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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
MTP-101-C is a screened, freeze-dried, encapsulated, full spectrum, healthy donor fecal microbiota product.
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
RECRUITINGIncidence of adverse events (AEs)
Incidence of adverse events (AEs) in ICB-treated cancer patients treated with MTP-101-C.
Time frame: Up to 2 months
Incidence of Dose-Limiting Toxicities (DLTs)
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
Time frame: Up to 2 months
Resolution of steroid relapsed/refractory irCAEs (cohort 1)
Resolution of steroid relapsed/refractory irCAEs (cohort 1) following MTP-101-C using cohort -specific endpoints including modified CTCAE grading system (cohort 1)
Time frame: Up to 2 months
Resolution of steroid relapsed/refractory IMC (cohort 2)
Resolution of steroid relapsed/refractory IMC (cohort 2) following MTP-101-C using cohort -specific endpoints including modified CTCAE grading system (cohort 1) or endoscopic assessment scale Full Mayo Score (FMS) (cohort 2). FMS includes Partial Mayo Score (PMS) plus endoscopic findings. PMS assesses Stool frequency (per day - normal number of stools to ≥ 5 more, Rectal bleeding (none to blood alone passes) and Physician's global assessment (normal to severe disease), all with scores ranging from 0 to 3. Scores range from 0 - 9 points. Endoscopic score findings range from 0 - 3. Total full scores range from 0 to12, with higher scores indicating more severe ulcerative colitis.
Time frame: Up to 2 months
Resolution of IMC following MTP-101-C in steroid relapsed/refractory irCAE (cohort 1)
Resolution of IMC following MTP-101-C in steroid relapsed/refractory irCAE (cohort 1) or IMC (cohort 2) using clinical endpoint Partial Mayo Score (PMS), which assesses Stool frequency (per day - normal number of stools to ≥ 5 more, Rectal bleeding (none to blood alone passes) and Physician's global assessment (normal to severe disease), all with scores ranging from 0 to 3. Scores range from 0 - 9 points, with higher scores indicating more severe ulcerative colitis.
Time frame: Up to 2 months
Resolution of IMC following MTP-101-C in steroid relapsed/refractory IMC (cohort 2)
Resolution of IMC following MTP-101-C in steroid relapsed/refractory irCAE (cohort 1) or IMC (cohort 2) using clinical endpoint Partial Mayo Score (PMS), which assesses Stool frequency (per day - normal number of stools to ≥ 5 more, Rectal bleeding (none to blood alone passes) and Physician's global assessment (normal to severe disease), all with scores ranging from 0 to 3. Scores range from 0 - 9 points, with higher scores indicating more severe ulcerative colitis.
Time frame: Up to 2 months
Patient Reported Outcomes - FACT-ICM
The FACT-ICM is a self-administered questionnaire that measures quality of life within the prior 7 days in patients being treated with immunotherapy, using 52 items with a 5-point Likert-type scale, (0 = Not at all to 5 = Very Much). Subscales include Physical Well-Being max score=28), Social/Family Well-Being (max score=28), Emotional Well-Being (max score=24), Functional Well-Being (max score=28), Immune Checkpoint Modulator Subscale (max score=100). Total scores= 0 to 208, with higher scores indicating better quality of life.
Time frame: At Screening, Day +28 through Day +35, Day +42 through Day +49
Patient Reported Outcomes - FACIT-general
FACIT-general is a self-administered questionnaire that measures quality of life within the prior 7 days in patients being treated with immunotherapy, using 27 items with a 5-point Likert-type scale, (0 = Not at all to 5 = Very Much). Subscales include Physical Well-Being max score=28), Social/Family Well-Being (max score=28), Emotional Well-Being (max score=24), Functional Well-Being (max score=28), Total scores= 0 to 108, with higher scores indicating better quality of life.
Time frame: At Screening, Week 1, Week 2, Week 3, Week 4
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