Clinical trial NCT04333914: Prospective Study in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 Infection
Official title: A Prospective, Controlled, Randomized, Multicenter Study of the Efficacy of an Autophagy Inhibitor (GNS561), an Anti-NKG2A (Monalizumab) and an Anti-C5aR (Avdoralimab) Compared to the Standard of Care in Patients With Advanced or Metastatic Cancer and SARS-CoV-2 (COVID-19) Infection.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2020-04-03
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: * COHORT 1 : Patients with mild symptoms or asymptomatic
* COHORT 2 : Patients with moderate/severe symptoms
Primary purpose: TREATMENT

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).


Eligibility criteria: INCLUSION CRITERIA:

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
* 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 1) 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 1) 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-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.

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.

Primary outcomes:
measure: 28-day survival rate
timeFrame: 28 days from randomization
Secondary outcomes:
measure: Time to clinical improvement
timeFrame: 28 days from randomization
measure: Clinical status
timeFrame: Day 7, Day 14, Day 28
measure: Clinical status
timeFrame: Day 7, Day 14, Day 28
measure: Mean change in the ranking on the ordinal scale from baseline to D7, D14 and D28
timeFrame: Day 7, Day 14, Day 28
measure: Mean change in the ranking of the NEWS2 score from baseline to D7, D14 and D28
timeFrame: Day 7, Day 14, Day 28
measure: Overall survival
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Length of stay in Intensive Care Unit
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Duration of mechanical ventilation or high flow oxygen devices
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Duration of hospitalization
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Rate of throat swab negativation
timeFrame: Day 7, Day 14, Day 28
measure: Quantitative SARS-CoV-2 virus in throat swab and blood samples
timeFrame: Day 7, Day 14, Day 28
measure: The rate of secondary infection by other documented pathogens (bacteria, fungi)
timeFrame: Day 7, Day 14, Day 28 (if available)
measure: Biological parameters
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Cost-Effectiveness Analyses (CEA)
timeFrame: 3 months (i.e. at the time of last patient last visit)
measure: Biological parameters
timeFrame: 3 months (i.e. at the the time of last patient last visit)
measure: Biological parameters
timeFrame: 3 months (i.e. at the the time of last patient last visit)
measure: Biological parameters
timeFrame: 3 months (i.e. at the the time of last patient last visit)
measure: Biological parameters
timeFrame: 3 months (i.e. at the the time of last patient last visit)
measure: Biological parameters
timeFrame: 3 months (i.e. at the the time of last patient last visit)
measure: The rate of patients with SARS-CoV-2 IgG antibodies at D7, D14 and D28
timeFrame: Day 7, Day 14, Day 28
Other outcomes:
Locations:
city: Lyon
country: France
facility: Centre Léon Bérard
state: Rhône
city: Clermont Ferrand
country: France
facility: CHU Clermont Ferrand
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Paris
country: France
facility: AP-HP Hôpital Saint Antoine
city: Paris
country: France
facility: AP-HP La Pitié Salpétrière
city: Paris
country: France
facility: Hôpital Saint-Joseph
city: Paris
country: France
facility: AP-HP Tenon
city: Paris
country: France
facility: AP-HP Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: GH Diaconesses Croix Saint Simon
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe (ICANS)
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Leon Berard
name: Virginie AVRILLON, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Leon Berard
name: Jean-Yves BLAY, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: