Official Title
A Prospective, Controlled, Randomized, Multicenter Study to Compare the Efficacy of a Chloroquine Analog (GNS561), an Anti-PD-1 (Nivolumab), an Anti-NKG2A (Monalizumab), an Anti-interleukine-6 Receptor (Tocilizumab) and an Anti-C5aR (Avdoralimab) Versus Standard of Care in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 (COVID-19) Infection.
Brief Summary

A prospective, controlled, randomized, multicenter study whose goal is to compare the efficacy of a chloroquine analog (GNS561), an anti PD-1 (nivolumab), an anti-NKG2A (monalizumab), an anti-C5aR (avdoralimab) 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. According to their severity level at the time of enrolment, eligible patients will be randomized into 2 different cohorts: - COHORT 1 (mild symptoms or asymptomatic): GNS561 vs anti-PD1 vs anti-NKG2A vs standard of care (randomization ratio 1:1:1:1). - COHORT 2 (moderate/severe symptoms): GNS561 vs anti-IL6 vs anti-C5aR vs standard of care (randomization ratio 1:1:1:1).

Suspended
SARS-CoV-2 (COVID-19) Infection
Advanced or Metastatic Hematological or Solid Tumor

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.
Chloroquine analog (GNS651)

Drug: Nivolumab
Cohorte 1 (arm C): 0.3mg/Kg, intravenously, single infusion at Day 1.
Anti-PD-1 (nivolumab)

Drug: Tocilizumab
Cohorte 2 (arm F): 400mg flat dose, intravenously, single infusion at Day 1.
Anti-IL-6 (tocilizumab)

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)
Anti-PD-1 (nivolumab)
Chloroquine analog (GNS651)
Standard of care
anti-C5aR (avdoralimab)
anti-NKG2A (monalizumab)

Drug: Avdoralimab
Cohorte 2 (arm H): 500mg, intravenously, at Day 1 then 200mg once daily every 2 days during 14 Days
anti-C5aR (avdoralimab)

Drug: Monalizumab
Cohorte 2 (arm G) : 50mg (flat dose),intravenously, single infusion at Day 1.
anti-NKG2A (monalizumab)

Eligibility Criteria

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.; Nota Bene : A maximum time of 7 days may have elapsed between the date of first
symptoms and the date of consent for patient cohort 1 (mild). In cohort 2 (severe), up to
10 days may have elapsed since the first symptoms.

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. Multidisciplinary approach that patient is 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 enrollment (in case of emergency situation, please refer to protocol section 12.1 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.

Exclusion Criteria:

E1. For cohort 1 only : Patient currently receiving therapy with an anti- PD-1, anti-
PD-L1, anti-CTLA4 or anti-NKG2A.

E2. For cohort 2 only: Patient currently receiving therapy with an anti- IL-6 or anti-IL-6R
or with an anti-C5aR.

E3. Contraindication to treatment with nivolumab or monalizumab (cohort 1 only) or to
tocilizumab or avdoralimab (cohort 2 only) as per respective SPC and IB, 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 (quinine, chloroquine, tafenoquine, hydroxychloroquine, mefloquine). Patients
previously exposed to CQ, HCQ or other quinoline derivates should have interrupted their
treatment at least 72h prior to randomization.

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, including but not limited to :

- Major surgery.

- Azithromycine and chloroquine or any quinoline derivatives (quinine, chloroquine, tafenoquine, hydroxychloroquine, mefloquine)

- 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 known active hepatitis B (chronic or acute; defined as having a positive
hepatitis B surface antigen [HBsAg] test at screening), known active hepatitis C (Patients
positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV
RNA at screening) or known 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.

Eligibility Gender
All
Eligibility Age
Minimum: 18 Years
Countries
France

Philippe CASSIER
Principal Investigator
Centre Leon Berard

Centre Leon Berard
NCT Number
Keywords
Oncology
Covid-19
IL-6/IL-6 receptor pathway
Immunotherapy
GNS561
anti-C5aR
MeSH Terms
Infection
Communicable Diseases
Neoplasm Metastasis
Chloroquine
Nivolumab