Either you have JavaScript disabled or your browser does not support Javascript . To work properly, this page requires JavaScript to be enabled.
How to enable JavaScript in your browser?

Tagraxofusp - Stemline Therapeutics

Drug Profile

Tagraxofusp - Stemline Therapeutics

Alternative Names: Diphtheria-toxin-interleukin-3-fusion-protein; DT(388)IL3; DT-388-IL-3; DT-IL-3; ELZONRIS; SL-401; tagraxofusp-erzs

Latest Information Update: 19 Mar 2020

At a glance

  • Originator Scott & White Healthcare; Texas A&M University
  • Developer Dana-Farber Cancer Institute; Stemline Therapeutics
  • Class Antineoplastics; Bacterial toxins; Immunotoxins; Interleukins; Recombinant fusion proteins
  • Mechanism of Action Peptide elongation factor 2 inhibitors
  • Orphan Drug Status

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

    Yes - Acute myeloid leukaemia; Blastic plasmacytoid dendritic cell neoplasm
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Blastic plasmacytoid dendritic cell neoplasm
  • Phase II Acute myeloid leukaemia
  • Phase I/II Multiple myeloma; Myelodysplastic syndromes; Myeloproliferative disorders
  • Preclinical Systemic scleroderma
  • No development reported Hairy cell leukaemia

Most Recent Events

  • 17 Mar 2020 Stemline Therapeutics initiates enrolment in a phase I/II trial for Blastic plasmacytoid dendritic cell neoplasm (Maintenance therapy)
  • 13 Jan 2020 Stemline Therapeutics plans a phase I/II trial for Blastic plasmacytoid dendritic cell neoplasm (Maintenance therapy) in Q1 2020
  • 07 Dec 2019 Updated efficacy and adverse events data from a phase I/II trial in Myelofibrosis and Multiple myeloma presented at the 61st Annual Meeting and Exposition of the American Society of Haematology (ASH-Hem 2019)

Development Overview

Introduction

Tagraxofusp is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein, being developed by Stemline Therapeutics, for the treatment of blastic plasmacytoid dendritic cell neoplasm, acute myeloid leukaemia, chronic myeloid leukaemia, myelofibrosis, multiple myeloma, myelodysplastic syndrome and systemic sclerosis. The intravenously administered agent consists of the first 388 amino acid residues of diphtheria toxin (DT388) fused to human interleukin-3 (IL-3). Tagraxofusp targets the IL-3 receptor (CD123) which is overexpressed on multiple haematological cancer cells. Once bound to the receptor, the protein is internalised and the DT388 payload is released. DT388 inhibits peptide elongation factor-2 and, therefore, protein synthesis, leading to apoptosis or cell death. Tagraxofusp is launched in the US and is under regulatory review in the EU for blastic plasmacytoid dendritic cell neoplasm (BPDCN). Clinical development for acute myeloid leukaemia, multiple myeloma, myelodysplastic syndromes and myeloproliferative disorders is ongoing in the US and Canada. Preclinical development in systemic sclerosis is underway in the US.

Stemline Therapeutics is also developing a second-generation variant of tagraxofusp , designated SL 501 [see Adis Insight drug profile 800040364].

Preclinical development in hairy-cell-leukaemia was underway in the US. However, no recent reports of development have been identified for the same.

Company Agreements

In November 2013, Stemline Therapeutics and The Leukemia & Lymphoma Society entered a collaboration to accelerate the development of tagraxofusp for the treatment of acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). The Leukemia & Lymphoma Society has provided over $US3 million under the company's Therapy Acceleration Program to support development, as well as providing a comprehensive educational programme to increase physician and patient awareness of BPDCN [1] .

Stemline Therapeutics in-licensed the exclusive worldwide rights to tagraxofusp , in June 2006, from the Scott & White Cancer Research Institute/Texas A&M Health Science Center College of Medicine . Tagraxofusp was known as DT388 IL3 before it was in-licensed by Stemline [2] [3] .

Key Development Milestones

In January 2019, Stemline Therapeutics announced that tagraxofusp is commercially available in the US for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adult and paediatric patients, aged ≥ 2 years, in both treatment-naïve and previously-treated populations [4] . The approval for the same was granted in December 2018 by the US FDA. The approval is based on the data from STML-401-0114 study [see below] [5] . The BLA was accepted in August 2018 by the US FDA and granted Priority Review. PDUFA date of February 21, 2019, was assigned to the drug [6] [7] . The rolling BLA submission was initiated in April 2018, and completed in June 2018 [8] . In January 2017, Stemline Therapeutics entered into an agreement with the US FDA on the registration pathway for tagraxofusp in BPDCN [9] [10] .

In July 2019, The EMA issued Day 120 List of Questions (LoQ) related to chemistry, manufacturing and controls (CMC), quality, non-clinical, and all stages of the clinical trial, including stage 4 involving lyophilised drug product to Stemline Therapeutics. Based on the LoQ, the company requested and received a clock stop extension and also requested a scientific advisory group meeting. Based on the timeline, the company anticipates opinion for the MAA from the CHMP in the first half of 2020. January 2019, Stemline Therapeutics submitted the marketing authorization application (MAA) for tagraxofusp to the European Medicines Agency (EMA) [11] [12] . Later, in the same month, Stemline Therapeutics announced that the validation of the MAA is completed by EMA [4] . The MAA seeks approval for treating patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). In November 2018, European Medicines Agency (EMA) has granted accelerated assessment for the upcoming centralised Marketing Authorization Application (MAA), for tagraxofusp in blastic plasmacytoid dendritic cell neoplasm [13] . In May 2018, Stemline announced that the company expects feedback from the EMA regarding potential regulatory filing in Europe [14] .

In August 2019, Stemline Therapeutics reorted establishment of a global Early Access Program (EAP), under which tagraxofusp (ELZONRIS) will be available before approval and outside of the ongoing clinical trials for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) [11] .

The Centers for Medicare and Medicaid Services (CMS) assigned a specific and permanent reimbursement J-code for tagraxofusp following the approval. The code became effective on October 1, 2019 [15] . In August 2019, the Centers for Medicare & Medicaid Services (CMS) granted approval for a new technology add-on payment (NTAP) for tagraxofusp for the treatment of adult and paediatric patients, two years and older, with BPDCN [16] . The on October 2019.

In August 2016, Stemline Therapeutics submitted the that the US FDA had granted breakthrough therapy designation to tagraxofusp for the treatment of BPDCN. The designation was granted on the basis of positive efficacy and safety data from the phase II trial evaluating tagraxofusp in BPDCN patients in both the first-line and relapsed/refractory settings [17]

Stemline received orphan drug designations for tagraxofusp for the treatment of BPDCN in the US in June 2013 and in the EU, in November 2015 [18] [19] .

The EMA and US FDA granted orphan drug designation to tagraxofusp, for the treatment of AML, in September 2015 and March 2011 respectively [20] [21]

In October 2017, Stemline Therapeutics released efficacy data stating that the primary endpoint was met in a pivotal phase II trial of tagraxofusp in 47 blastic plasmacytoid dendritic cell neoplasm (BPDCN) (STML-401-0114; NCT02113982). The trial has been completed. Also, in October 2017, Stemline released pooled safety data of tagraxofusp in acute myeloid leukaemia, BPDCN, myeloproliferative neoplasms, and multiple myeloma. In June 2017, the company reported updated clinical data from stages 1 and 2 of the study. In December 2016, the company presented positive safety and efficacy data from the phase II portion of the trial at the 58th Annual Meeting of American Society of Haematology (ASH-2016). In June 2016, Stemline presented data from the phase II part of the phase I/II study at the American Society of Clinical Oncology (ASCO-2016). In December 2015, the company presented positive safety and efficacy data from the lead-in expansion stage of the trial at the 57th Annual Meeting and Exposition of the American Society of Haematology (ASH-Hem-2015). In May 2015, Stemline Therapeutics reported positive clinical results from the trial. Updated safety and efficacy data from the trial were released in December 2017. The open-label, non-randomised phase I/II trial was initiated in September 2014 and consists of separate dose-escalation and dose-expansion parts [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [18] [37] [38] [39] ..

In December 2014, Stemline Therapeutics initiated a phase I/II trial in IL-3R expressing myeloproliferative neoplasms including mastocytosis, hypereosinophilic syndrome, myelofibrosis (MF) and chronic myelomonocytic leukaemia (CMML) (STML401-0314; NCT02268253). Enrolment of approximately 100 patients, with advanced myeloproliferative neoplasms, is underway in the US and Canada. The company plans to expand the trial to two parts Stage 3 with addition of a single-arm cohorts of patients with previously-treated chronic myelomonocytic leukaemia later in 2019. In the first part of Stage 3 (Stage 3a), enrichment strategies and certain efficacy endpoints, including spleen size reduction and bone marrow complete response with partial hematologic recovery will be assessed. In the second part (Stage 3b), the efficacy endpoints will be confirmed with primary evidences of efficacy to support future registration. In December 2018, Stemline Therapeutics presented the efficacy and safety data at the 60th Annual Meeting and Exposition of the American Society of Haematology (ASH Hem-2018). Later, in May 2019, updated data was presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO-2019). In June 2019, results were presented at the 24th Congress of the European Haematology Association (EHA-2019) [40] [11] [41] [42] [43] [44] [45] [46] [47] [23] [48] [49] [50] [51] [36] [52] [53] . As of January 2020, enrollment is ongoing for stage 3a cohort including of two patient populations- the relapsed/refractory patients, and first-line, poor prognosis patients not expected to benefit from first line cytoreductive treatment. The myelofibrosis cohort has been expanded to include 20-25 additional patients [54] [15] . In December 2019, Stemline Therapeutics presented updated safety and efficacy data from the trial at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem 2019). Results showed that tagraxofusp demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis [55] [56] .

Stemline Therapeutics is conducting a registrational phase I/II trial to investigate the efficacy and tolerability of tagraxofusp, as a consolidation therapy, in patients with late-stage acute myeloid leukaemia, who are in the first complete remission with minimum residual disease (MRD) following chemotherapy and high risk of relapse (STML401-0214; NCT02270463). The open-label trial is enrolling approximately 35 patients in the US and includes a brief lead-in that transitions into a larger expansion stage in this indication [57] [58] [38] . Results from the trial demonstrating that the maximum tolerated dose was not reached were presented at the 58th Annual Meeting and Exposition of the American Society of Haematology (ASH-Hem-2016). Updated safety data were released in December 2017 [23] [48] [59] [60] .

A phase I/II study of single-agent, intravenous tagraxofusp was completed in July 2014 at the Scott & White Cancer Institute and M. D. Anderson Cancer Center (NCT00397579) [36] [61] . The trial enrolled 91 adult or elderly patients with relapsed, refractory, or poor-risk AML or MDS at sites in Canada and the US. Tagraxofusp was well tolerated at clinically active doses and showed antitumour activity in patients with AML, MDS as well as in patients with BPDCN. Stemline reported in November 2012 that a heavily pretreated patient with refractory and recurrent BPDCN achieved a complete response following treatment with tagraxofusp. The complete response was recorded 30 days after treatment with five daily doses of tagraxofusp. There were no serious adverse events observed [62] [63] [64] [57] . Later, in January 2013, the company reported that a second heavily pretreated patient with refractory and recurrent BPCDN had achieved a complete response after a single cycle of tagraxofusp [37] .

Stemline Therapeutics initiated a phase I/II trial in January 2016 to investigate the safety and efficacy of tagraxofusp in combination with pomalidomide [see Adis Insight drug profile 800016607] and dexamethasone in patients with relapsed or refractory multiple myeloma (NCT02661022; STML-401-0414). The open-label trial will enrol approximately 32 patients in the US [65] . In December results from the trial were presented at the 61st American Society of Haematology (ASH-2019) [55] .

In March 2020, Stemline Therapeutics initiated a phase I/II trial to evaluate tagraxofusp as a maintenance therapy post-stem cell transplant (SCT) in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) [66] .

Stemline is also planning several trials in other malignancies and uncommon stem-cell derived myeloproliferative disorders [38] . Stemline Therapeutics plans to initiate clinical trials of tagraxofusp in combination with other therapies [50] .

In June 2017, Dana-Farber Cancer Institute in collaboration with Stemline Therapeutics initiated a phase I/II study to evaluate the maximum tolerated dose and safety of tagraxofusp in combination with azacitidine and venetoclax in patients with relapsed/refractory acute myeloid lukaemia, treatment-naïve AML not eligible for standard therapy and patients with high risk myelodysplastic syndrome (NCT03113643, 17-056). The open-label study intends to enrol approximately 36 patients in the US [67] .

Results presented in December 2013 at the 55th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2013) showed an overall response rate of 86% in the eight patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) that had been treated with a single, 5-day cycle of tagraxofusp [68] . In December 2014, preclinical results of tagraxofusp were presented for hairy cell leukaemia, myeloproliferative neoplasms and myeloma. Tagraxofusp was shown to block plasmacytoid dendritic cell-triggered growth of myeloma cells, inhibit the development of osteoclasts responsible for bone resorption in myeloma patients, and limit the viability of cancer stem cell-like multiple myeloma cells [69] .

In a multicentre phase I dose-escalation study, tagraxofusp demonstrated anticancer activity at tolerable doses in patients with relapsed, refractory, or poor-risk AML [2] .

In November 2019, Stemline Therapeutics presented preclinical data at the 83rd American College of Rheumatology and the 54th Association of Rheumatology Health Professionals Annual Scientific Meeting [70]

In June 2019, Stemline Therapeutics released preclinical data for tagraxofusp. Preclinical data demonstrated the activity of tagraxofusp against potentially pathogenic plasmacytoid dendritic cells (pDCs). Tagraxofusp inhibited inflammatory pDCs at concentrations that were lower than peak plasma concentrations observed in BPDCN patients treated with the drug [71] .

In June 2018, Stemline Therapeutics released preclinical data of tagraxofusp at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) [72] [73] .

In December 2017, Stemline reported that resistance to tagraxofusp in AML and BPDCN was associated with loss of the diphthamide synthesis pathway enzyme DPH 1 and could be reversed with azacitidine [74] .

In December 2019, pharmacodynamics data for tagraxofusp in primary patient MPN peripheral blood mononuclear cells with myelofibrosis and tagraxofusp alone or in combination with ruxolitinib [see Adis Insight Drug profile800026694] in leukaemia was presented at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2019) by Stemline Therapeutics [75] .

The combination of tagraxofusp and the tyrosine kinase inhibitor ITKI) imatinib (Gleevec®) showed a significant synergistic effect on the primary CML cell growth inhibition in vitro. Additionally, tagraxofusp prolonged the survival of mice inoculated with primary CML cells from patients in blast crisis, including those resistant to several TKIs [76] .

Stemline Therapeutics reported results from preclinical studies in combination with SL 801 [see Adis Insight drug profile 800023286] in haematological malignancies at the 58th Annual Meeting and Exposition of the American Society of Haematology (ASH-2016) [77] .

Preclinical study of tagraxofusp in combination with SL 801 is underway against multiple myeloma and haematological malignancies [78] .

In December 2011, Stemline announced data from two preclinical studies with tagraxofusp showing activity against various lymphoid malignancies. In one of those studies, tagraxofusp inhibited the growth of several Hodgkin's lymphoma cell lines and was active against mantle cell lymphoma, non-Hodgkin's lymphoma, and T-cell acute lymphoblastic leukaemia cell lines. In another study, tagraxofusp demonstrated cytotoxicity against primary tumour cells obtained from patients with BPDCN [79] . Positive preclinical data for tagraxofusp in CML have been reported [57] . Preclinical efficacy data in multiple myeloma were reported in May 2014. The studies were conducted in collaboration with Dana-Farber Cancer Institute [80] .

Investigator-sponsored trials

In August 2019, Stemline Therapeutics announced receipt of regulatory clearance for a phase I/II trial for tagraxofusp as a maintenance therapy post-stem cell transplant (SCT) in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) [11] .

Financing information

In August 2019, Stemline Therapeutics announced the pricing of an underwritten public offering of 5 000 000 shares of its common stock at a price of $US15.25 per share, with expected gross proceeds to Stemline of $US76 250 000. Stemline has also granted the underwriters a 30-day option to purchase up to 750 000 additional shares of its common stock at the public offering price, less underwriting discounts and commissions. The offering is expected to close on or about August 13, 2019, subject to customary closing conditions. Stemline will be using the net proceeds from this offering for commercial activities of tagraxofusp, clinical trials for additional indications including chronic myelomonocytic leukemia (CMML), myelofibrosis (MF), acute myeloid leukaemia (AML), and potentially other diseases such as certain lymphomas, clinical development of additional pipeline candidates (felezonexor, SL 1001, SL 901 and SL 701), research and development and regulatory activities, potential acquisitions and in-licensing; and other general corporate purposes [81] .

In January 2019, Stemline Therapeutics reported completion of an underwritten public offering of 10 222 222 shares of its common stock and closed gross proceeds of US$92 million. The proceeds from the offering will be utilised for commercial activities of tagraxofusp (SL 401) and its clinical trials in additional indications including chronic myelomonocytic leukaemia (CMML), myelofibrosis (MF) and other diseases, for clinical development of SL 801, SL 701 and potentially SL 901 [see Adis Insight drug profiles 800023286, 800033745 and 800053796], for research and development activities and for potential acquisitions and in-licensing [82] .

In January 2018, Stemline Therapeutics completed an underwritten public offering of 4 255 000 shares of its common stock and closed gross proceeds of $US59.5 million. The net proceeds will be used for the clinical, regulatory, manufacturing and potential commercial activities of tagraxofusp, for clinical development of SL 801 and SL 701 [see Adis Insight drug profiles and 800033745], for research and development activities, for potential acquisitions and in-licensing, for other general corporate purposes [22] [83] [84] .

In January 2017, Stemline Therapeutics reported underwritten public offering of $US45 million of its common stock. The net proceeds will be used for the clinical, regulatory, manufacturing and, if and when approved, potential commercial activities of tagraxofusp [85] .

Stemline completed an equity offering of common stock in January 2015, for net proceeds of approximately $US68 million. The company intends to use the proceeds from the offering to support the clinical development of its lead clinical candidates, including tagraxofusp, and also for other general corporate purposes [86] [87] .

In May 2013, Stemline Therapeutics priced an underwritten public offering of its common stock to a total gross proceeds of $US60 million. The company plans to use the net proceeds to support development of its clinical drug candidates, including tagraxofusp, and also for other general corporate purposes [88] .

Stemline completed an initial public offering of common stock in January 2013, for net proceeds of approximately $US32.5 million. Funds were to be used in part to advance development of tagraxofusp [89] .

Labelling information

The US approved label for tagraxofusp carries a black box warning regarding the increased risk of capillary leak syndrome [5] .

Patent Information

As of March 2019, Stemline Therapeutics holds patent rights, including issued US patents (7 763 242; 8 470 307; 9 181 317, and 9 631 006) covering methods of treating acute myeloid leukaemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN) and myelodysplastic syndrome (MDS) that expire in 2027, as well as seven issued patents in territories outside the US. The company also has additional pending US applications directed to methods of using tagraxofusp to treat other diseases that, if issued, would also expire in 2027 [3] .

Drug Properties & Chemical Synopsis

  • Route of administration IV
  • Formulation Infusion, unspecified
  • Class Antineoplastics, Bacterial toxins, Immunotoxins, Interleukins, Recombinant fusion proteins
  • Target Interleukin-3 receptor alpha subunit; Peptide elongation factor 2
  • Mechanism of Action Peptide elongation factor 2 inhibitors
  • WHO ATC code

    D11A-X (Other dermatologicals)

    L01 (Antineoplastic Agents)

  • EPhMRA code

    D11 (Other Dermatological Preparations)

    L1 (Antineoplastics)

  • Molecular formula C2553 H4026 N692 O798 S16
  • CAS Registry Number 2055491-00-2

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

acute myeloid leukaemia

not specified

PML-RARA fusion

interleukin 3

Flt-3

1

1

1

blastic plasmacytoid dendritic cell neoplasm

not specified

interleukin 3

1

myelodysplastic syndromes

not specified

interleukin 3

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Tagraxofusp - Stemline Therapeutics Flt-3 not specified
PML-RARA fusion not specified
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute myeloid leukaemia - - Phase II USA IV / Infusion Stemline Therapeutics 19 May 2016
Acute myeloid leukaemia in combination with azacitidine and venetoclax Combination therapy Phase I/II USA IV / Infusion Dana-Farber Cancer Institute, Stemline Therapeutics 26 Jun 2017
Blastic plasmacytoid dendritic cell neoplasm - In adolescents, In adults, In children Marketed USA IV / Infusion Stemline Therapeutics 30 Jan 2019
Blastic plasmacytoid dendritic cell neoplasm - - Preregistration European Union IV / Infusion Stemline Therapeutics 07 Jan 2019
Hairy cell leukaemia - - No development reported (Preclinical) USA IV / Infusion Stemline Therapeutics 28 Jan 2019
Multiple myeloma in Combination With Pomalidomide and Dexamethasone Combination therapy, Second-line therapy or greater Phase I/II USA IV / Infusion Stemline Therapeutics 01 Jan 2016
Myelodysplastic syndromes - Second-line therapy or greater Phase I/II USA IV / Infusion Stemline Therapeutics 31 Jul 2006
Myelodysplastic syndromes in combination with Azacitidine and venetoclax Combination therapy Phase I USA IV / Infusion Dana-Farber Cancer Institute, Stemline Therapeutics 26 Jun 2017
Myeloproliferative disorders in patients with Systemic mastocytosis, Advanced symptomatic hypereosinoophic disorder, Myelofibrosis and Chronic myelomonocytic leukaemia Late-stage disease Phase I/II Canada, USA IV / Infusion Stemline Therapeutics 16 Dec 2014
Systemic scleroderma systemic sclerosis - Preclinical USA IV / unspecified Stemline Therapeutics 13 Jun 2018

Orphan Status

Indication Patient Segment Country Organisation Event Date
Acute myeloid leukaemia - USA Stemline Therapeutics 09 Mar 2011
Acute myeloid leukaemia - European Union Stemline Therapeutics 10 Sep 2015
Blastic plasmacytoid dendritic cell neoplasm - USA Stemline Therapeutics 10 Jun 2013
Blastic plasmacytoid dendritic cell neoplasm - European Union Stemline Therapeutics 02 Nov 2015

Commercial Information

Involved Organisations

Organisation Involvement Countries
Texas A&M University Originator USA
Scott & White Healthcare Originator USA
Scott & White Healthcare Owner USA
Texas A&M University Owner USA
Stemline Therapeutics Licensee World
The Leukemia & Lymphoma Society Collaborator World
Dana-Farber Cancer Institute Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
ELZONRIS Stemline Therapeutics Acute myeloid leukaemia USA

Scientific Summary

  • Adverse Events Occasional: Chills; Fever; Hypoalbuminaemia; Hypotension; Hypoxaemia

Pharmacokinetics

Patients with acute myeloid leukaemia or myelodysplasia who received one cycle of tagraxofusp at doses between 4 and 12.5 ug/kg had Cmax values on day-1 that ranged from 0–350 ng/mL and correlated with dose. Day-12 Cmax values ranged from 0–179 ng/mL and correlated with day-12 anti-diphtheria toxin antibody levels [96] .

In vitro

studies of tagraxofusp in combination SL 801 in haematological malignancies demonstrated that the IC50s for tagraxofusp were 17 nM in K562 cells, 25 nM in RPMI-8226 cells, and 100 nM in L-428 cells, and the IC50s for SL 801 were 99 nM in K562 cells, 51 nM in RPMI-8226 cells, and 494 nM in L-428 cells. In combination with each other, tagraxofusp and SL 801 inhibited cell growth in all cell lines. Combination index (CI) values indicated that the interaction between the two drugs was synergistic at most dose combinations. CI values < 0.3 were observed in MV4-11 and L-428 cells indicating strong synergy [77] .

Adverse Events

Phase II

In a phase II trial conducted in patients with AML in first or second complete remission, most commonly reported treatment-related AEs, all grades, were thrombocytopenia (n = 3/9; 33%) and hypoalbuminemia (n = 3/9; 33%). The most common ≥ grade 3 treatment-related AE was thrombocytopenia (n = 1/9; 11%). No dose-limiting toxicities were reported at stage I and MTD was not reached. The data were released from 9 patients. Updated results released in December 2017, showed hypoalbuminaemia (44%), ALT increase (38%), AST increase (38%), and thrombocytopenia (38%) as the most common TRAEs. out of which, ALT increase (31%), AST increase (25%), and thrombocytopenia (19%) were grade III TRAEs. In two patients (13%), grade 3 CLS were observed. Five patients, including one who went to SCT at 3+ months, were relapse-free for at least 5+ months (range 5+ to 14+), including 2 ongoing (8+ months [on tagraxofusp] and 14+ months [SCT]) [23] [59] [60] .

Phase I/II:

Treatment related adverse events at all grades and at grades ≥3 from a phase II of phase I/II pivotal study in blastic plasmacytoid dendritic cell neoplasm (BPDCN) of tagraxofusp were transaminase elevation 52% and 40%, hypoalbuminaemia 39% and 0%, chills 31% and 0%, pyrexia 27% and 0%, nausea 23% and 0%, fatigue 23% and 0%, thrombocytopenia 19% and 19%, hypotension 19% and 0%, weight increased 19% and 0%, capillary leak syndrome 19% and 8%, anaemia 19% and 11%, decreased appetite 19% and 0%, and oedema peripheral 23% and 0%, respectively. All adverse events at all grades and at grades ≥3 were transaminase elevation 60% and 42%, hypoalbuminaemia 42% and 0%, pyrexia 42% and 0%, nausea 46% and 0%, fatigue 42% and 8%, anaemia 31% and 15%, thrombocytopenia 19% and 19%, chills 35% and 0%, decreased appetite 19% and 0%, hypotension 19% and 0%, oedema peripheral 46% and 0%, weight increased 27% and 0%, and capillary leak syndrome (CLS) 19% and 8%, respectively. Updated results showed alanine aminotransferase increase (52%), aspartate aminotransferase increase (50%), hypoalbuminaemia (50%), and thrombocytopenia (38%) as the most common treatment-related adverse events (TRAEs). TRAEs included capillary leak syndrome (19%), which was grade 5 in 2.4% (1/42) of BPDCN patients at 12ug/kg/day, 2.6% (4/153) of patients across all trials at all dosages, and 1.7% (2/119) of patients across all trials at 12ug/kg/day [23] [25] [32] . Previously data demonstrated that the treatment related adverse events at all grades and at grades ≥3 from a lead-in expansion stage of the pivotal phase I/II trial were transaminase elevation 64% and 43%, hypoalbuminemia 46% and 0%, pyrexia 39% and 0%, nausea 36% and 0%, fatigue 32% and 4%, anaemia 29% and 25%, thrombocytopenia 25% and 21%, chills 25% and 0%, decreased appetite 25% and 0%, hypotension 21% and 0% edema peripheral 21% and 0%, weight increased 18% and 0%, lymphopenia 18% and 14% and capillary leak syndrome (CLS) 18% and 11% , respectively. All adverse events at all grades and at grades ≥3 were transaminase elevation 71% and 43%, hypoalbuminemia 54% and 4%, pyrexia 54% and 7%, nausea 46% and 0%, fatigue 43% and 7%, anaemia 39% and 29%, thrombocytopenia 29% and 25%, chills 29% and 0%, decreased appetite 25% and 0%, hypotension 29% and 7% edema peripheral 25% and 0%, weight increased 25% and 0%, lymphopenia 18% and 14% and capillary leak syndrome (CLS) 18% and 11% , respectively. Dose related toxicities of grade 5 CLS and grade 3 infusion reaction were observed in 16 ug/kg/day dose group in patients with acute myeloid leukaemia (AML). Tagraxofusp was well tolerated at doses of 12 ug/kg/day or below [33] . In stages 1 and 2 of the phase II trial, the most common treatment-related adverse events (TRAEs) with tagraxofusp across BPDCN and other indications (n=134) were hypoalbuminemia (43%), transaminitis (43%), and thrombocytopenia (26%), by investigator-assessment. TRAEs included capillary leak syndrome (18%), of which 3 cases were grade 5 (2.2%) [31] [39] .

Updated results from the phase I/II trial demonstrated alanine aminotransferase increase, headache, hypoalbuminemia (all 17%), anemia, and thrombocytopenia (both 14%) as most common treatment related adverse events (TRAEs). There was one case of capillary leak syndrome (CLS), which was grade 3 with 43% overall survival (OS) at 18 months and 29% OS at 2 years [55] . Earlier results showed that tagraxofusp exhibited a manageable safety profile in 20 myeloproliferative disorder patients. The most common treatment-related adverse events (TRAEs) in patients with relapsed/refractory chronic myelomonocytic leukaemia, were hypoalbuminaemia (35%), thrombocytopenia (35%), nausea (30%), vomiting (30%), and fatigue (20%). The most common ≥ Grade 3 TRAEs were thrombocytopenia (35%) and nausea (5%). Capillary leak syndrome in three patients (15%; all Grade 1 and 2). During the trial, 100% (10/10) of patients with splenomegaly had spleen response, wherein 80% (8/10) had reductions ≥ 50% and 67% (4/6) with spleen size ≥ 5cm had reductions ≥ 50%. Three patients treated with tagraxofusp achieved bone marrow complete responses (BMCRs), including 1 patient who was bridged to stem cell transplant in remission on tagraxofusp. Further, in 23 relapsed/refractory myelofibrotic patients, the most common TRAEs were headache (22%), hypoalbuminaemia (22%), increased ALT (17%) and thrombocytopenia (17%). The most common ≥ Grade 3 TRAE was thrombocytopenia (2%). Capillary leak syndrome was seen in one patient (4%; Grade 3). Among the 14 evaluable patients with baseline splenomegaly, 57% had spleen size reductions: 43% (6/14) had reductions of > 25%, of which 3 patients had reductions of ≥ 45%. In 5 patients with baseline splenomegaly and monocytosis, 80% (4/5) had reductions of > 25%, of which 2 had reductions of ≥ 45%. Six patients, including 3 patients with monocytosis and 5 patients with platelets <100 K/uL, had treatment duration of 6 months or more. However, early report suggested that the TRAEs were hypoalbuminaemia and nausea (each 38%), vomiting (31%), fatigue, oedema, and thrombocytopenia (each 25%). The most common ≥grade 3 TRAEs were thrombocytopenia (13%) and nausea (6%). Spleen response was found in 50% (6/12) of evaluable patients, with baseline spleen size 5 cm or more BCM, of which 33% (4/12) had splenomegaly reduction by 33% or more and 25% (3/12) had splenomegaly reduction by 35% or more. Fifty percent (3/6) of patients with spleen response had treatment duration 8+ months, including 8+, 12+ and 14+ months (all 3 ongoing). Four patients with baseline thrombocytopenia had treatment durations 8+ months, 3 of which are ongoing. In a phase I/II trial in patients with myeloproliferative disorders, tagraxofusp was found to be well tolerated. Most commonly reported adverse events included thrombocytopaenia (n = 2/6; 33%) and fatigue (n = 2/6; 33%). Grade 3 or greater treatment-related AEs were thrombocytopaenia (n = 2/6; 24%) and anaemia (n = 1/6; 19%). Updated results showed no dose limiting toxicities and maximum tolerated dose (MTD) was not reached [40] [90] [41] [42] [44] [43] [45] [46] [47] [23] [48] [49] . Updated data from 27 patients showed that headache, hypoalbuminemia, increased levels of alanine aminotransferase, thrombocytopenia, and anaemia were the most commonly reported treatment-related adverse events (TRAEs, incidence ≥ 15%). Thrombocytopenia (8%) and anaemia (15%) were the most commonly reported grade 3 TRAE’s. Capillary leak syndrome was reported in 1 patient (grade 3) [56] [53] .

In a phase I/II trial in patients with multiple myeloma, the combination of pomalidomide (POM) and dexamethasone demonstrated a predictable and manageable safety profile [65] [55]

Tagraxofusp was well tolerated, with no cumulative adverse events, in 15 patients with BPDCN treated with multiple cycles of tagraxofusp administered at dose levels up to 12 µg/kg/day [34] [68] .

In a phase I dose-escalation trial, 38 adult patients with relapsed, refractory, or poor risk acute myeloid leukaemia were treated with tagraxofusp without dose-limiting toxicity [2] .

One cycle of tagraxofusp 4-12.5 ug/kg administered to patients with acute myeloid leukaemia or myelodysplasia resulted in mild-to-moderate toxicities that were transient. These included fever, chills, hypotension, transaminasaemia, hypoxaemia, and hypoalbuminaemia [96] .

Tagraxofusp was well-tolerated, with no unexpected AEs observed, when administered in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma patients. The most common treatment-related adverse events were thrombocytopenia (2/2, both grade 1) and hypoalbuminaemia (2/2, both grade 2). No drug-related toxicity was observed [95] [65] .

Pooled analysis

Tagraxofusp was found to be safe and well tolerated, and side effects were predictable and manageable. The lead-in dose escalation stages of both Phase 2 studies in AML and high-risk myeloproliferative neoplasms were completed without dose limiting toxicity (DLT) [48] [60] [53] .

Pooled analysis of tagraxofusp in patients (n=148) with blastic plasmacytoid dendritic cell neoplasm, acute myeloid leukaemia, myeloproliferative neoplasms, and multiple myeloma demonstrated most common treatment-related adverse events (TRAEs). The TRAEs were hypoalbuminemia (47%), aspartate aminotransferase increase (46%), alanine aminotransferase increase (45%), nausea (28%), and thrombocytopenia (28%). Also capillary leak syndrome (CLS), was reported in 19% of patients, of which 2% (3/148) were grade 5 [30] [39] .

Pharmacodynamics

Summary

Preclinical studies in multiple myeloma (MM) models showed that tagraxofusp significantly decreased the viability of malignant cells by targeting neighbouring plasmacytoid dendritic cells (pDCs) in the tumour microenvironment of the bone marrow. Tagraxofusp also demonstrated activity against MM cells, including those resistant to bortezomib (Velcade®), dexamethasone and lenalidomide (Revlimid®), and was active at picomolar concentrations. Tagraxofusp showed synergistic activity when combined with bortezomib, melphalan, lenalidomide or pomalidomide (Pomalyst®). Additionally, tagraxofusp inhibited the formation of osteoclasts, which cause bone loss, fractures and significant morbidity in MM patients, and stabilized the formation of bone-strengthening cells called osteoblasts [80] .

In preclinical studies, tagraxofusp showed activity against chronic myeloid leukemia and cancer stem cells from patients who are resistant to tyrosine kinase inhibitors [57] .

In vitro

studies of combination of tagraxofusp and SL 801 in CML, AML, MM, and HL cell lines demonstrated that tagraxofusp and SL 801 induced higher levels of caspase activation and LDH release in MV4-11 and L-428 cells than either drug alone [77] .

Preclinical studies in blastic plasmacytoid dendritic cell neoplasm (BPDCN) demonstrated that tagraxofusp was cytotoxic against CD123+ pDCs. A reduction in secreted IFNα and IL-6 was observed in cell culture supernatant, concurrently with pDC depletion [73] .

Preclinical ex vivo studies demonstrated that tagraxofusp was cytotoxic towards ex vivo from both healthy volunteers (n = 5) and systemic sclerosis patient donors (n = 3) to a similar extent. The ED50 of tagraxofusp against pDCs from healthy volunteers and systemic sclerosis patients was 4.3 and 3.3 ng/ml (74.5 and 57.2 pM), respectively. No effect was observed on B or T cells across the tagraxofusp dose range tested. A significant reduction in CpG-induced IFN-α secretion occurred simultaneously with tagraxofusp-mediated pDC depletion [72] .

In preclinical studies, combination of an hypomethylating agent and tagraxofusp showed therapeutic effect in primary chronic myelomonocytic leukaemia. Adding tagraxofusp at a concentration of 4.8nM to 1uM azacitidine in the assay induced a significant reduction in cell viability (p < 0.05). In colony assays, tagraxofusp, in combination with azacitidine, significantly reduced colony formation, compared with azacitidine alone (p < 0.05). Addition of azacitidine to increasing concentrations of tagraxofusp significantly reduced colony formation (p < 0.05). Moreover, a combination effect was observed across samples of different genotypes including patient samples with high risk genotypes, including NRAS/ASXL1/TET2 and mutations in SRSF2/TET2/STAG2 [92] .

Treatment with tagraxofusp alone or in combination with ruxolitinib in myelofibrosis and leukaemia in peripheral blood samples from patients showed that IC50 of tagraxofusp in UKE1 cells was 2.95-3.57nM. The IC50 of range of single agent ruxolitinib was 44.42-70.93nM. Tagraxofusp (5nM) addition to ruxolitinib reduced the IC50 range to 11.72-21.6nM. In peripheral blood mononuclear cells with CD123 expression, tagraxofusp was able to significantly reduce colony formation at a dose range of 2.5nM to 20nM. This includes two samples (151, 455) from patients with accelerated-phase disease. Tagraxofusp demonstrated activity across genotypes, including in cases with TP53 and ASXL1 mutations. A reduction in colony formation in samples treated with combination ruxolitinib and tagraxofusp was observed in several cases better than either agent alone [75] .

In preclinical studies, tagraxofusp was cytotoxic towards plasmacytoid dendritic cells (pDC) from both healthy volunteers (HV) (n=5) and systemic sclerosis (SSc) donors (n=5) to a similar extent. The ED50 of tagraxofusp in pDCs from HV and SSc was 4.3 and 3.2 ng/ml (74.4 and 55.4 pM), respectively. There was no effect observed on B or T cells across the tagraxofusp dose range tested. SSc pDC survival following 24 h incubation with tagraxofusp demonstrated a similar ED50 in both CpG- stimulated and unstimulated pDCs (n=5) but no effect on B/T cells or monocytes (A). Concurrent with the decline in pDC survival, reductions in CpG- induced IFN production and expression of the IFN- a- induced gene, GBP, were observed. This was further accompanied by a 68- fold reduction in secreted IFN- α and a 3- fold downregulation of GBP, a type 1 IFN- induced gene [70]

Immunogenicity

Summary

In a phase I study that involved patients with acute myeloid leukemia or myelodysplasia, pretreatment anti-diphtheria toxin antibody levels ranged from 0–9.6 ug/mL (mean = 2.3 ug/mL). After one cycle of tagraxofusp at doses between 4 and 12.5 ug/kg, day-15 antibody levels were 0–600 ug/mL (mean = 92 ug/mL); day-30 antibody levels were 1.1–306 ug/mL (mean = 82 ug/mL) [96] .

Therapeutic Trials

Phase II

Results from the phase II trial demonstrated decrease in minimal residual disease (MRD) in a patient with acute myeloid leukaemia (AML) in remission with MRD. The patient was treated at 12 ug/kg/day and then went on to stem cell transplant [48] .

Phase I/II

The primary endpoint was met in a phase II trial of tagraxofusp in blastic plasmacytoid dendritic cell neoplasm (BPDCN). Median overall survival (OS) was not reached in first-line BPDCN, including stages 1-2 and 3 at a dosage of 12 ug/kg/day (n=29) (range: 0.2 to 42.0 months, with median follow-up of 23.0 months [range: 0.2 to 41+ months]). The CR/CRc rate was 53.8% (7/13) (95% CI: 25.1, 80.8). The median duration of CR/CRc was not reached (range: 3.9 to 12.2 months).The results from the study included, in stages 1, 2 and 3 of the trial, the overall response rate (ORR) for BPDCN patients (n=45) was 82%, with a complete response (CR) rate of 60%. In first-line BPDCN patients (n=32) receiving tagraxofusp an overall response rate was 90% (26/29) (95% CI: 72.6, 97.8), complete response (CR) rate observed was 72% (21/29) (95% CI: 52.8, 87.3) plus CRc plus CRi (complete response + clinical CR [CR with residual skin abnormality] plus CR with incomplete bone marrow recovery), treated at all tested doses. A median duration of CR/CRc was not reached (range: 1.3 to 32.2 months), and 45% (13/29) of the patients were bridged to stem cell transplant (SCT). The first trial cohort recruited 13 patients with untreated BPDCN, and seven patients (54%) achieved CR or CR with a skin abnormality not indicative of active disease (CRc). The second cohort enrolled 15 patients with relapsed or refractory BPDCN, and one patient achieved CR and one patient achieved CRc [91] [5] . In relapsed/refractory patients, the ORR was 69% (9/13), with a 38% (5/13) CR + CRc + CRi rate, and one patient was bridged to stem cell transplant. In the stage 3 pivotal cohort, at a dosage of 12ug/kg/day, the primary endpoint was met, with a 54% (7/13) CR + CRc rate [95% CI: 25.1, 80.8], wherein the lower bound of the interval exceeded the pre-specified rate of 10%. In this cohort, an ORR of 77% (10/13) was seen and 46% (6/13) patients were bridged to SCT. Earlier results showed that, out of 16, first-line BPDCN patients treated at 12ug/kg/day, 11 patients were relapse-free (range: 1+ to 20+ months, ongoing). This included four patients receiving tagraxofusp therapy (range: 1+ to 15+ months, ongoing), six patients in durable remission from tagraxofusp, who were then successfully bridged to stem cell transplant (SCT) and remained in remission (range: 5+ to 20+ months progression-free after first tagraxofusp dose), and one additional patient undergoing SCT preparation. In the relapsed/refractory setting, 46% patients were relapse-free (range: 1+ to 7+ months). This included five patients receiving tagraxofusp therapy (range: 1+ to 4+ months, ongoing) and one patient in durable remission from tagraxofusp who was then successfully bridged to SCT and was in remission for approximately 8+ months, ongoing. The median progression-free and overall survival for first-line was not reached and for relapsed/refractory it was 8.5 months [30] [31] [25] [39] . Previously reported data for 24 evaluable patients showed that 89% ORR was observed, with a 100% ORR in first-line patients, and a 71% ORR in relapsed/refractory patients, including one compassionate use patient. In the 12 evaluable first-line patients, there were nine complete responses (CR), and two clinical complete responses (CRC). In the 10 evaluable first-line patients treated at 12 ug/kg/day, the CR/CRc rate was 100% (eight CR and two CRc). In the seven evaluable relapsed/refractory BPDCN patients, including one treated on a compassionate use basis, one CR and one CRc (29% CR/CRc rate) and three partial responses (PR) were observed. In the first-line BPDCN patients treated at 12 ug/kg/day, 75% (9/12) patients remained relapse-free (1+-13+ months), including five patients receiving ongoing tagraxofusp therapy (1+-9+ months; 1+-12+ cycles), and four patients who were successfully bridged to stem cell transplant (SCT) and remained in remission (6+-13+ months after the first dose of tagraxofusp and 1+-7+ months post-SCT). In the relapse/refractory patients, 43% were progression-free and receiving ongoing tagraxofusp (0.5+-3+ months) [32] . Previous data from a lead-in expansion stage of a pivotal phase I/II trial in BPDCN of tagraxofusp had demonstrated an overall response rate of 86%, with a 100% ORR in first-line BPDCN and a 60% ORR in relapsed/refractory BPDCN. There were four CR and four CRc, and 4 PR at all doses in all patients. At 12 ug/kg/day dose in all patients, 3 CR’s, 4 CRc’s and 3 PR’s were achieved. In first -line BPDCN patients, 4 CR’s, 4 CRc’s and 1 PR was observed at all doses and three PR’s were observed in relapsed/refractory (r/r) BPDCN patients. Of the nine evaluable BPDCN responders treated at 12 ug/kg/day, five patients (including two relapsed/refractory patients) remain in remission receiving tagraxofusp therapy and two additional patients were successfully bridged to stem cell transplant (SCT) [33] . Initial data from the pivotal study demonstrated that, out of 5 patients with BPDCN, 3 patients achieved major responses including complete responses at the multi-cycle dose-schedule of 12 ug/kg/day of tagraxofusp . Lower doses also showed major responses. The phase I/II study intends to enrol 60 patients of either blastic plasmacytoid dendritic cell neoplasm (BPDCN) or acute myeloid leukaemia (AML) [34] .

In a phase I/II trial in patients with multiple myeloma, the combination of pomalidomide (POM) and dexamethasone (DEX) about 56% of patients (5/9) had partial responses (PRs) [65] [55]

Updated results from the phase I/II trial demonstrated that 45% (9/20) of patients had symptom burden reduction, including 3 with symptom response per IWG-MRT 2013 MF response criteria. There were 53% (8/15) of patients with baseline splenomegaly >= 5cm who experienced a spleen size reduction; 20% (3/15) had a reduction >35% (specifically 100%, 47% and 46% reductions). About 100% (5/5) of patients with CMML-type features/monocytosis experienced a spleen size reduction, and 40% (2/5) of these patients had a reduction >35%. About 64% (7/11) of patients with thrombocytopenia (platelet count < 100x109/L) experienced a spleen size reduction, and 18% (2/11) had a reduction >35%; 60% (3/5) of patients with thrombocytopenia (platelet count < 50x109/L) experienced a spleen size reduction, and 20% (1/5) had a reduction >35% [55] . Earlier results demonstrated from the trial evaluating tagraxofusp in 18 myeloproliferative disorders patients demonstrated improvements in splenomegaly. During the trial, three patients achieved bone marrow complete responses, including 1 patient bridged to SCT in remission. Earlier, the median platelet count was 66K/uL (range 15 - 579). During the trial, 70% (14/20) of patients had baseline platelets < 100K/uL, of which six patients had platelets < 50K/uL at study entry. Updated data from the trial showed that treatment with tagraxofusp in patients (n=16) with relapsed/refractory chronic myelomonocytic leukaemia (CMML) reduced spleen size in 100% (8/8) patients with baseline splenomegaly and 2 bone marrow complete responses (BMCRs), including 75% who had reduction in splenomegaly of 50% or more. 60% of patients with baseline spleen size ≥5cm had reduction in splenomegaly of 50% or more. Two patients treated with tagraxofusp achieved bone marrow complete responses. In 57% (8/14) of patients with baseline spleen ≥5cm BCM spleen responses, 43% (6/14) had ≥29% and 21% (3/14) had ≥45% reduction of spleen size. Also, in 100% of patients with baseline spleen ≥5cm and monocytosis splenomegaly reductions, it was reported that 80% (4/5) had ≥29% and 40% (2/5) had ≥45%. 43% (6/14) of evaluable patients had a treatment duration of 6 months or more, including one at 8+ and one at 14+ months. During the trial, 89% (17/19) of patients had baseline splenomegaly defined as palpable spleen 5cm or more below costal margin (BCM) by physical exam. Five patients out of 18 patients were treated in the second line setting and 12 patients were treated in third-line setting, and beyond. Median age was 69 years (range 55-81); 60% patients were female. Of the 18 patients with DIPSS Plus risk group assessment available, three patients (17%) were intermediate-1, 10 patients (55%) were intermediate-2, and 5 patients (28%) were high-risk. Earlier tagraxofusp demonstrated spleen reductions and symptom improvement in subsets of patients myelofibrosis (n = 14) as well as chronic myelomonocytic leukaemia (n = 14). In myelofibrosis subset, treatment tagraxofusp showed spleen reductions 25% (range 29-100%) in six of 11 (55%) patients with baseline splenomegaly, including three patients (27%) with spleen reductions 35%, by physical exam. Baseline to best response was recorded as 5 to 0cm (100%), 19 to 10cm (47%), 35 to 19cm (46%), 30 to 20cm (33%), 17 to 12 cm (29%), and 14 to 10cm (29%) BCM. In patients with platelets <100K/uL, five spleen reductions occurred including one patient with a platelet count <50K/uL (100% spleen reduction). There was total symptom score (TSS) (range: 25%>100%) in 75% (9 of 12) of evaluable patients, out of which four patients (33%) had >50% TSS reduction. Median overall survival was not reached (median follow-up 6.5 months; range 0.1-20.6+ months). Earlier data had shown that 60% patients (n = 12) with baseline splenomegaly had spleen reductions of equal to 50% (range: 29-100%), including 33% with spleen reductions equal to 33% and 25% with spleen reductions equal to 35%. Notably, two of these three patients had baseline thrombocytopenia prior to administration of tagraxofusp : 1 patient with platelets <100K/microliter and 1 patient with platelets <50K/microliter. In chronic myelomonocytic leukaemia subset, there was 50% reduction in spleen size in 71% (5 of 7) of patients with baseline splenomegaly. Baseline splenomegaly of 5, 4, 2, and 2cm reduced to 0cm (100%) BCM and 20cm reduced to 10cm (50%) BCM. BM complete response was seen in 17% (2 of 12) of evaluable patients including one CR (15 months on treatment) and one BMCR (4+ months on treatment, ongoing) [41] [42] [43] [92] [44] [45] [46] [47] [23] [48] . Updated data from 27 (17 evaluable patients with baseline splenomegaly) showed that spleen size reductions were observed in 53% of patients, of which 4 patients had reductions of > 45%. In 5 patients with baseline splenomegaly and monocytosis (>1x109/L monocytes), 80% (4/5) had spleen size reductions, of which 2 had reductions of >45%. Objective responses (IWG-MRT 2013 responses) were observed in 7 patients including clinical improvement (CI) in 5 patients and and CI (Symptom) in 2 patients. Symptom response rate was 45% (defined as 50% reduction in TSS score). Reductions in both symptom score and spleen size was noted in 6/6 patients who had splenomegaly at baseline [56] [53] .

An overall response rate of 86% was reported in a total of eight patients (seven evaluable) with BPDCN treated with a single, 5-day cycle of tagraxofusp. Of the eight patients, five achieved a complete response, and one achieved a partial response. One of the patients with a complete response that lasted several months was retreated with tagraxofusp following relapse; in this patient, skin lesions cleared but disease progression subsequently developed in the bone marrow off-therapy [68] .

Data from a phase I/II trial showed that a single cycle of treatment with intravenously administered tagraxofusp resulted in two durable complete responses (CRs) of eight and >25 months duration, respectively, in patients with relapsed or refractory acute myeloid leukaemia (AML) (NCT00397579). There was an overall survival (OS) benefit observed in patients receiving one cycle of tagraxofusp, who were ≥third-line therapy for AML (n=35); the median OS for these patients was 3.6 months compared with the historical median OS data of 1.5 months for the third-line therapy in AML with standard of care. Moreover, at therapeutically relevant doses, defined as the MTD (16.6 µg/kg/day) or lower doses (9.4 or 12.5 µ/kg/day), the median OS after one cycle of tagraxofusp was 5.6 months for the third-line AML patients (n = 16). The median CR after a single cycle of tagraxofusp was 5 months. Additionally, two patients with relapsed/refractory BPDCN achieved two additional durable CRs after one cycle of tagraxofusp. Malignant blasts were no longer detectable in the bone marrow or plasma in BPDCN patients with CRs. Of the four patients experiencing remission, one was in remission for a period of over 20 months [62] [63] .

Phase I

Tagraxofusp was associated with two durable complete remissions, multiple blast reductions and disease stabilizations in patients with relapsed, refractory, or poor risk acute myeloid leukaemia in a phase I study. An earlier analysis reported 2 partial and 3 minor responses [57] [2] . Interim results from a phase I study, in which patients received one cycle of tagraxofusp at doses between 4 and 12.5 ug/kg, showed that among 38 evaluable patients with acute myeloid leukaemia, there was one complete response of 8 months duration, 2 partial remissions lasting 1 and 3 months, and 3 minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90%, and 90% lasting 1 to 2 months. In one evaluable patient with myelodysplasia, a partial response was achieved that lasted 4 months with improvement in haematologic parameters and conversion to transfusion independence [96] .

Future Events

Expected Date Event Type Description Updated
30 Jun 2020 Trial Update Stemline Therapeutics plans a clinical trial for Acute myeloid leukaemia (Combination therapy) in by the first half of 2020 (700310067) [11] 21 Aug 2019
30 Jun 2020 Regulatory Status Stemline Therapeutics announces intention to launch tagraxofusp for Blastic plasmacytoid dendritic cell neoplasm in Europe in mid 2020 [11] 06 Aug 2019
31 Mar 2020 Regulatory Status Stemline Therapeutics expects to receive an opinion by the Committee for Medicinal Products for Human Use (CHMP) for Blastic plasmacytoid dendritic cell neoplasm in the first quarter of 2020 [15] 21 Nov 2019
31 Mar 2020 Trial Update Stemline Therapeutics plans a phase I/II trial for Blastic plasmacytoid dendritic cell neoplasm (Maintenance therapy) in Q1 2020 [54] 17 Jan 2020
30 Jun 2019 Regulatory Status Stemline Therapeutics intends to provide registration-directed plans for tagraxofusp in Chronic myelomonocytic leukaemia in mid year 2019 (9266823) 15 May 2019
31 Mar 2019 Regulatory Status Stemline Therapeutics expects approval of Biologics License Application (BLA) for Blastic plasmacytoid dendritic cell neoplasm in USA in first quarter of 2019 [94] 09 Jan 2019
31 Mar 2019 Regulatory Status Stemline Therapeutics announces intention to submit MAA to EMA for Blastic plasmacytoid dendritic cell neoplasm in the first quarter of 2019 [93] 01 Feb 2019
21 Feb 2019 Regulatory Status FDA assigns PDUFA action date of 21/02/2019 for tagraxofusp for Acute myeloid leukaemia [6] 26 Dec 2018
31 Jan 2019 Regulatory Status Tagraxofusp will be commercially available for appropriate patients with blastic plasmacytoid dendritic cell neoplasm, through the Stemline ARC™ program, in early 2019 [91] 26 Dec 2018
30 Jun 2018 Regulatory Status Stemline Therapeutics expects to complete submission of a rolling Biologics License Application (BLA) for Blastic plasmacytoid dendritic cell neoplasm in the second quarter of 2018 (9240075) [47] 09 Jan 2019

Development History

Event Date Update Type Comment
17 Mar 2020 Trial Update Stemline Therapeutics initiates enrolment in a phase I/II trial for Blastic plasmacytoid dendritic cell neoplasm (Maintenance therapy) [66] Updated 19 Mar 2020
13 Jan 2020 Trial Update Stemline Therapeutics plans a phase I/II trial for Blastic plasmacytoid dendritic cell neoplasm (Maintenance therapy) in Q1 2020 [54] Updated 17 Jan 2020
07 Dec 2019 Scientific Update Updated efficacy and adverse events data from a phase I/II trial in Myelofibrosis and Multiple myeloma presented at the 61st Annual Meeting and Exposition of the American Society of Haematology (ASH-Hem 2019) [56] [55] Updated 16 Dec 2019
07 Dec 2019 Scientific Update Pharmacodynamics data from preclinical studies in Myeloproliferative disorders presented at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2019) [75] Updated 12 Dec 2019
08 Nov 2019 Scientific Update Pharmacodynamics data from preclinical studies in Systemic scleroderma presented at the 83rd American College of Rheumatology and the 54th Association of Rheumatology Health Professionals Annual Scientific Meeting (ARP/ARHP-2019) [70] Updated 07 Feb 2020
07 Nov 2019 Regulatory Status Stemline Therapeutics expects to receive an opinion by the Committee for Medicinal Products for Human Use (CHMP) for Blastic plasmacytoid dendritic cell neoplasm in the first quarter of 2020 [15] Updated 21 Nov 2019
06 Aug 2019 Regulatory Status The Centers for Medicare & Medicaid Services grants approval for a new technology add-on payment (NTAP) for tagraxofusp for Blastic plasmacytoid dendritic cell neoplasm (In adolescents, In adults, In children) [16] Updated 10 Aug 2019
02 Aug 2019 Regulatory Status Stemline Therapeutics receives a regulatory clearance for a phase II trial in Blastic plasmacytoid dendritic cell neoplasm [11] Updated 21 Nov 2019
02 Aug 2019 Trial Update Stemline Therapeutics plans a clinical trial for Acute myeloid leukaemia (Combination therapy) in by the first half of 2020 [11] Updated 21 Aug 2019
02 Aug 2019 Regulatory Status Stemline Therapeutics announces intention to launch tagraxofusp for Blastic plasmacytoid dendritic cell neoplasm in Europe in mid 2020 [11] Updated 06 Aug 2019
02 Aug 2019 Trial Update Stemline Therapeutics initiates a global early-access programme for Blastic plasmacytoid dendritic cell neoplasm [11] Updated 06 Aug 2019
02 Aug 2019 Trial Update Stemline Therapeutics plans a investigator sponsored phase II trial for Blastic plasmacytoid dendritic cell neoplasm (Maintenance therapy) [11] Updated 06 Aug 2019
13 Jun 2019 Scientific Update Safety data from a phase I/II trial in Myeloproliferative disorders presented at the 24th Congress of the European Haematology Association (EHA-2019) [40] [90] Updated 29 Aug 2019
31 May 2019 Scientific Update Updated safety and efficacy data from a phase I/II trial in Myeloproliferative disorders presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO-2019) [42] [41] Updated 08 Jun 2019
27 May 2019 Patent Information Stemline Therapeutics has pending patents for tagraxofusp in USA [3] Updated 27 May 2019
15 May 2019 Patent Information Stemline Therapeutics has patent protection for tagraxofusp in USA and countries outside the US Updated 27 May 2019
10 May 2019 Regulatory Status Stemline Therapeutics intends to provide registration-directed plans for tagraxofusp in Chronic myelomonocytic leukaemia in mid year 2019 Updated 15 May 2019
30 Jan 2019 Phase Change - Marketed Launched for Blastic plasmacytoid dendritic cell neoplasm (In adolescents, In children, In adults) in USA (IV) [4] Updated 01 Feb 2019
30 Jan 2019 Regulatory Status European Medicines Agency completes its validation of the Marketing Authorization Application of tagraxofusp for Blastic plasmacytoid dendritic cell neoplasm [4] Updated 01 Feb 2019
28 Jan 2019 Phase Change - No development reported No recent reports of development identified for preclinical development in Hairy-cell-leukaemia in USA (IV, Infusion) Updated 28 Jan 2019
07 Jan 2019 Phase Change - Preregistration Preregistration for Blastic plasmacytoid dendritic cell neoplasm in European Union (IV) [12] Updated 09 Jan 2019
21 Dec 2018 Phase Change - Registered Registered for Blastic plasmacytoid dendritic cell neoplasm (In adults, In adolescents, In children) in USA (IV) [5] [91] - First global approval Updated 09 Jan 2019
21 Dec 2018 Regulatory Status Tagraxofusp will be commercially available for appropriate patients with blastic plasmacytoid dendritic cell neoplasm, through the Stemline ARC™ program, in early 2019 [91] Updated 26 Dec 2018
21 Dec 2018 Scientific Update Updated efficacy data from a phase I/II trial in Blastic plasmacytoid dendritic cell neoplasm released by Stemline Therapeutics (9257376; 9257389) Updated 26 Dec 2018
01 Dec 2018 Scientific Update Pharmacodynamics data from a preclinical trial in Myeloproliferative disorders presented at the 60th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2018) [92] Updated 08 Jan 2019
01 Dec 2018 Scientific Update Updated efficacy and adverse events data from a phase I/II trial in Myeloproliferative disorders (Late-stage disease) presented at the 60th Annual Meeting and Exposition of the American Society of Haematology (ASH-Hem-2018) [43] Updated 08 Jan 2019
01 Dec 2018 Scientific Update Efficacy and adverse events data from a phase I/II trial in Myeloproliferative disorders presented at the 60th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2018) [44] Updated 05 Jan 2019
22 Nov 2018 Regulatory Status European Medicines Agency grants accelerated assessment for the upcoming centralized Marketing Authorization Application for tagraxofuspin in Acute myeloid leukaemia [13] Updated 22 Nov 2018
08 Nov 2018 Regulatory Status Stemline Therapeutics announces intention to submit MAA to EMA for Blastic plasmacytoid dendritic cell neoplasm in the first quarter of 2019 [93] Updated 01 Feb 2019
08 Nov 2018 Regulatory Status Stemline Therapeutics plans to launch tagraxofusp for Blastic plasmacytoid dendritic cell neoplasm [93] Updated 16 Nov 2018
13 Aug 2018 Regulatory Status FDA assigns PDUFA action date of 21/02/2019 for tagraxofusp for Acute myeloid leukaemia [6] Updated 26 Dec 2018
13 Aug 2018 Regulatory Status US FDA grants Priority Review for tagraxofusp in Acute myeloid leukaemia [6] Updated 16 Aug 2018
09 Aug 2018 Regulatory Status Stemline Therapeutics expects approval of Biologics License Application (BLA) for Blastic plasmacytoid dendritic cell neoplasm in USA in first quarter of 2019 [94] Updated 09 Jan 2019
25 Jun 2018 Regulatory Status Stemline Therapeutics completes rolling BLA submission to the US FDA for Blastic plasmacytoid dendritic cell neoplasm [7] Updated 26 Jun 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
18 Jun 2018 Scientific Update Updated adverse events data from a phase I/II trial in Chronic myeloid leukaemia released by Stemline Therapeutics Updated 21 Jun 2018
15 Jun 2018 Scientific Update Pharmacodynamics data from a preclinical trial in Blastic plasmacytoid dendritic cell neoplasm released by Stemline Therapeutics [73] Updated 19 Jun 2018
14 Jun 2018 Scientific Update Updated adverse events and efficacy data from a phase I-II trial in Myeloproliferative disorders presented at the 23rd Congress of the European Haematology Association (EHA-2018) [45] [46] Updated 18 Jul 2018
13 Jun 2018 Phase Change - Preclinical Preclinical trials in Systemic scleroderma in USA (IV) before June 2018 [72] Updated 12 Jul 2018
13 Jun 2018 Scientific Update Pharmacodynamics data from a preclinical trial Blastic plasmacytoid dendritic cell neoplasm and systemic scleroderma in at the 19th Annual Congress of the European League Against Rheumatism (EULAR-2018) [72] Updated 12 Jul 2018
13 Jun 2018 Trial Update Stemline Therapeutics plans a clinical trial for Systemic scleroderma [72] Updated 12 Jul 2018
05 Apr 2018 Phase Change - Preregistration Preregistration for Blastic plasmacytoid dendritic cell neoplasm in USA (IV) [8] Updated 09 Jan 2019
16 Mar 2018 Regulatory Status Stemline Therapeutics expects to complete submission of a rolling Biologics License Application (BLA) for Blastic plasmacytoid dendritic cell neoplasm in the second quarter of 2018 [14] [47] Updated 09 Jan 2019
16 Mar 2018 Scientific Update Efficacy data from a phase I/II trial in Myeloproliferative neoplasms released by Stemline Therapeutics [47] Updated 22 Mar 2018
13 Dec 2017 Scientific Update Updated adverse events data from a phase I/II trial in Acute myeloid leukaemia released by Stemline Therapeutics [23] Updated 18 Dec 2017
13 Dec 2017 Scientific Update Updated efficacy and adverse events data from a phase I/II trial in Myelofibrosis and Chronic myelomonocytic leukaemia released by Stemline Therapeutics [23] Updated 18 Dec 2017
13 Dec 2017 Scientific Update Updated efficacy and adverse events data from a phase II trial in Blastic plasmacytoid dendritic cell neoplasm released by Stemline Therapeutics [23] Updated 18 Dec 2017
16 Nov 2017 Trial Update Stemline Therapeutics completes enrolment in its phase II trial for Blastic plasmacytoid dendritic cell neoplasm in USA [28] Updated 22 Nov 2017
31 Oct 2017 Scientific Update Pooled top-line adverse events data from clinical trials in Blastic plasmacytoid dendritic cell neoplasm, Myeloproliferative neoplasms and Multiple myeloma released by Stemline Therapeutics [30] Updated 03 Nov 2017
31 Oct 2017 Scientific Update Top-line efficacy data from a phase III trial in Blastic plasmacytoid dendritic cell neoplasm released by Stemline Therapeutics [30] Updated 03 Nov 2017
26 Jun 2017 Phase Change - I/II Phase I/II clinical trials in Acute myeloid leukaemia (Combination therapy) in USA (IV) (NCT03113643) Updated 04 Jan 2019
26 Jun 2017 Phase Change - I/II Phase-I/II clinical trials in Myelodysplastic syndromes (Combination therapy) in USA (IV) (NCT03113643) Updated 04 Jan 2019
23 Jun 2017 Scientific Update Safety and efficacy data from a phase II trial in Blastic plasmacytoid dendritic cell neoplasm released by Stemline Therapeutics [31] Updated 10 Jul 2017
06 Jan 2017 Regulatory Status Stemline Therapeutics announces intention to submit BLA to US FDA in 2H2017 [10] Updated 16 Jan 2017
06 Dec 2016 Scientific Update Safety and efficacy results from the phase II trials in Acute myeloid leukaemia and Myeloproliferative disorders presented at the 58th Annual Meeting and Exposition of the American Society of Haematology (ASH-Hem-2016 (9208402) [49] Updated 15 Dec 2016
05 Dec 2016 Scientific Update Safety and efficacy data from a phase II trial in Blastic plasmacytoid dendritic cell neoplasm presented at the 58th Annual Meeting of American Society of Haematology (ASH-2016) [25] Updated 13 Dec 2016
03 Dec 2016 Scientific Update Pharmacokineics and pharmacodynamics data from in vitro studies in Haematological malignancies presented at the 58th Annual Meeting and Exposition of the American Society of Haematology (ASH-2016) [77] Updated 02 Feb 2017
03 Dec 2016 Scientific Update Adverse events data from a phase I trial in Multiple myeloma presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2016) [95] Updated 27 Jan 2017
02 Dec 2016 Phase Change - Preclinical Preclinical trials in Haematological malignancies (Combination therapy) in USA (IV) [78] Updated 07 Dec 2016
02 Dec 2016 Phase Change - Preclinical Preclinical trials in Multiple myeloma (Combination therapy) in USA (IV) [78] Updated 07 Dec 2016
23 Aug 2016 Regulatory Status Tagraxofusp receives Breakthrough Therapy status for Blastic plasmacytoid dendritic cell neoplasm in USA [17] Updated 24 Aug 2016
16 Jul 2016 Phase Change - No development reported No recent reports of development identified for preclinical development in Chronic-myeloid-leukaemia in USA (IV, Infusion) Updated 16 Jul 2016
16 Jul 2016 Phase Change - No development reported No recent reports of development identified for preclinical development in Lymphoma in USA (IV, Infusion) Updated 16 Jul 2016
04 Jun 2016 Scientific Update Efficacy and safety data from a phase I/II trial in Acute myeloid leukaemia presented at the American Society of Clinical Oncology (ASCO-2016) [32] Updated 08 Jun 2016
19 May 2016 Phase Change - II Phase-II clinical trials in Blastic plasmacytoid dendritic cell neoplasm in USA (IV) [24] Updated 09 Jan 2019
19 May 2016 Phase Change - II Phase-II clinical trials in Acute myeloid leukaemia in USA (IV) [24] , NCT02113982) Updated 24 May 2016
14 Mar 2016 Trial Update Stemline Therapeutics initiates enrolment in a phase I/II trial for Acute myeloid leukaemia (First-line therapy) in USA (IV) [50] before March 2016 Updated 31 Mar 2016
14 Mar 2016 Trial Update Stemline Therapeutics plans a clinical trial in 2016 [50] Updated 31 Mar 2016
04 Jan 2016 Scientific Update Efficacy and adverse events data from a phase I/II trial in Blastic plasmacytoid dendritic cell neoplasm (BPDCN) presented at the 57th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem - 2015) [33] Updated 04 Jan 2016
01 Jan 2016 Phase Change - I/II Phase-I/II clinical trials in Multiple myeloma (Combination therapy, Second-line therapy or greater) in USA (IV) (NCT02661022) Updated 01 Feb 2016
02 Nov 2015 Regulatory Status Tagraxofusp receives Orphan Drug status for Blastic plasmacytoid dendritic cell neoplasm (BPDCN) in European Union [19] Updated 03 Nov 2015
10 Sep 2015 Regulatory Status Tagraxofusp receives Orphan Drug status for Acute myeloid leukaemia in European Union [20] Updated 11 Sep 2015
28 May 2015 Scientific Update Efficacy and adverse events data from a phase I/II trial in Blastic plasmacytoid dendritic cell neoplasm released by Stemline Therapeutics [34] Updated 12 Jun 2015
01 Feb 2015 Trial Update Stemline Therapeutics initiates enrolment in a phase I/II trial for Acute myeloid leukaemia (Second-line or greater therapy) in USA (NCT02270463) Updated 04 Jan 2019
16 Dec 2014 Phase Change - I/II Phase-I/II clinical trials in Myeloproliferative disorders (Late-stage disease) in Canada (IV) after December 2014 (NCT02268253) Updated 18 Jul 2018
16 Dec 2014 Phase Change - I/II Phase-I/II clinical trials in Myeloproliferative disorders (Late-stage disease) in USA (IV) (NCT02268253; 9172741) Updated 20 Dec 2014
05 Dec 2014 Phase Change - Preclinical Preclinical trials in Hairy cell leukaemia in USA (IV) Updated 29 Dec 2014
16 Oct 2014 Trial Update Stemline Therapeutics initiates a phase I/II study in Acute myeloid leukaemia (Second-line therapy or greater) in USA (NCT02270463; 9169678) Updated 20 Oct 2014
10 Oct 2014 Trial Update Stemline Therapeutics plans a phase I/II trial for Myeloproliferative disorders (Late-stage disease) in USA (NCT02268253) Updated 13 Nov 2014
09 Oct 2014 Trial Update Stemline Therapeutics plans a phase I/II trial for Acute myeloid leukaemia (Second-line or greater therapy) in USA (NCT02270463) Updated 15 Dec 2014
01 Sep 2014 Phase Change - I/II Phase-I/II clinical trials in Blastic plasmacytoid dendritic cell neoplasm in USA (IV) (NCT02113982) Updated 09 Jan 2019
01 Sep 2014 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia in USA (IV) (NCT02113982) Updated 11 Dec 2015
01 Sep 2014 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia in USA (IV) (NCT02113982) Updated 31 Jul 2014
28 Jul 2014 Trial Update Stemline Therapeutics completes a phase I/II trial in Acute myeloid leukaemia (Second-line therapy or greater) and Myelodysplastic syndromes (Second-line therapy or greater) in USA and Canada (NCT00397579; 9166188) Updated 31 Jul 2014
20 May 2014 Phase Change - Preclinical Preclinical trials in Multiple myeloma in USA (unspecified route) Updated 26 May 2014
20 May 2014 Scientific Update Pharmacodynamics data from preclinical studies in Multiple myeloma released by Stemline Therapeutics [80] Updated 26 May 2014
14 Nov 2013 Scientific Update Adverse events and efficacy data presented at the 55th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2013) [68] Updated 02 Dec 2013
10 Jun 2013 Regulatory Status Tagraxofusp receives Orphan Drug status for Blastic plasmacytoid dendritic cell neoplasm in USA [18] Updated 09 Jan 2019
10 Dec 2012 Scientific Update Updated efficacy data from a phase I/II trial in Haematological malignancies presented at the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH-2012) [63] Updated 12 Dec 2012
08 Nov 2012 Trial Update Stemline Therapeutics is advancing tagraxofusp into a phase IIb trial in refractory/relapsed Acute myeloid leukaemia [64] Updated 14 Nov 2012
09 Dec 2011 Phase Change - Preclinical Preclinical trials in Lymphoma in USA (unspecified route) Updated 09 Dec 2011
09 Mar 2011 Regulatory Status Tagraxofusp receives Orphan Drug status for Acute myeloid leukaemia in USA Updated 10 Mar 2011
01 Dec 2010 Phase Change - Preclinical Preclinical trials in Chronic myeloid leukaemia in USA (IV) Updated 02 Dec 2010
01 Dec 2010 Scientific Update Efficacy data from a phase I trial in acute myeloid leukaemia, and pharmacodynamics data from preclinical trials in Chronic Myeloid Leukaemia presented at the 52nd Annual Meeting and Exposition of the American Society of Hematology (ASH-2010) [57] Updated 02 Dec 2010
11 Dec 2007 Scientific Update Interim efficacy, adverse events, pharmacokinetics and immunogenicity data from a phase I trial in acute myeloid leukaemia and myelodysplasia presented at the 49th Annual Meeting and Exposition of the American Society of Hematology (ASH-2007) [96] Updated 16 Jan 2008
31 Jul 2006 Phase Change - I/II Phase-I/II clinical trials in Myelodysplastic syndromes in USA (IV) (NCT00397579) Updated 02 Dec 2010
31 Jul 2006 Phase Change - I/II Phase-I/II clinical trials in Acute myeloid leukaemia in USA (IV) (NCT00397579) Updated 09 Mar 2007
01 Jun 2006 Licensing Status Tagraxofusp licensed to Stemline Therapeutics worldwide Updated 09 Mar 2007
28 Jan 2000 Phase Change - Preclinical Preclinical trials in Leukaemia in Canada (unspecified) Updated 09 Mar 2007

References

  1. Stemline Therapeutics, Inc. and The Leukemia & Lymphoma Society Announce Collaboration to Accelerate the Development of SL-401 in Hematologic Cancers and Increase Awareness of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).

    Media Release
  2. Stemline Therapeutics In-Licenses Phase I Oncology Compound.

    Media Release
  3. Stemline Therapeutics SEC 10-K filing. Internet-Doc 2019;.

    Available from: URL: https://www.sec.gov/Archives/edgar/data/1264587/000110465919015293/a19-30101_110k.htm
  4. Stemline Therapeutics Announces Validation of Marketing Authorization Application (MAA) by the European Medicines Agency (EMA).

    Media Release
  5. FDA approves first treatment for rare blood disease.

    Media Release
  6. Stemline Therapeutics Announces that FDA Accepts ELZONRIS(T) Biologics License Application (BLA) and Grants Priority Review.

    Media Release
  7. Stemline Therapeutics Announces Completion of Rolling BLA Submission for ELZONRIS(Tm) (tagraxofusp; SL-401) for the Treatment of BPDCN.

    Media Release
  8. Stemline Therapeutics Announces Start of Rolling BLA Submission for SL-401.

    Media Release
  9. Stemline Therapeutics Provides Update on Pivotal BPDCN Trial.

    Media Release
  10. Stemline Therapeutics Announces Positive FDA Meeting and Agreement on Expedited Pathway to Full Approval of SL-401 in First-Line BPDCN.

    Media Release
  11. Stemline Therapeutics Reports Second Quarter 2019 Financial Results.

    Media Release
  12. Stemline Therapeutics Announces Submission of European Marketing Authorization Application (MAA) for ELZONRIS(Tm).

    Media Release
  13. Stemline Therapeutics Announces that European Medicines Agency (EMA) Grants Accelerated Assessment for planned ELZONRIS Marketing Authorization Application (MAA).

    Media Release
  14. Stemline Therapeutics Reports First Quarter 2018 Financial Results.

    Media Release
  15. Stemline Therapeutics Reports Third Quarter 2019 Financial Results.

    Media Release
  16. Stemline Therapeutics Announces that CMS Grants New Technology Add-on Payment (NTAP) to ELZONRIS(Rm) .

    Media Release
  17. Stemline Therapeutics Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for SL-401.

    Media Release
  18. Stemline Therapeutics' SL-401 Receives Orphan Drug Designation for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).

    Media Release
  19. Stemline Therapeutics Announces SL-401 Receives EU Orphan Drug Designation for Treatment of BPDCN.

    Media Release
  20. Stemline Therapeutics Announces SL-401 Receives EU Orphan Drug Designation for Treatment of Acute Myeloid Leukemia (AML).

    Media Release
  21. Stemline Therapeutics Receives Orphan Drug Designation for SL-401 for the Treatment of Acute Myeloid Leukemia.

    Media Release
  22. Stemline Therapeutics Closes $59.6 Million Public Offering of Common Stock.

    Media Release
  23. Stemline Therapeutics Presents Detailed SL-401 Pivotal Data in BPDCN at ASH and Kicks Off its BPDCN Awareness Campaign; Updated Results From Ongoing Trials in Additional Malignancies Also Presented.

    Media Release
  24. Stemline Therapeutics SL-401 Phase 2 BPDCN Data Selected for Oral Presentations at the Upcoming ASCO and EHA Meetings.

    Media Release
  25. Stemline Therapeutics SL-401 Phase 2 BPDCN Data Delivered Via Oral Presentation at ASH; High Response Rates Maintained Across All Lines.

    Media Release
  26. Stemline Therapeutics Announces Completion of Enrollment in Stage 3 of the SL-401 Pivotal Trial in BPDCN.

    Media Release
  27. Stemline Therapeutics Reports Fourth Quarter 2016 Financial Results.

    Media Release
  28. Stemline Therapeutics Announces Oral Presentation of SL-701 Phase 2 Data in Second-Line Glioblastoma at the 22nd Annual Meeting of the Society of Neuro-Oncology (SNO).

    Media Release
  29. Stemline Therapeutics Reports Second Quarter 2017 Financial Results.

    Media Release
  30. Stemline Therapeutics Announces that Pivotal Trial of SL-401 in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Meets Primary Endpoint.

    Media Release
  31. Stemline Therapeutics Presents SL-401 Updated Stage 1 and 2 Data from Ongoing Pivotal Trial in BPDCN and Safety Experience Across Multiple Indications, Today at EHA.

    Media Release
  32. Stemline Therapeutics SL-401 Phase 2 BPDCN Data Delivered Via Oral Presentation at ASCO; High Response Rates Demonstrated Across All Lines As Enrollment Proceeds.

    Media Release
  33. Stemline Therapeutics Presents Clinical Update From Ongoing SL-401 Pivotal BPDCN Trial at the American Society of Hematology (ASH) Annual Meeting.

    Media Release
  34. Stemline Therapeutics Announces Top-Line Results From Lead-In Stage of Ongoing BPDCN Pivotal Trial.

    Media Release
  35. Stemline Therapeutics In-Licenses Novel Oral Small Molecule Nuclear Transport Inhibitor Targeting XPO1.

    Media Release
  36. Stemline Therapeutics Announces Opening of SL-401 Corporate IND and Start of Clinical Trials in BPDCN and AML.

    Media Release
  37. Stemline Therapeutics' Lead Clinical Candidate, SL-401, Induces Another Complete Response in a Patient with a Drug-Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm.

    Media Release
  38. Stemline Therapeutics Reports Third Quarter 2014 Financial Results and Provides Corporate Update.

    Media Release
  39. SL-401 in Patients With Acute Myeloid Leukemia (AML) and Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

    ctiprofile
  40. Pemmaraju N, Ali H, Gupta V, Yacoub A, Schiller G, Lee S, et al. Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (Sl-401) in Patients with Intermediate, or High Risk, Relapsed/Refractory Myelofibrosis. EHA-2019 2019; abstr. PF668.

    Available from: URL: https://library.ehaweb.org/eha/2019/24th/266467/naveen.pemmaraju.results.from.ongoing.phase.1.2.clinical.trial.of.tagraxofusp.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1550
  41. Patnaik MM, Ali H, Gupta V, Schiller GJ, Lee S, Yacoub A, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with relapsed/refractory chronic myelomonocytic leukemia (CMML). ASCO-2019 2019; abstr. 7059.

    Available from: URL: http://abstracts.asco.org/239/AbstView_239_270203.html
  42. Pemmaraju N, Ali H, Gupta V, Schiller GJ, Lee S, Yacoub A, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with intermediate or high risk relapsed/refractory myelofibrosis. ASCO-2019 2019; abstr. 7058.

    Available from: URL: http://abstracts.asco.org/239/AbstView_239_269823.html
  43. Patnaik MM, Ali H, Gupta V, Schiller GJ, Lee S, Yacoub A, et al. Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Relapsed/Refractory Chronic Myelomonocytic Leukemia (CMML). ASH-Hem-2018 2018; abstr. 1821.

    Available from: URL: https://ash.confex.com/ash/2018/webprogram/Paper119302.html
  44. Pemmaraju N, Gupta V, Schiller GJ, Lee S, Yacoub A, Ali H, et al. Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate or High Risk Relapsed/Refractory Myelofibrosis. ASH-Hem-2018 2018; abstr. 1773.

    Available from: URL: https://ash.confex.com/ash/2018/webprogram/Paper119201.html
  45. Pemmaraju N, Gupta V, Schiller G, Lee S, Yacoub A, Ali H, et al. Results from Ongoing Phase 1/2 Trial of Sl-401 in Patients with Intermediate or High Risk Relapsed/Refractory Myelofibrosis. EHA-2018 2018; abstr. PF618.

    Available from: URL: http://link.adisinsight.com/Ag4a5
  46. Patnaik M, Ali H, Gupta V, Schiller G, Lee S, Yacoub A, et al. Results from Ongoing Phase 1/2 Trial of Sl-401 in Patients with Relapsed/Refractory Cmml. EHA-2018 2018; abstr. PF626.

    Available from: URL: http://link.adisinsight.com/r9DTf
  47. Stemline Therapeutics Reports Fourth Quarter 2017 Financial Results.

    Media Release
  48. Stemline Therapeutics Presents SL-401 Lead-in Results from its Ongoing Phase 2 Trial in AML in Remission with MRD and Phase 2 Trial in High-Risk Myeloproliferative Neoplasms (MPN) at ASH.

    Media Release
  49. Patnaik MM, Gupta V, Gotlib JR, Carraway HE, Wadleigh M, Schiller GJ, et al. Results from Ongoing Phase 2 Trial of SL-401 in Patients with Advanced, High-Risk Myeloproliferative Neoplasms Including Chronic Myelomonocytic Leukemia. ASH-Hem-2016 2016; abstr. 4245.

    Available from: URL: http://www.bloodjournal.org/content/128/22/4245
  50. Stemline Therapeutics Reports Fourth Quarter 2015 Financial Results.

    Media Release
  51. Stemline Therapeutics Initiates SL-401 Clinical Trial in Four Rare Myeloproliferative Neoplasms.

    Media Release
  52. Stemline Therapeutics Announces FDA Acceptance of IND for SL-701, a Synthetic Multi-Peptide Vaccine Targeting Glioma Brain Tumors.

    Media Release
  53. Tagraxofusp (SL-401) in Patients With Chronic Myelomonocytic Leukemia (CMML) or Myelofibrosis (MF). [Prior Title: SL-401 in Patients With Advanced, High Risk Myeloproliferative Neoplasms (Systemic Mastocytosis, Advanced Symptomatic Primary Eosinophilic Disorder, Myelofibrosis, Chronic Myelomonocytic Leukemia).]

    ctiprofile
  54. Stemline Therapeutics Announces Preliminary 2019 Net Revenues for ELZONRIS(R)(tagraxofusp) and Highlights Commercial and Clinical Growth Drivers .

    Media Release
  55. Stemline Therapeutics Recaps ELZONRIS Clinical Data Presentations in Patients with Myelofibrosis (oral presentation) and Multiple Myeloma at the 61st American Society of Hematology (ASH) Annual Meeting.

    Media Release
  56. Pemmaraju N, Gupta V, Ali H, Yacoub A, Wang ES, Lee S, et al. Results from a Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate, or High Risk, Relapsed/Refractory Myelofibrosis. ASH-Hem-2019 2019; abstr. 558.

    Available from: URL: https://ash.confex.com/ash/2019/webprogram/Paper131217.html
  57. Stemline Therapeutics, Inc. Announces Presentations of SL-401 Clinical and Pre-Clinical Efficacy at the 52nd Annual Meeting of the American Society of Hematology (ASH).

    Media Release
  58. Stemline Therapeutics Initiates SL-401 Trial in AML Patients in First Complete Response With Minimal Residual Disease, the Second SL-401 Trial Initiated in 2H14.

    Media Release
  59. Lane AA, Sweet KL, Wang ES, Donnellan WB, Walter RB, Stein AS, et al. Results from Ongoing Phase 2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD). ASH-Hem-2016 2016; abstr. 215.

    Available from: URL: http://www.bloodjournal.org/content/128/22/215
  60. A Phase 1/2 Study of SL-401 as Consolidation Therapy for Adult Patients With Adverse Risk Acute Myeloid Leukemia in First CR, and/or Evidence of Minimal Residual Disease (MRD) in First CR

    ctiprofile
  61. Therapy Targeting the Interleukin-3 Receptor (IL3R) for Patients With Relapsed or Refractory and Elderly or Poor-Risk Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome With DTIL3 (IND 11314): a Phase I/II Clinical Trial.

    ctiprofile
  62. Stemline Therapeutics Provides Second Quarter 2014 Financial Results and Corporate Update.

    Media Release
  63. Stemline Therapeutics, Inc. Announces Presentations of SL-401 Updated Clinical Trial Results in Acute Myeloid Leukemia (AML) and Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) and SL-101 Preclinical Efficacy Data Against Hodgkin's Lymphoma at the 54th Annual Meeting of the American Society of Hematology (ASH).

    Media Release
  64. Stemline Therapeutics' Lead Clinical Candidate SL-401 Induces a Complete Response in a Patient with a Drug-Refractory Plasmacytoid Dendritic Cell Neoplasm.

    Media Release
  65. A Phase 1/2 Open Label Study of SL-401 in Combination With Pomalidomide and Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma

    ctiprofile
  66. Stemline Therapeutics Reports Fourth Quarter 2019 Financial Results.

    Media Release
  67. Phase 1 Study of SL-401 in Combination With Azacitidine or Azacitidine/Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia (AML) or in Treatment-Naive Subjects With AML Not Eligible for Standard Induction Therapy or in Subjects With High-Risk Myelodysplastic Syndrome (MDS)

    ctiprofile
  68. Stemline Therapeutics Announces Five Presentations at the American Society of Hematology (ASH) Annual Meeting, Including a Clinical Update of SL-401 in BPDCN.

    Media Release
  69. Stemline Therapeutics Announces Multiple Preclinical Presentations Highlighting Its Pipeline of IL-3R-Directed Therapeutics at the American Society of Hematology (ASH) Annual Meeting.

    Media Release
  70. Lindsay R, Chen J, Spiera R, Gordon J, Kioon M-DA, Barrat F, et al. CD123 + ?Plasmacytoid Dendritic Cells from Systemic Sclerosis Patients Are Susceptible to the Cytotoxic Activity of Tagraxofusp, a CD123- Targeted Therapy . ACR/ARHP-2019 2019; abstr. 1064.

    Available from: URL: https://www.rheumatology.org/Annual-Meeting
  71. Stemline Therapeutics Announces Presentation of ELZONRIS (tagraxofusp) Preclinical Data in Systemic Sclerosis, an Autoimmune Disorder, at EULAR Congress.

    Media Release
  72. Kioon M-DA, Lindsay R, Chen J, Gordon J, Spiera R, Barrat F, et al. Sl-401, a Novel Targeted Therapy Directed to the Interleukin-3 Receptor (Cd123), Kills Plasmacytoid Dendritic Cells from Systemic Sclerosis Patients. EULAR-2018 2018; abstr. FRI0398.

    Available from: URL: https://b-com.mci-group.com/Abstract/Statistics/AbstractStatisticsViewPage.aspx?AbstractID=402929
  73. Stemline Therapeutics Announces Presentation of ELZONRIS(T) (tagraxofusp; SL-401) Preclinical Data in Systemic Sclerosis, an Autoimmune Disorder, at EULAR Congress.

    Media Release
  74. Stemline Therapeutics Announces Four SL-401 Presentations at Upcoming ASH Meeting.

    Media Release
  75. Krishnan A, Pagane M, Roshal M, McGovern E, Stone-Molloy Z, Chen J, et al. Evaluation of Tagraxofusp (SL-401) Alone and in Combination with Ruxolitinib for the Treatment of Myeloproliferative Neoplasms. ASH-Hem-2019 2019; abstr. 2967.

    Available from: URL: https://ash.confex.com/ash/2019/webprogram/Paper129397.html
  76. Stemline Therapeutics Announces Oral Presentation of SL-401, a Clinical-Stage Targeted Therapy, Demonstrating Notable Preclinical Activity in an Additional Indication, Chronic Myeloid Leukemia (CML), at the 15th International Conference on CML.

    Media Release
  77. Gionco J, Chen J, Lindsay R, Macri V, Brooks CL. SL-401, a Targeted Therapy Directed to the Interleukin-3 Receptor (CD123), and SL-801, a Reversible Inhibitor of Exportin-1 (XPO1), Display Synergistic Anti-Tumor Activity Against Hematologic Malignancies in Vitro. ASH-Hem-2016 2016; abstr. 128:4724.

    Available from: URL: http://www.bloodjournal.org/content/128/22/4724
  78. Stemline Announces Seven Presentations, Including Oral Presentation of Updated SL-401 Phase 2 BPDCN Data, at the 2016 ASH Meeting this Weekend.

    Media Release
  79. Stemline Therapeutics, Inc. Announces Two Poster Presentations of SL-401 Efficacy Data Against Lymphoid Cancers at the 53rd Annual Meeting of the American Society of Hematology (ASH).

    Media Release
  80. Stemline Therapeutics Announces Presentation of SL-401 Preclinical Efficacy Data in Multiple Myeloma at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

    Media Release
  81. Stemline Therapeutics Announces Pricing of $76,250,000 Public Offering of Common Stock .

    Media Release
  82. Stemline Therapeutics Closes $92 Million Public Offering of Common Stock.

    Media Release
  83. Stemline Therapeutics Prices $51.8 Million Public Offering of Common Stock.

    Media Release
  84. Stemline Therapeutics Announces Proposed Public Offering of Common Stock- 2018.

    Media Release
  85. Stemline Therapeutics Prices $45 Million Public Offering of Common Stock.

    Media Release
  86. Stemline Therapeutics Reports Fourth Quarter 2014 Financial Results.

    Media Release
  87. Stemline Therapeutics Announces Proposed Public Offering of Common Stock.

    Media Release
  88. Stemline Therapeutics Prices $60 Million Public Offering of Common Stock.

    Media Release
  89. Stemline Therapeutics Reports Year-End 2012 Financial Results.

    Media Release
  90. Patnaik M, Ali H, Gupta V, Yacoub A, Schiller G, Lee S, et al. Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (Sl-401) in Patients with Relapsed/Refractory Chronic Myelomonocytic Leukemia (Cmml). EHA-2019 2019; abstr. PF672.

    Available from: URL: https://library.ehaweb.org/eha/2019/24th/266471/mrinal.patnaik.results.from.ongoing.phase.1.2.clinical.trial.of.tagraxofusp.html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1550
  91. FDA Approves ELZONRIS(T) (tagraxofusp), the First Treatment for Blastic Plasmacytoid Dendritic Cell Neoplasm and First CD123-Targeted Therapy.

    Media Release
  92. Krishnan A, Li B, Pagane M, McGovern E, Stone-Molloy Z, Chen J, et al. Evaluation of Combination Tagraxofusp (SL-401) and Hypomethylating Agent (HMA) Therapy for the Treatment of Chronic Myelomonocytic Leukemia (CMML). ASH-Hem-2018 2018; abstr. 1809.

    Available from: URL: https://ash.confex.com/ash/2018/webprogram/Paper120035.html
  93. Stemline Therapeutics Reports Third Quarter 2018 Financial Results.

    Media Release
  94. Stemline Therapeutics Reports Second Quarter 2018 Financial Results.

    Media Release
  95. Htut M, Gasparetto C, Zonder J, Martin TG, Scott EC, Chen J, et al. Results from Ongoing Phase 1/2 Trial of SL-401 in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma. ASH-Hem-2016 2016; abstr. 5696.

    Available from: URL: http://www.bloodjournal.org/content/128/22/5696
  96. Frankel AE, Smith ER, George TA, Liu JS, Lee J, Park SK, et al. Phase I study demonstrates activity and tolerability of diphtheria toxin interleukin-3 fusion protein in patients with AML and MDS. Blood 2007;110(11):273.

  97. Stemline Therapeutics Highlights Recent Clinical and Regulatory Developments and Details Upcoming Milestones following its Annual Shareholder Meeting .

    Media Release
Back to top