Assessing the Tolerance and Clinical Benefit of feCAl tranSplantation in patientS With melanOma

Prospective randomIzed Clinical Trial Assessing the Tolerance and Clinical Benefit of feCAl tranSplantation in patientS With melanOma Treated With CTLA-4 and PD1 Inhibitors

Recent studies suggest that patients with metastatic melanoma whose gut microbiome is colonized by eubiotic bacteria have a stronger anti-cancer response to anti CTLA-4 and anti PD1. The hypothesis of this research is that a pooled standardized fecal microbiome transfer (FMT) will shift melanoma patients' gut microbiome towards a composition close to that associated with a better response, and will therefore increase the response to a combination of anti CTLA-4 and anti PD1, without affecting the safety of these drugs. The present trial is the first randomized trial of FMT in patients with unresectable or metastatic melanoma. It will include patients who have neither been exposed to anti CTLA-4 nor anti PD1 or PDL-1, prior to inclusion in the study. The pooled standardized fecal microbiome transfer administered in this study is an experimental drug MaaT013, a microbiome restoration biotherapeutic, produced by MaaT Pharma, and composed of pooled-donor, full-ecosystem intestinal microbiome. The MaaT013 product has a standardized richness (in number of species present) higher than a product obtained from a mono donor (455 species approximately against 274 on average) and contains bacteria species (mentioned in the rationale) associated with better response to anti- CTLA-4 and anti PD1.

PICASSO is a prospective, randomized, proof of concept clinical trial. This trial is about assessing the tolerance and clinical benefit of fecal microbiome transfer in patients with melanoma in addition to the usual treatment with immunotherapy combining ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor).

In the proposed research, we will compare faecal transplantation using MaaT013 to placebo in 70 patients.

Patients not exposed to anti CTLA-4 and anti PD1 or PDL-1 patients before the trial will be randomized to receive either: ipilimumab + nivolumab + MaaT013 (n = 35) or ipilimumab + nivolumab + placebo (n = 35).

The estimated duration of the study is 37 months. Administration of MaaT013 or placebo will be performed every 3 weeks between baseline and week 9 then from week 15 to week 23 every 4 weeks. A total of 7 fecal microbiome transfer will be performed.

Prior to the first administration (the day before) an evacuating enema by (MOVIPREP or equivalent) will be done, For subsequent administrations, an evacuating enema (equivalent to the specialty Normacol®) will be administered rectally before the transplantation of fecal microbiota or the placebo.

Blood and stool samples will be collected as well as biopsies for the purposes of the study.

An evaluation of the patient's condition will be made at week 27, Unblinding will be performed for patients who have progressed. Patients with disease progression who received placebo will be considered for receiving MaaT013, in an open-label basis, concurrently with nivolumab infusions, at week 31, 35, 39, 43 and 47.

. The end-of-follow-up visit for all patients is scheduled for week 51. Patients who met the inclusion criteria, received Ipilimumab+Nivolumab, who consented to have a baseline stool microbiota analysis before starting treatment with ipilimumab + nivolumab. They will form a cohort of 50 patients.

Inclusion Criteria:

• Patients aged 18 to 80
• Patients with unresectable or metastatic melanoma
• Patients with ECOG performance of 0-2
• Patients able to provide written informed consent and understand the risks associated with MaaT013
• Have measurable disease as per RECIST version 1.1, on a tumor evaluation (either CT scan, physical evaluation or ultrasonography) performed less than 2 weeks before screening visit
• Requiring a treatment with Ipilimumab and PD1 inhibitor (Nivolumab) and having no contraindication to these drugs nor to their excipients
• Patients unexposed to ipilimumab and anti PD1 or anti PDL1 except if they have received it in the adjuvant setting (if the last dose of Ipilimumab® or anti PD1 or anti PDL1 was received at least 6 months before randomization).
• Negative pregnancy test (serum)
• Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab, ipilimumab and 6 months after the last dose of study treatment (ie, 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo approximately five half-lives)
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab, ipilimumab and 7 months after the last dose of study treatment {i.e., 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo approximately five half-lives.}
• Hemoglobin ≥9 g/dL
• Platelets ≥ 100000mm3
• Neutrophils ≥ 1500/mm3
• Creatinine Clearance ≥ 50mL/mn
• AST ≤ 3N
• ALT ≤ 3N
• Total bilirubin ≤ 1.5N (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
• Alkaline phosphatase ≤ 3N
• INR < 1.5
• Prothrombin ≥ 70%
• TCA < 1.2
• No Hepatocellular insufficiency

Exclusion Criteria:

• Pregnant or breastfeeding women
• Antibiotics in the last two weeks prior to the FMT
• Inability to retain enemas
• Expected to require any other form of systemic or localized anti-neoplastic therapy while on study
• Active infection requiring systemic therapy.
• Active, known or suspected autoimmune disease.
• No health insurance,
• Patients already included in a clinical research other than an observational study (e.g: registry, cohort).
• Patient on AME (state medical aid) (unless exemption from affiliation)
• Patients guardianship/legal protection/curatorship
• Contraindication to fecal transplantation
• Known hypersensitivity to Normacol or Moviprep® or equivalent patent medicines enema or one of their components.
• Fluid-electrolyte disorders with sodium retention (heart failure, hyperaldosteronism, drug-induced edema)
• Recent acute coronary syndrome or unstable ischemic heart disease
• Congestive heart failure ≥ Class III or IV as defined by New York Heart Association
• Hypersensitivity to the active substances or to any of the excipients: Aspartame (E951), Acesulfame, potassium (E950), lemon flavor (maltodextrin, citral, lemon essential oil, lime essential oil, xanthan gum, vitamin E)
• Gastrointestinal obstruction or perforation
• Gastric emptying disorders (gastroparesis),
• Ileus,
• Phenylketonuria (due to the presence of aspartame),
• Deficiency in glucose-6-phosphate dehydrogenase (due to the presence of ascorbate),
• Toxic megacolon, in severe forms of inflammation of the intestinal tract, including Crohn's disease and ulcerative colitis.