Phase II Trial of Healthy-donor Derived Full-spectrum Microbiome Therapeutic MTP-101-C in Steroid Relapse/Refractory Immune-related Cutaneous Adverse Events (irCAEs) and Immune-mediated Colitis (IMC) (FMT-ELIMINATE)
Overview
- Phase
- Phase 2
- Intervention
- MTP-101-C
- Conditions
- Immune-mediated Colitis (IMC)
- Sponsor
- Diwakar Davar
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Incidence of Dose-Limiting Toxicities (DLTs)
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
Multiple retrospective studies suggest that the administration of corticosteroids to treat irAEs is safe, and does not compromise efficacy of ICI therapy in cancer patients. While ~67% of patients respond to corticosteroids, 33% of patients require biologic therapy such as TNFα inhibitors (e.g. infliximab), integrin α4β7 inhibitors (e.g. vedolizumab), or JAK/STAT inhibitors (e.g. tofactinib). This study aims to determine that distinct pathobionts govern the development of irCAE and IMC; and that the administration of hdFMT may reverse steroid-refractory irCAEs or IMC. The use of hdFMT has been shown to be effective in steroid and biologic (TNFα and/or integrin α₄β₇ inhibitor) refractory colitis in PD-1 and/or CTLA-4 ICI treated cancer patients in single-institution case series.
Detailed Description
The study will be conducted over a 42-day period. Patients receiving anti-PD(L)1 and/or anti-CTLA-4 singly or in combination with other investigational agents are eligible to enroll. Enrollment is not limited by setting (adjuvant, metastatic) and/or line of therapy (1L, 2L etc.). Once enrolled, patients will be enrolled to receive MTP-101-C (encapsulated fecal microbiota, containing \~5 x 1011 bacteria derived from healthy donors) without prior antibiotic conditioning. MTP-101-C will be continued for 28 days during which steroids will be tapered rapidly. irAE endpoint assessment will be repeated following completion of hdFMT (D+28 to D+35) and at 6 weeks (D+42 to D+49). Biospecimens will be obtained periodically. The total duration of MTP-101-C therapy is 4 weeks. This study aims to determine distinct pathobionts govern the development of distinct irAEs including steroid-refractory irCAE or IMC; and that the administration of hdFMT ameliorates irCAE or IMC based on validated cohort-specific assessments: modified CTCAE grading system (cohort 1) or endoscopic assessment scale (full Mayo score, FMS) (cohort 2). Further, this trial aims to show that amelioration of inflammatory pathology is associated with key secondary objectives including: 1) improvements in an irAE toxicity-specific PRO FACT-ICM; and 2) clinically assessment scales. Also, this study will measure the correlation between symptom amelioration and changes in integrated biomarkers include measures of intestinal inflammation (fecal calprotectin), bacterial engraftment (metagenomic) and reactivity to donor bacteria (IgG-seq); exploring the effects of microbiome modulation upon time to steroid discontinuation, time to resumption of therapy, time to next treatment clinical remission by FMS, clinical remission by PMS, and key survival endpoints.
Investigators
Diwakar Davar
Assistant Professor of Medical oncology
University of Pittsburgh
Eligibility Criteria
Inclusion Criteria
- •Able to swallow oral medication.
- •The participant provides written informed consent for the trial.
- •Willingness to use contraception for duration of trial participation. Male participants: A male participant must agree to use a contraception per protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
- •Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
- •Not a woman of childbearing potential (WOCBP) per protocol; OR A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
- •Clinically confirmed inflammatory irCAE or endoscopically confirmed IMC. Cohort 1 (irCAE): Patients with maculopapular rash, psoriasiform, lichenoid eruptions or bullous pemphigoid of at least grade 3 severity per CTCAE grading system (i.e. \>30% BSA with moderate or severe symptoms) during Screening.
- •Cohort 2 (IMC): Endoscopically confirmed inflammatory colitis as determined by colonoscopy or flexible sigmoidoscopy during Screening with minimum severity per Mayo endoscopic subscore 1-¬3 \[MES1-3\].
- •Prior receipt of anti-PD(L)1 and/or anti-CTLA-4 singly or in combination with other approved or investigational agents including chemotherapy or targeted therapy.
- •NOTE: Patient may have received or are receiving ICI therapy as standard-of-care or part of a clinical trial.
- •Patient must have received treatment with an anti-PD-(L)1 ICI, anti-CTLA-4 ICI singly and/or in combination with other approved and/or investigational anti-cancer agent(s), as their most recent therapy prior to development of colitis.
Exclusion Criteria
- •Multiple irAEs besides irCAE or IMC.
- •Patients with concurrent ≥Grade 3 irAEs besides irCAE or IMC that necessitate systemic immune suppression are not candidates for this trial.
- •Patients with irCAE and/or IMC that are not otherwise clarified in Section 5.1.5 (irCAE including alopecia etc.) are not candidates for this trial.
- •Patients with concomitant irAEs that are well controlled (≤Grade 1 or Grade 2 on repletion medication) may be enrolled at the discretion of Sponsor-Investigator.
- •Diagnosis of immunodeficiency, immunosuppression or any other form of immunosuppressive therapy besides steroids/biologics within 7 days prior to the first dose of MTP-101-C treatment.
- •Patients at high risk of MDRO colonization including: nursing home residence, age \>85, underlying diseases (dementia, poorly controlled diabetes, chronic wounds), in-dwelling medical devices (urinary catheters, feeding tubes, PEG tubes) and a prior history of MDRO colonization.
- •Contraindication to endoscopy (cohort 2 only).
- •Contraindication to MTP-101-C administration.
- •Any prior head/neck and/or abdominal surgery resulting in potentially altered absorption of orally administered FMT pills.
- •Active bacterial infection requiring systemic antibiotic therapy.
Arms & Interventions
MTP-101-C (Cohort 1: Steroid R/R biologic-naive dermatitis)
Patients given MTP-101-C (encapsulated fecal microbiota, containing \~5 x 1011 bacteria derived from healthy donors). Dosing: 5 capsules/day (Day 1); 2 capsules/day (D2-D28)
Intervention: MTP-101-C
MTP-101-C (Cohort 2: Steroid R/R biologic-naive colitis)
Patients given MTP-101-C (encapsulated fecal microbiota, containing \~5 x 1011 bacteria derived from healthy donors). Dosing: 5 capsules/day (Day 1); 2 capsules/day (D2-D28)
Intervention: MTP-101-C
Outcomes
Primary Outcomes
Incidence of Dose-Limiting Toxicities (DLTs)
Time Frame: Up to 2 months
Incidence of dose-limiting toxicities (DLTs) in ICB-treated cancer patients treated with MTP-101-C. DLT is defined as any adverse event(s) (AEs) considered possibly, probably, or definitely related to MTP-101-C, which occur during the treatment phase. During DLT monitoring period, no further accrual will be permitted. Any patient who has started the studied treatment will be evaluable for safety. AEs will be considered DLTs if deemed related to study therapy: Hematologic: Grade 4 neutropenia, Febrile neutropenia, Grade ≥ 3 neutropenic infection, Grade ≥ 3 thrombocytopenia with bleeding, Grade 4 thrombocytopenia. Non-hematologic: Grade ≥ 3 toxicities (non-laboratory), Grade ≥ 3 nausea, vomiting or diarrhea despite maximal medical intervention, Grade 4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Other (non-AST/ALT) non-hematologic Grade ≥ 3 laboratory value if the abnormality leads to overnight hospitalization
Incidence of adverse events (AEs)
Time Frame: Up to 2 months
Incidence of adverse events (AEs) in ICB-treated cancer patients treated with MTP-101-C.
Secondary Outcomes
- Patient Reported Outcomes - FACT-ICM(At Screening, Day +28 through Day +35, Day +42 through Day +49)
- Resolution of steroid relapsed/refractory irCAEs (cohort 1)(Up to 2 months)
- Resolution of steroid relapsed/refractory IMC (cohort 2)(Up to 2 months)
- Resolution of IMC following MTP-101-C in steroid relapsed/refractory irCAE (cohort 1)(Up to 2 months)
- Resolution of IMC following MTP-101-C in steroid relapsed/refractory IMC (cohort 2)(Up to 2 months)
- Patient Reported Outcomes - FACIT-general(At Screening, Week 1, Week 2, Week 3, Week 4)