Prospective Study in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 Infection

NCT04333914 | Completed Phase 2 DMC

• 2 other identifiers: ET20-076 - IMMUNONCOVID-202020-001373-70
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 12

Brief Summary

A prospective, controlled, randomized, multicenter study whose goal is to compare the efficacy of an autophagy inhibitor (GNS561), an anti-NKG2A (monalizumab) and an anti-C5aR (avdoralimab) 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-NKG2A vs standard of care (randomization ratio 1:1:1).
• COHORT 2 (moderate/severe symptoms): anti-C5aR vs standard of care (randomization ratio 1:1).

Conditions

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

Keywords

Oncology; COVID-19; IL-6/IL-6 receptor pathway; Immunotherapy; GNS561; anti-C5aR; anti-NKG2A

Outcome Measures

Primary Outcomes (1)

• 28-day survival rate

  28-day survival rate, defined by the proportion of patients still alive 28 days after randomization. If vital status at 28 days post randomisation is not available due to early transfer in an external resuscitation unit, patients will be considered as failure at the date of the transfer. Comparison of each experimental arm (GNS561 then monalizumab for cohort1 and avdoralimab for cohort2) to control arm will be performed using a Fisher exact test.

  28 days from randomization

Secondary Outcomes (21)

• Time to clinical improvement

  28 days from randomization

• Clinical status

  Day 7, Day 14, Day 28

• Clinical status

  Day 7, Day 14, Day 28

• Mean change in the ranking on the ordinal scale from baseline to D7, D14 and D28

  Day 7, Day 14, Day 28

• Mean change in the ranking of the NEWS2 score from baseline to D7, D14 and D28

  Day 7, Day 14, Day 28

Study Arms (4)

Autophagy inhibitor (GNS651)

EXPERIMENTAL

Drug: Autophagy inhibitor (GNS651); Other: Standard of care

Standard of care

OTHER

Other: Standard of care

anti-NKG2A (Monalizumab)

EXPERIMENTAL

Other: Standard of care; Drug: Monalizumab

anti-C5aR (Avdoralimab)

EXPERIMENTAL

Other: Standard of care; Drug: Avdoralimab

Interventions

Autophagy inhibitor (GNS651) DRUG

Cohort 1 (arm B): 200mg q.d. orally for 10 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.

Autophagy inhibitor (GNS651)

Standard of care OTHER

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.

Autophagy inhibitor (GNS651); Standard of care; anti-C5aR (Avdoralimab); anti-NKG2A (Monalizumab)

Avdoralimab DRUG

Cohorte 2 (arm H): 500mg, intravenously, at Day 1 then 200mg once daily every 2 days during 14 Days

anti-C5aR (Avdoralimab)

Monalizumab DRUG

Cohorte 2 (arm G) : 50mg (flat dose),intravenously, single infusion at Day 1.

anti-NKG2A (Monalizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• I1. Age 18 or older at the time of enrolment for women and age 60 or older at the time of enrolment for men.
• 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) without indication of transfer in a rescucitation unit.; 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).
• Note: Item cancelled (addendum 2 - October 2020)
• I6. Life-expectancy longer than 3 months.
• I7. Adequate bone marrow and end-organ function defined by the following laboratory results:
• Bone marrow:
• Hemoglobin ≥ 9.0 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/ALT ≤ 5 ULN

You may not qualify if:

• E1. For cohort 1 only: Patient currently receiving therapy with an anti-NKG2A.
• E2. For cohort 2 only: Patient currently receiving therapy with an anti-C5aR.
• E3. Patient presents a contraindication to monalizumab treatment (cohort 1 only) or to avdoralimab (cohort 2 only) as per respective IB, including known hypersensitivity to one of these study drugs or severe hypersensitivity reaction to any monoclonal antibody.
• E4. For cohort 1 only: Patient known to have intolerance or hypersensitivity to chloroquine or any quinoline derivatives (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 received 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
• 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.

Sponsors & Collaborators

• Centre Leon Berard: lead

Study Sites (12)

Centre Léon Bérard

Lyon, Rhône, 69373, France

Location

Centre Jean Perrin

Clermont-Ferrand, 63000, France

Location

CHU Clermont Ferrand

Clermont-Ferrand, 690003, France

Location

Centre Oscar Lambret

Lille, 59020, France

Location

AP-HP Hôpital Saint Antoine

Paris, 75012, France

Location

AP-HP La Pitié Salpétrière

Paris, 75013, France

Location

Hôpital Saint-Joseph

Paris, 75014, France

Location

AP-HP Tenon

Paris, 75248, France

Location

AP-HP Hôpital Bichat Claude Bernard

Paris, 75877, France

Location

GH Diaconesses Croix Saint Simon

Paris, 75960, France

Location

Institut de cancérologie Strasbourg Europe (ICANS)

Strasbourg, 67200, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

MeSH Terms

Conditions

COVID-19; Infections; Neoplasms

Interventions

Standard of Care; avdoralimab; monalizumab

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Virginie AVRILLON, M.D.

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

• Jean-Yves BLAY, M.D., Ph.D.

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: * COHORT 1 : Patients with mild symptoms or asymptomatic * COHORT 2 : Patients with moderate/severe symptoms

Study Record Dates

• First Submitted: April 1, 2020
• First Posted: April 3, 2020
• Study Start: April 15, 2020
• Primary Completion: July 6, 2021
• Study Completion: December 31, 2021
• Last Updated: September 30, 2022

Record last verified: 2021-08

Locations

FR (12)