Prospective randomIzed Clinical Trial Assessing the Tolerance and Clinical Benefit of feCAl tranSplantation in patientS With melanOma Treated With CTLA-4 and PD1 Inhibitors
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 70
- 试验地点
- 5
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
At week 27, unblinding will be performed on patients who progressed. For those who received Placebo, Maat 013 will be administrated in open label.
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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),
- •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.
研究组 & 干预措施
Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab
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
干预措施: MaaT013 (Drug)
Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab
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
干预措施: Ipilimumab (Drug)
Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab
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
干预措施: Nivolumab (Drug)
Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab
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
干预措施: MoviPrep (Drug)
Fecal microbiotherapy (MaaT013) associated to ipilimumab and nivolumab
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
干预措施: Normacol (Drug)
fecal microbiotherapy Placebo associated to ipilimumab and nivolumab
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
干预措施: MaaT013 (Drug)
fecal microbiotherapy Placebo associated to ipilimumab and nivolumab
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
干预措施: Ipilimumab (Drug)
fecal microbiotherapy Placebo associated to ipilimumab and nivolumab
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
干预措施: Nivolumab (Drug)
fecal microbiotherapy Placebo associated to ipilimumab and nivolumab
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
干预措施: MoviPrep (Drug)
fecal microbiotherapy Placebo associated to ipilimumab and nivolumab
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
干预措施: Normacol (Drug)
fecal microbiotherapy Placebo associated to ipilimumab and nivolumab
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
干预措施: Placebo of Maat013 (Drug)
结局指标
主要结局
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
时间窗: During the 27 weeks of the trial.
Safety will be measured by the occurrence of treatment-related adverse events of Grade 3, grade 4 and grade 5, as graded by the CTCAE v 5.0, during the 27 weeks of the trial
次要结局
- 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.(During the 27 weeks of the trial.)
- To assess changes in the tumor microenvironment in patients who have received MaaT013 and 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(During the 27 weeks of the trial.)
- Changes in signatures of peripheral blood T or immune cells cell. T cell or other immune cells will be sorted and transcriptomic analysis will be performed to determine changes induce by MaaT013 or placebo treatment.(During the 27 weeks of the trial.)
- To assess the evolution of gut microbial members and metabolites;(During the baseline and 9 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(During the 51 weeks of the trial.)
- To assess progression-free survival at week 15, 27, 51(During the 15, 27 and 51 weeks of the trial.)
- To assess response (either partial or complete), stable disease and progression at week 15, 27, 51(During the 15, 27 and 51 weeks of the trial.)
- To assess overall survival at week 15, 27, 51.(During the 15, 27 and 51 weeks of the trial.)
- 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(During the 15, 27 and 51 weeks of the trial.)
- Best overall response rate, with confirmation of response, rated by RECIST (19)(During the 27 weeks of the trial.)
- To assess disease control rate (complete or partial response or stable disease)(During the 15, 27 and 51 weeks of the trial.)
- To assess pseudo progression rate(During the 15, 27 and 51 weeks of the trial.)
- The description of favorable gut microbiome will be based upon analyses performed in patients of the placebo arm,(During the 27 weeks of the trial.)