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

Primary Purpose

Melanoma

Status

Recruiting

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

MaaT013

Ipilimumab

Nivolumab

MoviPrep

Normacol

Placebo of Maat013

About this trial

This is an interventional treatment trial for Melanoma focused on measuring 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

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Hôpital Nantes Hôtel DieuRecruiting
Hôpital Saint LouisRecruiting
Hôpital Gustave RoussyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab

fecal microbiotherapy Placebo associated to ipilimumab and nivolumab

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

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

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

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

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

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.

To assess the efficacy and safety of MaaT013 combined with Ipilimumab and Nivolumab in the randomized part of the trial.

Full Information

NCT ID

NCT04988841

First Posted

June 25, 2021

Last Updated

September 25, 2023

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT04988841

Brief Title

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

Acronym

PICASSO

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 20, 2022 (Actual)

Primary Completion Date

January 20, 2024 (Anticipated)

Study Completion Date

June 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Multi-center, prospective, randomized, double blinded, pilot, proof-of concept, clinical trial

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

At week 27, unblinding will be performed on patients who progressed. For those who received Placebo, Maat 013 will be administrated in open label.

Allocation

Randomized

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab

Arm Type

Experimental

Arm Description

Arm Title

fecal microbiotherapy Placebo associated to ipilimumab and nivolumab

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

MaaT013

Other Intervention Name(s)

fecal microbiotherapy

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

Ipilimumab

Intervention Description

Anti cytotoxicT-lymphocyte-associated protein 4 ( immunothérapy)

Intervention Type

Drug

Intervention Name(s)

Nivolumab

Intervention Description

AntiPD1 ( immunothérapy)

Intervention Type

Drug

Intervention Name(s)

MoviPrep

Other Intervention Name(s)

Osmotic laxative solution

Intervention Description

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)

Intervention Type

Drug

Intervention Name(s)

Normacol

Other Intervention Name(s)

hypertonic enema solution

Intervention Description

hypertonic enema solution

Intervention Type

Drug

Intervention Name(s)

Placebo of Maat013

Other Intervention Name(s)

fecal microbiotherapy placebo

Intervention Description

expérimental drug placebo of MaaT013

Primary Outcome Measure Information:

Title

Description

Safety will be measured by the occurrence of Grade 3 and grade 4 adverse events (AE), as graded by the CTCAE v 5.0

Time Frame

During the 27 weeks of the trial.

Secondary Outcome Measure Information:

Title

Description

Time Frame

During the 27 weeks of the trial.

Title

To assess changes in the tumor microenvironment in patients who have received MaaT013 and placebo ;

Description

Changes in the tumor micro environment (TME) pre and post MaaT013 or placebo

Time Frame

During the 27 weeks of the trial.

Title

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

Description

Time Frame

During the 27 weeks of the trial.

Title

Description

Changes in peripheral blood immune cell subpopulations pre and post MaaT013 or placebo

Time Frame

During the 27 weeks of the trial.

Title

To assess the evolution of gut microbial members and metabolites;

Description

Time Frame

During the 27 weeks of the trial.

Title

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

Description

Time Frame

During the 51 weeks of the trial.

Title

To assess the efficacy and safety of MaaT013 combined with Ipilimumab and Nivolumab in the randomized part of the trial.

Description

Time Frame

During the 27 weeks of the trial.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Franck CF CARBONNEL, Professor

Phone

+ (33) 145213722

Franck.carbonnel@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Caroline CR ROBERT, Professor

Phone

+ (33) 142114210

Caroline.ROBERT@gustaveroussy.fr

Facility Information:

Facility Name

Hôpital Nantes Hôtel Dieu

City

Nantes

ZIP/Postal Code

44000

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Quereux Gaelle, PhD

Phone

0240087901

gaelle.quereux@chu-nantes.fr

Facility Name

Hôpital Saint Louis

City

Paris

ZIP/Postal Code

75010

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

CELESTE LEBBE, PHd

Phone

0142499392

celeste.lebbe@aphp.fr

Facility Name

Hôpital Gustave Roussy

City

Villejuif

ZIP/Postal Code

94800

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Robert Caroline

Phone

0142116497

caroline.robert@gustaveroussy.fr

12. IPD Sharing Statement

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

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