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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
19
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.
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.
Cohorte 2 (arm H): 500mg, intravenously, at Day 1 then 200mg once daily every 2 days during 14 Days
Cohorte 2 (arm G) : 50mg (flat dose),intravenously, single infusion at Day 1.
Centre Léon Bérard
Lyon, Rhône, France
Centre Jean Perrin
Clermont-Ferrand, France
CHU Clermont Ferrand
Clermont-Ferrand, France
Centre Oscar Lambret
Lille, France
AP-HP Hôpital Saint Antoine
Paris, France
AP-HP La Pitié Salpétrière
Paris, France
Hôpital Saint-Joseph
Paris, France
AP-HP Tenon
Paris, France
AP-HP Hôpital Bichat Claude Bernard
Paris, France
GH Diaconesses Croix Saint Simon
Paris, France
...and 2 more locations
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.
Time frame: 28 days from randomization
Time to clinical improvement
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
Clinical status will be assessed using a 7-point ordinal scale : 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities; 3. Hospitalized, not requiring supplemental oxygen; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalized, on invasive mechanical ventilation or ECMO; 7. Death.
Time frame: Day 7, Day 14, Day 28
Clinical status
The NEWS2 score (National Early Warning Score) allocates a score based on six physiological parameters (respiratory rate / oxygen saturation / systolic blood pressure / heart rate / consciousness / temperature). It Determines the degree of illness of a patient and prompts critical care intervention. The total possible score ranges from 0 to 21. The higher the score, the greater the clinical risk. A total score close to 0 corresponds to a low risk and a total score higher than 7 corresponds to a high risk.
Time frame: Day 7, Day 14, Day 28
Mean change in the ranking on the ordinal scale from baseline to D7, D14 and D28
Mean change in clinical status from baseline will be assessed by using a 7-point ordinal scale.
Time frame: Day 7, Day 14, Day 28
Mean change in the ranking of the NEWS2 score from baseline to D7, D14 and D28
Mean change in clinical status from baseline will be assessed by using the NEWS2 score (National Early Warning Score). The NEWS2 score (National Early Warning Score) allocates a score based on six physiological parameters (respiratory rate / oxygen saturation / systolic blood pressure / heart rate / consciousness / temperature). It Determines the degree of illness of a patient and prompts critical care intervention. The total possible score ranges from 0 to 21. The higher the score, the greater the clinical risk. A total score close to 0 corresponds to a low risk and a total score higher than 7 corresponds to a high risk.
Time frame: Day 7, Day 14, Day 28
Overall survival
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 time of last patient last visit)
Length of stay in Intensive Care Unit
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 time of last patient last visit)
Duration of mechanical ventilation or high flow oxygen devices
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 time of last patient last visit)
Duration of hospitalization
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 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
The rate of secondary infection by other documented pathogens (bacteria, fungi)
Time frame: Day 7, Day 14, Day 28 (if available)
Biological parameters
Changes from baseline in neutrophils count (G/L)
Time frame: 3 months (i.e. at the time of last patient last visit)
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
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 time of last patient last visit)
Cost-Effectiveness Analyses (CEA)
Incremental Cost-Effectiveness Ratios (ICERs) expressed in cost per Life Year Gained.
Time frame: 3 months (i.e. at the time of last patient last visit)
Biological parameters
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
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
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
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
Changes from baseline in pro-inflammatory cytokine (IL6)
Time frame: 3 months (i.e. at the the time of last patient last visit)
The rate of patients with SARS-CoV-2 IgG antibodies at D7, D14 and D28
Time frame: Day 7, Day 14, Day 28
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