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Prospective, Controlled, Randomized, Multicenter Study to Compare the Efficacy of a Chloroquine Analog (GNS561), an Anti PD-1 (Nivolumab) and an Anti-interleukine-6 Receptor (Tocilizumab) vs Standard of Care in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 (COVID-19) Infection

Trial Profile

Prospective, Controlled, Randomized, Multicenter Study to Compare the Efficacy of a Chloroquine Analog (GNS561), an Anti PD-1 (Nivolumab) and an Anti-interleukine-6 Receptor (Tocilizumab) vs Standard of Care in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 (COVID-19) Infection

Status: Recruiting
Phase of Trial: Phase II

Latest Information Update: 12 May 2020

At a glance

  • Drugs GNS 561 (Primary) ; Nivolumab (Primary) ; Tocilizumab (Primary)
  • Indications COVID 2019 infections; Haematological malignancies; Pneumonia; Severe acute respiratory syndrome; Solid tumours
  • Focus Therapeutic Use
  • Acronyms IMMUNONCOVID; IMMUNONCOVID-20
  • Most Recent Events

    • 07 Apr 2020 New trial record
    • 03 Apr 2020 Status changed from not yet recruiting to recruiting.

Trial Overview

Purpose

This is a prospective, controlled, randomized, multicenter study whose goal is to compare the efficacy of a chloroquine analog (GNS561), an anti PD-1 (nivolumab) and an anti-interleukine-6 receptor (tocilizumab) versus standard of care in patients with advanced or metastatic cancer who have Sars-CoV-2 infection not eligible to a resuscitation unit.

Primary Endpoints

28-day survival rate

description: 28-day survival rate, defined by the proportion of patients still alive 28 days after randomization.
The 28-day survival rate will be described in each arm of each cohort.
time_frame: 28 days from randomization

Other Endpoints

Time to clinical improvement

description: Time to clinical improvement defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale (WHO-ISARIC) or live discharge from the hospital, whichever comes first.
time_frame: 28 days from randomization

Clinical status

description: Clinical status will be assessed using a 7-point ordinal scale :
Not hospitalized, no limitations on activities
Not hospitalized, limitation on activities;
Hospitalized, not requiring supplemental oxygen;
Hospitalized, requiring supplemental oxygen;
Hospitalized, on non-invasive ventilation or high flow oxygen devices;
Hospitalized, on invasive mechanical ventilation or ECMO;
Death.
time_frame: Day 7, Day 14, Day 28

Mean change in clinical status from baseline to days

description: Mean change in clinical status from baseline will be assessed using a 7-point ordinal scale.
time_frame: Day 7, Day 14, Day 28

Overall survival

description: Overall survival will be defined by the time from date of randomization until date of death, regardless of the cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
time_frame: 3 months (i.e. at the the time of last patient last visit)

Length of stay in Intensive Care Unit

description: The length of stay in Intensive Care Unit (from the date of admission in the Unit to the date of discharge).
time_frame: 3 months (i.e. at the the time of last patient last visit)

Duration of mechanical ventilation or high flow oxygen devices

description: The duration of mechanical ventilation or high flow oxygen devices (from the date of intubation to the stop date of mechanical ventilation or high flow oxygen)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Duration of hospitalization

description: The duration of hospitalization (from the date of hospitalization to the date of definitive discharge for live patients)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Rate of throat swab negativation

time_frame: Day 7, Day 14, Day 28

Quantitative SARS-CoV-2 virus in throat swab and blood samples

time_frame: Day 7, Day 14, Day 28

Rate of secondary infection by other documented pathogens

time_frame: Day 7, Day 14, Day 28 (if available)

Biological parameters

description: Changes from baseline in neutrophils count (G/L)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

description: Treatment-Emergent Adverse Events, Serious Adverse Events, Suspected Unexpected Serious Adverse Reactions, New Safety Issues described using the NCI-CTC AE classification v5.
Number of participants with a discontinuation or temporary suspension of study drugs (for any reason).
time_frame: 3 months (i.e. at the the time of last patient last visit)

Cost-Effectiveness Analyses (CEA)

description: Incremental Cost-Effectiveness Ratios (ICERs) expressed in cost per Life Year Gained.
time_frame: 3 months (i.e. at the the time of last patient last visit)

Biological parameters

description: Changes from baseline in lymphocytes count (G/L)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Biological parameters

description: Changes from baseline in platelets count (G/L)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Biological parameters

description: Changes from baseline in hemoglobin count (g/dL)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Biological parameters

description: Changes from baseline in CRP count (mg/L)
time_frame: 3 months (i.e. at the the time of last patient last visit)

Biological parameters

description: Changes from baseline in pro-inflammatory cytokine (IL6)
time_frame: 3 months (i.e. at the the time of last patient last visit) [1]

Diseases Treated

Indication Qualifiers Patient Segments
COVID 2019 infections treatment -
Haematological malignancies treatment stage III, stage IV
Pneumonia treatment -
Severe acute respiratory syndrome treatment -
Solid tumours treatment stage III, stage IV

Subjects

  • Subject Type patients
  • Number

    Planned: 273

  • Sex male & female
  • Age Group ≥ 18 years; adult; elderly

Patient Inclusion Criteria

I1. Age 18 or older at the time of enrolment. I2. Histologically or cytologically confirmed diagnosis of advanced or metastatic hematological or solid tumor (hematological or solid tumor, any type and any localization). I3. Documented diagnosis of COVID-19 (diagnostic test performed in a certified laboratory) or symptoms of COVID-19 associated with radiological signs of pneumonia as described by Shi et al.; I4. Cohort 2: patients with pneumonia confirmed by chest imaging, and an oxygen saturation (Sao2) of 94% or less while they are breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) (Pao2:Fio2) at or below 300 mg Hg. I5. Patient not eligible for a transfer to Resuscitation Unit (either due to underlying medical condition - including cancer - or due to lack of available bed). I6. Life-expectancy longer than 3 months. I7. Adequate bone marrow and end-organ function defined by the following laboratory results: - Bone marrow: - Hemoglobin ≥ 7.0 g/dL, - Absolute Neutrophils Count (ANC) ≥ 1.0 Gi/L, - Platelets ≥ 100 Gi/L; - Hepatic function: - Total serum bilirubin ≤ 1.5 x ULN (except patients with Gilbert's syndrome who must have total serum bilirubin ≤ 3.0 x ULN), - AST and ALT ≤ 5 ULN - Renal function: - Serum creatinine ≤ 2.0 x ULN or Cr. Cl. ≥ 30ml/min/1.73m² (MDRD or CKD-EPI formula); I8. Willingness and ability to comply with the study requirements; I9. Signed and dated informed consent indicating that the patient has been informed of all the aspects of the trial prior to enrolment (in case of emergency situation, please refer to protocol section 13.1 PATIENT INFORMATION AND INFORMED CONSENT); I10. Women of childbearing potential (Appendix 2) are required to have a negative serum pregnancy test within 72 hours prior to study treatment start. A positive urine test must be confirmed by a serum pregnancy test; I11. Women of childbearing potential and male patients must agree to use adequate highly effective contraception (Appendix 2) for the duration of study participation and up to 6 months following completion of therapy; I12. Patient must be covered by a medical insurance.

Patient Exclusion Criteria

E1. For cohort 1 only : Patient currently receiving therapy with an anti- PD-1, anti- PD-L1, or anti-CTLA4. E2. For cohort 2 only: Patient currently receiving therapy with an anti- IL-6 or anti-IL-6R. E3. Contraindication to treatment with nivolumab (cohort 1 only) or to tocilizumab (cohort 2 only) as per respective SPC, including known hypersensitivity to one of these study drugs or severe hypersensitivity reaction to any monoclonal antibody. E4. Patient known to have intolerance or hypersensitivity to chloroquine or any quinoline derivates (e.g., quinine, chloroquine, mefloquine). E5. Patient has active autoimmune disease that has required systemic treatment in the past 3 months before the date of randomisation or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids at doses higher than 10 mg/d prednisone equivalents or immunosuppressive agents. Note 1: Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the study. Note 2: Patients may receive corticosteroids as required for the management of SARS-CoV-2-related symptoms. E6. Patient requires the use of one of the following forbidden treatment during the study treatment period: - Major surgery. - Live vaccines. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever and BCG. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. E7. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to the date of randomisation unstable arrhythmias or unstable angina, Known Left Ventricular Ejection Fraction (LVEF) < 50%. Note: Patients with known coronary artery disease, congestive heart failure not meeting the above criteria must be on a stable medical regimen that is optimized in the opinion of the treating physician and in consultation with a cardiologist if appropriate. E8. Patient has Active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening), Active hepatitis C (Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA at screening) or Human Immunodeficiency Virus (HIV) infection (HIV 1/2 antibodies). E9. Prior allogeneic bone marrow transplantation or solid organ transplant in the past. E10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator. E11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. E12. Pregnant or breastfeeding patient, or expecting to conceive children within the projected duration of the trial, starting with the screening visit through 6 months after the last dose of study drugs.

Trial Details

Identifiers

Identifier Owner
NCT04333914 ClinicalTrials.gov: US National Institutes of Health
EudraCT2020-001373-70 European Clinical Trials Database
ET20-076 -
ET20-076IMMUNONCOVID20 -

Organisations

  • Affiliations Genoscience

Trial Dates

  • Initiation Dates

    Planned : 01 Apr 2020

    Actual : 15 Apr 2020

  • Primary Completion Dates

    Planned : 01 Jun 2020

  • End Dates

    Planned : 01 Aug 2020

Other Details

  • Design multicentre; open; parallel; prospective; randomised
  • Phase of Trial Phase II
  • Location France
  • Focus Therapeutic Use

Interventions

Drugs Route Formulation
GNS 561Primary Drug Oral Capsule
NivolumabPrimary Drug Intravenous Infusion, Injection
TocilizumabPrimary Drug Intravenous Infusion, Injection

Chloroquine analog (GNS651)

Drug: Chloroquine analog (GNS651) (Cohort 1 (arm B): 200mg bid loading dose for 2 days then, 200 qd orally for 14 consecutive days. Cohorte 2 (arm E): 200mg bid loading dose for 2 days then, 200 qd/day orally, per os, for 14 consecutive days. If for any reason a treatment is not given within the allowed treatment window (± 12h) it will be cancelled (i.e., missed for that time point), and treatment will be resumed at the next dosing day.) Other: Standard of care (In cohorts 1 and 2, patients allocated in the standard of care arms should receive best supportive care, as per the investigator's discretion and the local routine practices. With regards to the respiratory symptoms and medical resoures at investigational site, the following should be given according to the patient's condition: oxygen supplementation, non-invasive ventilation, invasive ventilation, antibiotherapy, vasopressor support, renal replacement therapy, or extracorporeal membrane oxygenation. Additional care and medications should be administered in the patient's best interest.)

Anti-PD-1 (nivolumab)

Drug: Nivolumab (Cohorte 1 (arm C): 0.3mg/Kg, intravenously, single infusion at Day 1.) Other: Standard of care (In cohorts 1 and 2, patients allocated in the standard of care arms should receive best supportive care, as per the investigator's discretion and the local routine practices. With regards to the respiratory symptoms and medical resoures at investigational site, the following should be given according to the patient's condition: oxygen supplementation, non-invasive ventilation, invasive ventilation, antibiotherapy, vasopressor support, renal replacement therapy, or extracorporeal membrane oxygenation. Additional care and medications should be administered in the patient's best interest.)

Anti-IL-6 (tocilizumab)

Drug: Tocilizumab (Cohorte 2 (arm F): 400mg flat dose, intravenously, single infusion at Day 1.) Other: Standard of care (In cohorts 1 and 2, patients allocated in the standard of care arms should receive best supportive care, as per the investigator's discretion and the local routine practices. With regards to the respiratory symptoms and medical resoures at investigational site, the following should be given according to the patient's condition: oxygen supplementation, non-invasive ventilation, invasive ventilation, antibiotherapy, vasopressor support, renal replacement therapy, or extracorporeal membrane oxygenation. Additional care and medications should be administered in the patient's best interest.)

Standard of care

Other: Standard of care (In cohorts 1 and 2, patients allocated in the standard of care arms should receive best supportive care, as per the investigator's discretion and the local routine practices. With regards to the respiratory symptoms and medical resoures at investigational site, the following should be given according to the patient's condition: oxygen supplementation, non-invasive ventilation, invasive ventilation, antibiotherapy, vasopressor support, renal replacement therapy, or extracorporeal membrane oxygenation. Additional care and medications should be administered in the patient's best interest.)

Trial Centres

Investigators

Investigator Centre Name Trial Centre Country
Albane DE KERAUTEM, Dr
01 44 12 71 95 adekerautem@hpsj.fr
show details
Hôpital Saint-Joseph France
Fanny POMMERET, Dr
01 42 11 42 11 FANNY.POMMERET@gustaveroussy.fr
show details
Gustave Roussy France
Gérard ZALCMAN, Pr
01 40 25 74 64 gerard.zalcman@aphp.fr
show details
AP-HP Hôpital Bichat Claude Bernard France
Jacques CADRANEL, Pr
01 56 01 61 47 jacques.cadranel@aphp.fr
show details
AP-HP Tenon France
Julien GAUTIER
+33 4.26.55.68.29 julien.gautier@lyon.unicancer.fr
show details
-
Mohamad MOHTY, Pr.
mohamad.mohty@inserm.fr
show details
AP-HP Hôpital Saint Antoine France
Paul GOUGIS, Dr.
01 42 17 85 33 paul.gougis@aphp.fr
show details
AP-HP La Pitié Salpétrière France
Philippe Cassier
philippe.cassier@lyon.unicancer.fr
show details
Centre Leon Berard, Centre Léon Bérard France

Centres

Centre Name Location Trial Centre Country
-
-
-
AP-HP Hôpital Bichat Claude Bernard Paris France
AP-HP Hôpital Saint Antoine Paris France
AP-HP La Pitié Salpétrière Paris France
AP-HP Tenon Paris France
Centre Leon Berard
-
-
Centre Léon Bérard Lyon, Rhône France
Gustave Roussy Villejuif France
Hôpital Saint-Joseph Paris France

Trial History

Event Date Event Type Comment
12 May 2020 Other trial event Last checked against ClinicalTrials.gov record. Updated 12 May 2020
13 Apr 2020 Other trial event New source identified and integrated European Clinical Trials Database (EudraCT2020-001373-70). Updated 13 Apr 2020
07 Apr 2020 New trial record New trial record Updated 07 Apr 2020
03 Apr 2020 Status change - recruiting Status changed from not yet recruiting to recruiting. Updated 08 Apr 2020

References

  1. ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2016;.

    Available from: URL: http://clinicaltrials.gov
  2. European Clinical Trials Database. Trial-Reg 2016;.

    Available from: URL: https://www.clinicaltrialsregister.eu
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