Fecal Microbiota Transplant + Anti-PD-1 Therapy for Metastatic Colorectal Cancer

Overseen By Michael J Overman, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Anti-PD-1 therapy

Must not be taking: Live vaccines, Immunosuppressants

Disqualifiers: Ileostomy, Colostomy, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 15

Duration: 6 months

15 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have received any systemic anti-cancer therapy within 2 weeks of starting the study treatment, except for ongoing nivolumab or pembrolizumab therapy.

What data supports the effectiveness of the treatment Fecal Microbiota Transplantation combined with anti-PD-1 therapy for metastatic colorectal cancer?

Research shows that combining fecal microbiota transplantation (FMT) with anti-PD-1 therapy has been effective in treating melanoma, with some patients experiencing complete responses. This suggests potential benefits for other cancers, like colorectal cancer, by enhancing the immune response and overcoming resistance to treatment. ^{1 2 3 4 5}

Is Fecal Microbiota Transplant plus Anti-PD-1 Therapy safe for humans?

Research shows that combining Fecal Microbiota Transplant (FMT) with anti-PD-1 therapy is generally safe, with no severe side effects from FMT alone and some immune-related side effects from the combination therapy in melanoma patients. ^{1 2 3 4 6}

How is the treatment of Fecal Microbiota Transplant + Anti-PD-1 Therapy for Metastatic Colorectal Cancer different from other treatments?

This treatment is unique because it combines fecal microbiota transplantation (FMT), which involves transferring healthy gut bacteria from a donor, with anti-PD-1 therapy, a type of immunotherapy that helps the immune system attack cancer cells. This combination aims to enhance the effectiveness of immunotherapy by improving the gut microbiome, which can influence the body's response to cancer treatment. ^{1 3 4 7 8}

Research Team

Michael J Overman, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with metastatic colorectal cancer that didn't respond to anti-PD-1 therapy. They must have a certain type of tumor (dMMR or MSI-H), good kidney and liver function, no severe allergies to pembrolizumab or nivolumab, not be pregnant, and agree to use effective contraception.

Inclusion Criteria

My cancer has spread and can be measured by scans.

My blood counts are within a healthy range.

Participant (or legally acceptable representative) must provide written informed consent for the trial

Exclusion Criteria

I don't have any health issues that could affect the study's results.

I haven't had cancer treatment in the last 2 weeks.

I have not had major surgery in the last 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment

Patients receive metronidazole, vancomycin, and neomycin prior to colonoscopic FMT

8 days

1 visit (in-person)

Treatment

Patients undergo colonoscopic FMT and receive pembrolizumab or nivolumab with fecal microbiota transplantation capsules

6 months

Multiple visits (in-person and virtual) every 14-21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Fecal Microbiota Transplantation
• Nivolumab
• Pembrolizumab

Trial Overview The study tests if fecal microbiota transplants combined with pembrolizumab or nivolumab can help control metastatic colorectal cancer in patients who previously did not respond to anti-PD-1 therapies. It includes questionnaires, antibiotics before the transplant, biopsies, and follow-up assessments.

Participant Groups

Group I: Arm II (FMT, nivolumab) Experimental Treatment 7 Interventions

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.

Group II: Arm I (FMT, pembrolizumab) Experimental Treatment 8 Interventions

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.

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The gut microbiome can predict the risk of developing immune-related adverse events (irAEs) in melanoma patients undergoing immune checkpoint blockade (ICB) therapy, with two distinct bacterial community clusters identified that show a nearly 7-fold difference in risk.

Specific bacterial strains, such as Bacteroides dorei in the high-risk group and Bacteroides vulgatus in the low-risk group, were linked to the likelihood of developing irAEs, suggesting that the gut microbiome composition may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma. Usyk, M., Pandey, A., Hayes, RB., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation plus Anti-PD-1 Is Safe in a First-line Setting. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation Effectively Cures a Patient With Severe Bleeding Immune Checkpoint Inhibitor-Associated Colitis and a Short Review. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Bacteroides vulgatus and Bacteroides dorei predict immune-related adverse events in immune checkpoint blockade treatment of metastatic melanoma. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. [2022]