial in patients with malignant pleural mesothelioma, durvalumab demonstrated acceptable tolerability. Thirty-one patients (57%) reported grade 3 or higher grade adverse events (AEs). Nineteen patients (35%) had immune-related (ir) AEs including two grade 3 irAEs [137] [138] .

Treatment with ibrutinib (560 mg, daily) + durvalumab, 10 mg/kg every two-week, led to a favourable safety profile in patients with solid tumours, in a phase Ib/II trial. Clinically meaningful differences in the safety profile were not observed across tumour types, except differences due to tumour type, location, and prior therapies. Grade ≥3 treatment-emergent adverse events that occurred in ≥5% of patients included hyponatraemia (10%), dyspnoea (7%), maculopapular rash (7%), pneumonia (7%), anaemia (6%) and diarrhoea (6%). The open–label trial enrolled 124 patients [266] [268] .

Phase I:

Long-term follow-up results of the open-label, phase Ib dose-escalation trial of durvalumab, in combination with tremelimumab [see AdisInsight drug profile 800020650], demonstrated a good safety profile in patients with advanced non-squamous NSCLC. The most common treatment-related adverse events (AEs) were fatigue (19%), pruritus (17%), diarrhoea (15%), reduced appetite (14%) and rash (14%). A treatment-related AE was experienced by 14 patients (7%) that caused treatment discontinuation, and 23% experienced a grade 3/4 treatment-related AE. There was one treatment-related death due to multifactorial hypoxia [202] . Interim results showed that the overall adverse events (AEs) were manageable and generally reversible with standard treatment. Across all dose cohorts, the most frequently reported treatment related AEs (grade 3/4) were colitis, diarrhoea, and elevated lipase and elevated liver function tests. Of 102 patients, 20 stopped the study due to drug-related AEs. One related grade 3/4 adverse events (AE) was observed in 30% patients and 16% discontinued treatment due to a related adverse event [203] [126] [201] .

In a phase I study of durvalumab plus dabrafenib and/or trametinib in patients with malignant melanoma, overall adverse events were consistent with known safety profiles of the combination components. No exacerbation of immune-related AEs was noted [126] .

According to phase I data, durvalumab has demonstrated an acceptable safety profile in patients with advanced solid tumours [169] [338] . Drug-related AEs at grade 3 or higher occurred in 8% of patients with NSCLC, and in 10% of patients with SCCHN [126] . Immunogenicity occurred infrequently (2 of 196 patients), and had no effect on the pharmacokinetic or pharmacodynamic profiles of durvalumab (Study 1108) [279] .

In a phase I trial, in 40 evaluable patients, the safety profile of monalizumab and durvalumab combination was consistent with the monotherapy profiles of each agent. In the microsatellite-stable colorectal cancer (MSS-CRC) expansion cohort, arthralgia (7.5%), increased aspartate transaminase (AST) (7.5%), hypothyroidism (7.5%), pruritus (7.5%), and rash (7.5%) were the most common treatment-related adverse events (AE). Grade 3/4 AEs observed in three patients were restricted to sepsis (n=1, grade 4) and increased lipase (n=1, grade 3), which were resolvable, and increased AST (n=1, grade 3) [246] [247] [250] .

In a phase I trial, treatment with the combination therapy of durvalumab and trastuzumab, reported no dose limiting toxicities at dose level 1 (n=6) or dose expansion (n=9) during cycle 1, in patients with breast cancer. One patient developed ≥ grade 3 irAE (grade 4 diabetes mellitus) [72] [71] .

Treatment with 20 mg/kg durvalumab, in combination with 1 mg/kg tremelimumab, was safe and generally well tolerated in patients (n=30) with advanced solid tumours (extensive disease small-cell lung cancer), in a phase I trial. Out of 30 evaluable patients, 20 of them (67%) were reported ≥1 treatment-related adverse events (TRAEs). The most common AEs were fatigue (n=7 [23%]) and pruritus (n=7 [23%]). Additionally, seven patients (23%) had grade 3/4 TRAEs. No patients were discontinued due to TRAEs and there were no treatment-related deaths reported [295] [294] .

Pooled analysis

The pooled pharmacokinetic exposure-safety analysis of the phase I/II 1108 trial and phase II ATLANTIC trial in patients with urothelial carcinoma (UC) and other solid tumours observed that durvalumab 10 mg/kg IV q2w regimen was a well tolerated dose as single agent in UC patients, and no association of pharmacokinetic (PK) exposure with safety, overall. A higher PK exposure was not associated with an increased risk of AE, for grade 3+ AE (all types) and AE leading to treatment discontinuation (p-value ranged from < 0.00005 to 0.88; n = 158, 929 and 434 for study 1108 UC cohort, study 1108 all patients and ATLANTIC all patients, respectively) [191] [273] [189] .

In a phase II trial being conducted in patients with glioblastoma, treatment-related adverse events (TRAEs) by max CTCAE grade (Gr) were Gr1: 35.5%; Gr2: 41.9%; Gr3: 9.7%; and Gr4/5: 0%. Most commonly reported adverse events included (≥3 pts) fatigue, headache, hemiparesis, gait disturbance, increased AST, and decreased platelets/WBCs/lymphs. The trial is being conducted in 159 patients [121] [120] .

Phase II:

In the phase II NIBIT-MESO-1 trial, the combination of tremelimumab and durvalumab was safe and manageable in malignant mesothelioma patients. Twenty-four patients (60%) experienced any grade irAEs: 5 patients (12.5%) had grade 3-4 AEs, the most frequent being hepatotoxicity (7.5%). AEs were generally manageable and reversible per protocol guidelines. Three patients (7.5%) discontinued due to treatment-related AEs (1 trombocytopenia, 1 limbic encephalitis, 1 liver toxicity) [332] [139] .

In the phase II BALTIC trial in patients with platinum refractory or resistant extensive-stage SCLC, the combination of durvalumab with tremelimumab demonstrated a tolerable safety profile. Grade 3 or higher adverse events (AEs; all cause) were reported in 10 patients (48%), of which 4 patients (19%) experienced an event deemed possibly causally related to treatment by the investigator. One patient (4.8%) discontinued due to a possibly causally related AE [243] [242] .

Interim data from 40 patients from a phase I/II study demonstrated that the most common (≥15%) treatment-related AEs were fatigue (20%), increased ALT (18%), pruritus (18%), and increased AST (15%). The most common grade ≥3 related AE was asymptomatic increased AST (10%). There have been 24 discontinuations in the study, 3 due to treatment-related AEs (grade 3 pneumonitis, grade 3 colitis/diarrhoea, asymptomatic grade 4 elevated AST and ALT), 16 due to progressive disease, 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, probable HCC rupture), and 1 other (patient entering hospice care) [333] .

Treatment with durvalumab alone, and in combination with tremelimumab, was generally well toletared in patients (n=267) with recurrent or metastatic head and neck cancer, in the phase II CONDOR trial. Treatment-related adverse events of any grade were highest for durvalumab alone (63.1%), followed by durvalumab+tremelimumab (57.9%) and tremelimumab alone (55.4%). Grade 3 or 4 event rates were reported highest for tremelimumab (16.9%), followed by durvalumab+tremelimumab (15.8%) and durvalumab (12.3%). Out of 267 evaluable patients, 12 patients were discontinued the therapy due to a treatment-related adverse event, including seven patients in the combination arm and five in the tremelimumab monotherapy arm. Furthermore, one death in the combination therapy group was associated with treatment [105] [107] .

PhaseI/II: Durvalumab in combination with motolimod was generally well tolerated in a phase I/II study in patients with recurrent, platinum-resistant ovarian cancer. The most frequent (in ≥25% pts) treatment-emergent adverse events (AEs, all causality) were palmar-plantar erythrodysesthesia syndrome (PPES)/rash, stomatitis, fatigue, abdominal pain, nausea, pyrexia, and vomiting. Grade 3 treatment-related AEs in ≥ 2 pts included PPES/rash, stomatitis, lymphocyte count decreased, lipase increased, and anemia. The data is reported from 40 patients enrolled in the phase II of the study [216] [215]

Pharmacodynamics

Summary

Dose-dependent suppression of soluble PD-L1 was observed after treatment with durvalumab in patients with advanced solid tumours in a phase I trial (Study 1108) [279] .

Durvalumab suppressed B7-H1 mediated suppression of T-cell activation and enhanced sub-optimal T-cell activation during in vitro studies. Furthermore, durvalumab did not trigger cytokine release in whole blood and was only able to activate T-cells in the presence of an active T-cell receptor signal. In vivo activity was also recorded during a xenograph study with antitumor activity dependent on tumour specific human T-cells [341] .

Combination of NKG2A and PD-1 checkpoint inhibitors exhibited significantly enhanced anti-tumour responses, whereas monotherapy with these agents showed modest anti-tumour efficacy in an in vivo murine model of PD-L1 expressing solid tumours. With the combination therapy, approximately twice as many mice achieved complete tumour cell regression compared with anti-PD-1 treatment alone. In mice studies, blockage of both NKG2A/HLA-E and PD-1/PD-L1 pathways enhanced anti-tumour responses of NK and CD8+ T cells in vitro and in vivo. This data supports combination of monalizumab with durvalumab for treatment of solid tumours [198] [337] .

Immunogenicity

Summary

In a phase I/II study, treatment with durvalumab in combination MEDI 0680 in patients with cancer, increased Ki67+ (proliferating) CD4+ and CD8+ T cells. Treatment also resulted in elevatvation of circulating IFN-γ, CXCL 9, CXCL 10, and CXCL11 levels, which indicated pharmacodynamic activity of PD-1/PD-L1 pathway blockade. Results were reported from 30 patients enrolled in an open-label study