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

Study Overview
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Brief Summary
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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.

Detailed Description
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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 60 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 = 30) or ipilimumab + nivolumab + placebo (n = 30). 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.

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

Conditions
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Melanoma

Intervention / Treatment
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* Drug: MaaT013
* Drug: Ipilimumab
* Drug: Nivolumab
* Drug: MoviPrep
* Drug: Normacol
* Drug: Placebo of Maat013


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, prospective, randomized, double blinded, pilot, proof-of concept, clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab<br>Fecal microbiotherapy MaaT013 (actif arm) enemas will be administered by nurses, at the hospital, in the dermatology department in which the patients are treated for their melanoma. Nurses will be trained to administer enemas. The enema will be administered to the patient in the left lateral position with instructions to retain it for at least 20 minutes | Drug: MaaT013<br>* study is an experimental drug , produced by MaaT Pharma, and composed of pooled-donor, full-ecosystem intestinal microbiome (455 species approximately against 274 on average)<br>* Other names: fecal microbiotherapy;Drug: Ipilimumab<br>* Anti cytotoxicT-lymphocyte-associated protein 4 ( immunothérapy)<br>Drug: Nivolumab<br>* AntiPD1 ( immunothérapy)<br>Drug: MoviPrep<br>* Osmotic laxative solution : patients take a single dose of two liters of Moviprep® or equivalent the night before the first administration of experimental treatment (Fecal microbiota transfer or placebo)<br>* Other names: Osmotic laxative solution;Drug: Normacol<br>* hypertonic enema solution<br>* Other names: hypertonic enema solution;|
| Placebo Comparator: fecal microbiotherapy Placebo associated to ipilimumab and nivolumab<br>Placebo fecal microbiotherapy will be administered by nurses, at the hospital, in the dermatology department in which the patients are treated for their melanoma. Nurses will be trained to administer enemas. The enema will be administered to the patient in the left lateral position with instructions to retain it for at least 20 minutes | Drug: MaaT013<br>* study is an experimental drug , produced by MaaT Pharma, and composed of pooled-donor, full-ecosystem intestinal microbiome (455 species approximately against 274 on average)<br>* Other names: fecal microbiotherapy;Drug: Ipilimumab<br>* Anti cytotoxicT-lymphocyte-associated protein 4 ( immunothérapy)<br>Drug: Nivolumab<br>* AntiPD1 ( immunothérapy)<br>Drug: MoviPrep<br>* Osmotic laxative solution : patients take a single dose of two liters of Moviprep® or equivalent the night before the first administration of experimental treatment (Fecal microbiota transfer or placebo)<br>* Other names: Osmotic laxative solution;Drug: Normacol<br>* hypertonic enema solution<br>* Other names: hypertonic enema solution;Drug: Placebo of Maat013<br>* expérimental drug placebo of MaaT013<br>* Other names: fecal microbiotherapy placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess whether the safety of a 23-week treatment with MaaT013, combined with ipilimumab+nivolumab, is different from that of ipilimumab+nivolumab+placebo in patients with melanoma naïve to Ipilimumab and anti-PD1 | Safety will be measured by the occurrence of Grade 3 and grade 4 adverse events (AE), as graded by the CTCAE v 5.0 | During the 27 weeks of the trial. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess whether a 23-week treatment with MaaT013, combined with Ipilimumab and Nivolumab, is more efficient than Ipilimumab and Nivolumab + placebo in patients with melanoma naïve to Ipilimumab and anti PD1. | The best overall response rate, rated by immunological Response Evaluation Criteria in Solid Tumors (iRECIST; 19) in the experimental and control arms and among them, within the subgroup of patients who carried the unfavourable baseline microbiota. | During the 27 weeks of the trial. | 
| To assess changes in the tumor microenvironment in patients who have received MaaT013 and placebo ; | Changes in the tumor micro environment (TME) pre and post MaaT013 or placebo | During the 27 weeks of the trial. | 
| Changes in plasma levels of proteins or metabolites that play a role in immune activity against cancer and/or are associated with gut microbiome composition, pre and post MaaT013 or placebo | Changes in plasma levels of proteins or metabolites that play a role in immune activity against cancer and/or are associated with gut microbiome composition, pre and post MaaT013 or placebo : IL-6, IL-8, MCP1, IL-1β, TNF α, sCD25, sCTLA-4, sPD-L1, short chain fatty acids (SCFA), all in micromol/L | During the 27 weeks of the trial. | 
| To assess peripheral blood T cell subpopulations that have been identified as associated with gut microbiome composition or response to anti CTLA-4 and anti PD1 in previous human studies; CD244+ T cells, monocytes subpopulations, memory T cells and Tregs | Changes in peripheral blood immune cell subpopulations pre and post MaaT013 or placebo | During the 27 weeks of the trial. | 
| To assess the evolution of gut microbial members and metabolites; | Microbial composition will be described by 16S ribosomal RNA gene sequencing as follows: Microbial diversity indices (Shannon, Simpson, etc…) Proportions of each bacterial taxa in the microbiome of each volunteer Microbial metagenomes will be described by shotgun sequencing as follows: Number of bacterial genes (richness) Proportions of each metagenomic unit (species) in the microbiome of each volunteer Proportions of Kegg Orthology functional categories in the microbiome of each volunteer Microbial metabolomes will be described by global metabolomic Liquid Chromatography with tandem mass spectrometry as follows: proportions of metabolites in the microbiome of each volunteer proportions of specific pathways (KEGG) in the microbiome of each volunteer | During the 27 weeks of the trial. | 
| To assess, on an open basis, the efficacy and safety of MaaT013 combined with Nivolumab in a subset of patients who failed to respond to placebo | Overall response rate, either complete or partial, rated by Response Evaluation Criteria in Solid Tumours in patients with a stable disease or disease progression who received MaaT013, in an open-label basis. | During the 51 weeks of the trial. | 
| To assess the efficacy and safety of MaaT013 combined with Ipilimumab and Nivolumab in the randomized part of the trial. | Overall response rate, either complete or partial, rated by Response Evaluation Criteria in Solid Tumours in patients with a stable disease or disease progression who received MaaT013, in an open-label basis. | During the 27 weeks of the trial. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fecal microbiome transfer, Microbiome restoration biotherapeutic, Full-ecosystem intestinal microbiome, Response to anti- CTLA-4 and anti PD1, the tumor microenvironment, Peripheral blood T cell subpopulations, Efficacy and safety of MaaT013