PICASSO. Prospective randomIzed clinical trial assessing the tolerance and clinical benefit of feCAl tranSplantation in patientS with melanOma treated with CTLA-4 and PD-1 inhibitors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Mar 2022 → 22 Apr 2025

Decision date (initial)

2024-09-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

French Ministry of Health (PHRC-K 2019)

External identifiers

EU CT number

2024-516100-42-00

EudraCT number

2020-002932-64

ClinicalTrials.gov

NCT04988841

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

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

Secondary objectives 14

1. 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
2. To assess changes in the tumor microenvironment in patients who have received MaaT013 and placebo
3. To assess 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
4. Changes in signatures of peripheral blood T or immune cells cell
5. To assess the evolution of gut microbial members and metabolites
6. 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+Ipilimumab and Nivolumab in the randomized part of the trial
7. To assess progression-free survival at week 15, 27, 51
8. To assess overall survival at week 15, 27, 51
9. To assess best overall response rate, either complete or partial, with or without confirmation of response, rated by iRECIST v1.1 and PET scan at weeks 15, 27 and 51, using EORTC criteria.
10. To assess disease control rate (complete or partial response or stable disease)
11. To assess pseudo progression rate
12. The description of favorable gut microbiome will be based upon baseline analyses performed in patients of the placebo arm, but also in patients who met the inclusion criteria, received Ipilimumab+Nivolumab, agreed to have a stool microbiome analyses at baseline and week 9 but did not receive MaaT013 or placebo. The proportion of responder will be specifically evaluated in patients with unfavorable gut microbiome, and among them, in patients whose microbiome shifted towards a composition close to that of MaaT013
13. Best overall response rate, without confirmation of response, rated by RECIST
14. To assess response (either partial or complete), stable disease and progression at week 15, 27, 51

Conditions and MedDRA coding

Melanoma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Patients aged 18 to 80
2. Patients with unresectable or metastatic melanoma
3. Patients with ECOG performance of 0-2
4. Patients able to provide written informed consent
5. Patients able to understand the risks associated with MaaT013
6. 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
7. Requiring a treatment with Ipilimumab and PD1 inhibitor (Nivolumab) and having no contraindication to these drugs nor to their excipients
8. 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)
9. Negative pregnancy test (serum)
10. 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)
11. 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
12. Hemoglobin ≥9 g/dL
13. Platelets ≥ 100000/mm3
14. Neutrophils ≥ 1500/mm3
15. Creatinine Clearance ≥ 50mL/mn
16. AST ≤ 3N (< 5x ULN in case of liver metastases
17. ALT ≤ 3N (< 5x ULN in case of liver metastases)
18. Total bilirubin ≤ 1.5N (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
19. Alkaline phosphatase ≤ 3N
20. INR < 1.5 (or within the therapeutic range in patients treated with anticoagulants)
21. Prothrombin ≥ 70% (or within the therapeutic range in patients treated with anticoagulants)
22. TCA < 1.2 (or within the therapeutic range in patients treated with anticoagulants
23. No Hepatocellular insufficiency

Exclusion criteria 23

1. Pregnant or breastfeeding women
2. Antibiotics in the last two weeks prior to the FMT
3. Inability to retain enemas
4. Expected to require any other form of systemic or localized anti-neoplastic therapy while on study
5. Active infection requiring systemic therapy
6. Patients with a negative Epstein-Barr virus result
7. Active, known or suspected autoimmune disease.except vitiligo and controlled complemented endocrine autoimmune disease
8. No health insurance
9. Patients already included in a clinical research other than an observational study (e.g: registry, cohort)
10. Patient on AME (state medical aid) (unless exemption from affiliation)
11. Patients guardianship/legal protection/curatorship
12. Contraindication to fecal transplantation
13. Known hypersensitivity to Normacol or Moviprep® or equivalent patent medicines enema or one of their components
14. Fluid-electrolyte disorders with sodium retention (heart failure, hyperaldosteronism, drug-induced edema)
15. Recent acute coronary syndrome or unstable ischemic heart disease
16. Congestive heart failure ≥ Class III or IV as defined by New York Heart Association
17. 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
18. Gastrointestinal obstruction or perforation
19. Gastric emptying disorders (gastroparesis)
20. Ileus
21. Phenylketonuria (due to the presence of aspartame)
22. Deficiency in glucose-6-phosphate dehydrogenase (due to the presence of ascorbate)
23. -Toxic megacolon, in severe forms of inflammation of the intestinal tract, including Crohn's disease and ulcerative colitis

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Safety will be measured by the occurrence of treatment-related adverse events of Grade 3, grade 4 and grade 4 , as graded by the CTCAE v 5.0 during the 27 weeks of the trial

Secondary endpoints 14

1. Efficacy will be assessed by the best overall response rate, between baseline and week 27, without confirmation of partial or complete response, rated by Response Evaluation Criteria in Solid Tumors (RECIST v1.1; 19) in the experimental and control arms
2. Changes in the tumor micro environment (CD3, CD8, FoxP3, CD56, granzyme B, CD68, CD163, CD20, PD1) pre and post MaaT013 or placebo
3. 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 ipilimumab + nivolumab with MaaT013 or placebo
4. Changes in peripheral blood immune cell subpopulations pre and post ipilimumab + nivolumab with MaaT013 or placebo
5. Changes in gut microbiome and metabolites pre and post MaaT013 or placebo and in patients who met the inclusion criteria, received Ipilimumab+Nivolumab, agreed to have stool microbiome analyses at baseline and week 9, but did not receive MaaT013 or placebo
6. Best response rate, either complete or partial, rated by RECIST and iRECIST in patients with disease progression who received placebo and subsequently, MaaT013, in an open-label basis
7. Progression-free survival rated by RECIST and iRECIST at week 15, 27, 51
8. Overall survival rated by RECIST and iRECIST at week 15, 27, 51
9. Best overall response rate, with or without confirmation of complete or partial response, rated by iRECIST and PET scan at weeks 15, 27 and 51 using EORTC criteria
10. Disease control rate (complete or partial response or stable disease) rated by RECIST and iRECIST
11. Pseudo progression rate evaluated by iRECIST
12. The favorable gut microbiome is the one associated with the favorable response to ipilimumab and nivolumab. The description of favorable microbiome will be based upon baseline analyses performed in patients of the placebo arm, but also in patients who met the inclusion criteria, received Ipilimumab+Nivolumab, who consented to have a baseline stool microbiota analysis, but were not included in the randomized trial.
13. Best overall response rate, with confirmation of response, between baseline and week 27 rated by RECIST
14. Time point assessment of response (either partial or complete), stable disease and progression at week 15, 27 and 51

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Franck Carbonnel

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Franck Carbonnel

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications