Fecal Microbiota Transplant and Re-introduction of Anti-PD-1 Therapy (Pembrolizumab or Nivolumab) for the Treatment of Metastatic Colorectal Cancer in Anti-PD-1 Non-responders

NCT04729322 | Active Not Recruiting Phase 2 FDA Drug

• 3 other identifiers: 2020-0186NCI-2020-13897P50CA221707
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the effect of fecal microbiota transplant and re-introduction of anti-PD-1 therapy (pembrolizumab or nivolumab) in treating anti-PD-1 non-responders with colorectal cancer that has spread to other places in the body (metastatic). Fecal microbiota transplants contain the normal bacteria and viruses found in fecal (stool) material. Immunotherapy with monoclonal antibodies, such as pembrolizumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab or nivolumab with fecal microbiota transplants may help to control the disease.

Conditions

Metastatic Colorectal Adenocarcinoma; Metastatic Small Intestinal Adenocarcinoma; Stage IV Colorectal Cancer AJCC v8; Stage IV Small Intestinal Adenocarcinoma AJCC v8; Stage IVA Colorectal Cancer AJCC v8; Stage IVB Colorectal Cancer AJCC v8; Stage IVC Colorectal Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Objective response rate

  Assessed by Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST). Will be summarized by mean, standard error, and 95% confidence interval.

  Up to 3 years post-treatment

Study Arms (2)

Arm I (FMT, pembrolizumab)

EXPERIMENTAL

Patients receive metronidazole PO Q8H on days -14 to -8 and then vancomycin PO Q6H and neomycin PO Q6H on days -8 to -6. Patients then undergo colonoscopic FMT on day -5. POST-COLONOSCOPIC FMT: Patients receive standard of care pembrolizumab IV over 30 minutes on day 1. Patients also receive fecal microbiota transplantation capsule PO on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients receive fecal microbiota transplantation capsule PO on day 1. Cycles repeat every 21 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

Procedure: Biopsy; Procedure: Fecal Microbiota Transplantation; Drug: Fecal Microbiota Transplantation Capsule; Drug: Metronidazole; Drug: Neomycin; Biological: Pembrolizumab; Other: Questionnaire Administration; Drug: Vancomycin

Arm II (FMT, nivolumab)

EXPERIMENTAL

Patients receive metronidazole PO Q8H on days -14 to -8 and then vancomycin PO Q6H and neomycin PO Q6H on days -8 to -6. Patients then undergo colonoscopic FMT on day -5. POST-COLONOSCOPIC FMT: Patients receive standard of care nivolumab IV over 30 minutes on day 1. Patients also receive fecal microbiota transplantation capsule PO on days 1 and 8 of cycles 1-2. Beginning in cycle 4, patients receive fecal microbiota transplantation capsule PO on day 1 of every other cycle. Cycles repeat every 14 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

Procedure: Biopsy; Procedure: Fecal Microbiota Transplantation; Drug: Fecal Microbiota Transplantation Capsule; Drug: Metronidazole; Biological: Nivolumab; Other: Questionnaire Administration; Drug: Vancomycin

Interventions

Biopsy PROCEDURE

Undergo biopsy

Also known as: BIOPSY_TYPE, Bx

Arm I (FMT, pembrolizumab); Arm II (FMT, nivolumab)

Fecal Microbiota Transplantation PROCEDURE

Undergo colonoscopic FMT

Also known as: Fecal Material Transplantation, Fecal Transplantation, FMT, Poo Transplant, Poop Transplant, Stool Transplant

Arm I (FMT, pembrolizumab); Arm II (FMT, nivolumab)

Fecal Microbiota Transplantation Capsule DRUG

Given PO

Also known as: Fecal Microbiota Preparation Delivery Capsule, FMPCapDE, FMT Capsule DE, FMT Capsule Delivery, FMT DE Capsule

Arm I (FMT, pembrolizumab); Arm II (FMT, nivolumab)

Metronidazole DRUG

Given PO

Also known as: Flagyl, Flagyl I.V. RTU, Tricom

Arm I (FMT, pembrolizumab); Arm II (FMT, nivolumab)

Neomycin DRUG

Given PO

Also known as: Neomycin Complex

Arm I (FMT, pembrolizumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Arm II (FMT, nivolumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Arm I (FMT, pembrolizumab)

Questionnaire Administration OTHER

Ancillary studies

Arm I (FMT, pembrolizumab); Arm II (FMT, nivolumab)

Vancomycin DRUG

Given PO

Arm I (FMT, pembrolizumab); Arm II (FMT, nivolumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants are eligible to be included in the study only if all of the following criteria apply:
• At least 18 years of age on the day of signing informed consent
• Histologically/cytologically confirmed diagnosis of solid tumor
• Tumor that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) as determined by one of three methods:
• Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, MSH2 or MSH6
• PCR determined microsatellite instability at \>30% of tested microsatellites
• Next-generation determined MSI-H based upon instability at multiple microsatellites as determined by the specific next generation sequencing panel
• Have metastatic disease that is measurable based on iRECIST v1.1.
• Demonstrated prior progression on anti-PD1/L1 based therapy by radiographic progression. The potential for psuedoprogression should be excluded by concurrent carcinoembryonic antigen (CEA) or other tumor marker or ctDNA elevation, or clinical symptom progression, or short interval repeat imaging confirming progression.
• Must have received at least 2 doses of a PD1/PD-L1 inhibitor
• Progressive disease either during therapy or within 2 months of last dose of therapy.
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Patients must be willing to undergone mandatory tumor biopsies at pre-treatment, at time of colonoscopy if possible and on-treatment (unless deemed unsafe by interventional radiology or by approval by study PI).
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Estimated life-expectancy of \> 4 months.

You may not qualify if:

• Participants are excluded from the study if any of the following criteria apply:
• Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks of study treatment (excluding continuation of ongoing nivolumab or pembrolizumab therapy).
• If participant received major surgery within last 4 weeks, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Has an ileostomy or colostomy bag.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities (excluding skin toxicity), not require corticosteroids, and not have had radiation pneumonitis.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Has a diagnosis of immunodeficiency (excluding IgA deficiency).
• Has an active autoimmune condition and is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10mg of prednisone or equivalent per day.
• Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab or nivolumab and/or any of its excipients.
• Serious adverse immune related adverse events (grade 3 or 4) with previous immune checkpoint therapy, that were symptomatic and required prolong immunosuppression (\>6weeks).
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the study subject's best interest to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• M D Anderson Cancer Center

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Biopsy; Fecal Microbiota Transplantation; Parturition; Metronidazole; Benchmarking; Neomycin; Nivolumab; pembrolizumab; Vancomycin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Biological Therapy; Therapeutics; Pregnancy; Reproduction; Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena; Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Management Audit; Organization and Administration; Health Services Administration; Program Evaluation; Quality of Health Care; Quality Assurance, Health Care; Health Care Quality, Access, and Evaluation; Health Care Evaluation Mechanisms; Aminoglycosides; Glycosides; Carbohydrates; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Glycopeptides; Glycoconjugates; Peptides

Study Officials

• Michael J Overman

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2021
• First Posted: January 28, 2021
• Study Start: February 22, 2021
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: December 23, 2025

Record last verified: 2025-12

Locations

US (1)