FMT + Pembrolizumab for Non-Small Cell Lung Cancer

Overseen By Danielle L Bednarz, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Diwakar Davar

Must be taking: Anti-PD(L)1 ICI

Must not be taking: Live vaccines, Immunosuppressants

Disqualifiers: Small cell NSCLC, Active infections, 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

Compensation: Varies

Number of Visits: 12

26 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a fecal microbiota transplant (FMT), combined with the drug pembrolizumab, can help the body fight non-small cell lung cancer (NSCLC) resistant to standard treatments. Researchers aim to determine if introducing healthy bacteria from a donor can enhance the immune response against the cancer. The trial is open to individuals with stage IV NSCLC who have already received and progressed on certain cancer therapies. Participants should be willing to undergo FMT through procedures like colonoscopy and take oral capsules. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions a 2-week period without prior chemotherapy, targeted therapy, or small molecule therapy before starting the study. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that combining Fecal Microbiota Transplant (FMT) with immunotherapy, such as pembrolizumab, is generally safe for patients. Studies have explored FMT in cancer treatment and found it well-tolerated. For instance, one study found that FMT combined with immunotherapy helped patients fight cancer without major side effects.

Another study using oral microbiota capsules (a type of FMT) with immunotherapy also reported safety and effectiveness. This suggests that FMT, whether administered directly to the colon or as capsules, is safe to use with treatments like pembrolizumab.

Pembrolizumab is a well-known cancer treatment already approved by the FDA for various cancers, indicating it has been tested for safety in humans. People taking pembrolizumab might experience side effects, but these are usually manageable.

In summary, both FMT and pembrolizumab have demonstrated good safety in studies. While some side effects may occur, they are usually not severe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using fecal microbiota transplant (FMT) combined with pembrolizumab for treating non-small cell lung cancer because it introduces a novel way to potentially boost the immune response. Unlike standard treatments like chemotherapy and radiation, which directly target cancer cells, this combination aims to enhance the body's natural defenses. FMT is unique because it involves transferring healthy gut bacteria, which may improve how the immune system responds to pembrolizumab, an immunotherapy drug. By potentially altering the gut microbiome, this approach could help pembrolizumab work more effectively, offering a promising new strategy for patients.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

In this trial, participants will receive a combination of Fecal Microbiota Transplant (FMT) and Pembrolizumab. Research has shown that FMT can enhance the body's immune response to tumors when used with cancer treatments. Studies have found that FMT can improve patient responses to treatments like Pembrolizumab. Evidence suggests that the gut microbiome, the community of tiny organisms in the intestines, plays a crucial role in enhancing these treatments. For example, one study found that patients with non-small cell lung cancer (NSCLC) who received FMT along with Pembrolizumab lived longer overall. This combination appears promising in helping the body fight cancer more effectively. ^{1 2 3 6 7}

Who Is on the Research Team?

Diwakar Davar, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

Adults with PD-L1 Positive NSCLC that has worsened after anti-PD(L)1 therapy can join. They must have measurable disease, good organ function, and agree to use contraception. Excluded are those pregnant or breastfeeding, with certain infections like active COVID-19 or HIV, severe allergies to immunotherapy drugs, recent live vaccines, autoimmune diseases needing treatment in the last 2 years, or other cancers within 3 years.

Inclusion Criteria

I agree to follow the contraception guidelines and not donate sperm for 120 days after my last treatment.

My cancer has worsened despite treatment with specific immune therapy.

You are expected to live for at least 12 weeks, based on a specific scoring system.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

I do not have active infections like TB, COVID-19, HIV, or Hepatitis B/C.

I cannot receive FMT due to specific health reasons.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

5 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive Healthy Donor FMT (hdFMT) via colonoscopy and pembrolizumab every 3 weeks

9 weeks

3 visits (in-person)

Treatment Phase 2

Participants receive R-FMT via sigmoidoscopy or oral capsules every 9 weeks and pembrolizumab every 3 weeks

up to 2 years

8 visits (in-person) for FMT, 34 visits (in-person) for pembrolizumab

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Fecal Microbiota Transplant (FMT)
• Pembrolizumab

Trial Overview The trial is testing if fecal microbiota transplant (FMT) can boost the immune system's cancer-fighting abilities when combined with Pembrolizumab in patients whose NSCLC has relapsed or is resistant to previous treatments. Participants will receive FMT through endoscopic procedures alongside standard immunotherapy.

How Is the Trial Designed?

Group I: Healthy Donor Fecal Microbiota Transplant (hdFMT) with Pembrolizumab Experimental Treatment 2 Interventions

The hdFMT along with an intestinal biopsy will be performed as outpatient by a gastroenterologist. The hdFMT is infused into the colon by performing a colonoscopy (Treatment Phase 1) and by a sigmoidoscopy or oral capsules (Treatment Phase 2). FMT will be performed on Cycle 1 Day 1 and Cycle 3 Day 1 during Treatment Phase 1 and every 9 weeks starting with Cycle 4 Day 1 during Treatment Phase 2. Pembrolizumab, 200mg, will be administered as a 30-minute IV infusion every 3 weeks starting Cycle 1 Day 1 (same day as the hdFMT), and continue on Day 1 of each 21-day cycle.

Fecal Microbiota Transplant (FMT) is already approved in United States for the following indications:

Approved in United States as Fecal Microbiota Transplant for:

• Recurrent Clostridioides difficile infection (CDI)

Who Is Running the Clinical Trial?

Diwakar Davar

Lead Sponsor

Trials

12

Recruited

420+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Gateway Fund for Cancer Research (GFCR)

Collaborator

Trials

1

Recruited

30+

Published Research Related to This Trial

Faecal microbiota transplantation (FMT) is being established as a safe second-line treatment for recurrent Clostridium difficile infections, with a comprehensive framework developed to ensure donor screening and clinical application comply with the European Tissue Act.

The framework includes rigorous donor recruitment and screening processes, laboratory protocols for processing faecal samples, and a structured follow-up system to monitor patient outcomes, ensuring safety and traceability in FMT procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Faecal microbiota transplantation: establishment of a clinical application framework. Jørgensen, SMD., Hansen, MM., Erikstrup, C., et al.[2022]

Capsulized autologous faecal microbiota transplantation (FMT) was found to be safe and well tolerated in a study of 24 healthy volunteers, with no serious side effects reported during the treatment.

While both the FMT and placebo groups showed improvements in general and intestinal health after antibiotic treatment, there was no significant difference in the time it took for participants to normalize their intestinal habits, indicating that FMT did not provide additional benefits over placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of frozen, capsulized autologous faecal microbiota transplantation. A randomized double blinded phase I clinical trial. Stefansson, M., Bladh, O., Flink, O., et al.[2023]

In a pilot study involving age-eligible volunteers (50 to 75 years) in Ontario, 73% of men and 56% of women with positive fecal occult blood tests (FOBT) proceeded to colonoscopy, indicating a generally high acceptance of follow-up procedures after positive screening results.

However, the median time to colonoscopy was significantly delayed, averaging 121 days for men and 202 days for women, suggesting that accessibility issues may hinder timely follow-up care for colorectal cancer screening.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endoscopic follow-up of positive fecal occult blood testing in the Ontario FOBT Project. Paszat, L., Rabeneck, L., Kiefer, L., et al.[2022]

Immunotherapy, particularly checkpoint inhibitors, has demonstrated promising results in treating various cancers, leading to FDA approvals for specific types of tumors, including those that are microsatellite instability-high (MSI-high) or mismatch repair deficient (dMMR).

Nivolumab has been specifically approved by the FDA for use in patients with MSI-high or dMMR colorectal cancer, highlighting the significance of MSI status in managing this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[MSI Status in Colorectal Cancer]. Mishima, S., Yoshino, T.[2019]

A patient with microsatellite instability-high (MSI-H) colorectal cancer treated with the PD-1 inhibitor pembrolizumab showed disease progression, highlighting that not all MSI-H tumors respond to immunotherapy despite having typical molecular features.

The study identified a biallelic loss of the β2-microglobulin gene, which is crucial for antigen presentation, and noted a high infiltration of natural killer cells and M2 macrophages in the tumor, suggesting potential mechanisms of resistance to PD-1 blockade and informing future immunotherapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer. Gurjao, C., Liu, D., Hofree, M., et al.[2022]

The study of 247 individuals found that detecting methylated Wif-1 in serum or urine is more accurate than traditional guaiac fecal occult blood tests (FOBT) for screening advanced colorectal neoplasia, achieving a C-statistic of 0.90.

Fecal microbiota dysbiosis did not show improved accuracy over FOBT for colorectal cancer screening, suggesting that while blood and urine tests may be useful alternatives, changes in gut bacteria alone are not reliable indicators.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The detection of the methylated Wif-1 gene is more accurate than a fecal occult blood test for colorectal cancer screening. Amiot, A., Mansour, H., Baumgaertner, I., et al.[2021]

Fecal microbiota transplantation (FMT) was successfully performed in two immunocompromised children with refractory diarrhea, leading to symptom remission without any infectious complications.

The procedure resulted in the reconstruction of a diverse microbiota, indicating that FMT is a safe and effective treatment option for managing diarrhea in immunocompromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation for refractory diarrhea in immunocompromised diseases: a pediatric case report. Zhong, S., Zeng, J., Deng, Z., et al.[2020]

Fecal immunochemical tests (FITs) are superior to guaiac-based FOBTs (gFOBTs) for colorectal cancer screening due to their higher sensitivity for detecting cancers and advanced adenomas, as well as better participant acceptance.

FITs offer flexibility in adjusting positivity cutoffs based on specific screening scenarios, making them the preferred choice for most situations, while gFOBTs are only suitable for scenarios with limited colonoscopy resources.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Fecal Occult Blood Tests: the FIT revolution. Young, GP., Symonds, EL., Allison, JE., et al.[2022]

A 71-year-old man with immune checkpoint inhibitor (ICI) colitis, which did not respond to standard treatments like corticosteroids and biologic therapy, showed improvement after receiving fecal microbiota transplantation (FMT).

This case suggests that FMT may be a promising alternative treatment for severe ICI colitis, especially in patients who do not respond to conventional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Fecal Microbial Transplantation for Immune Checkpoint Inhibitor Colitis. Fasanello, MK., Robillard, KT., Boland, PM., et al.[2020]

Fecal microbiota transplantation (FMT) has shown promise in facilitating clinical and endoscopic remission in patients with active ulcerative colitis (UC), based on randomized controlled trials and meta-analyses.

While FMT appears to be safe with mostly mild adverse events, there is a need for further research to clarify its efficacy in Crohn's disease (CD) and to address important factors like donor selection and treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current Evidence for the Management of Inflammatory Bowel Diseases Using Fecal Microbiota Transplantation. Jeon, SR., Chai, J., Kim, C., et al.[2020]

Pembrolizumab significantly improved progression-free survival (PFS) in patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer, with a median PFS of 16.5 months compared to 8.2 months for standard chemotherapy, indicating its efficacy as a first-line treatment.

The FDA found no safety concerns during the approval process, and while both pembrolizumab and standard of care had similar adverse reactions, the duration of treatment with pembrolizumab was nearly double that of standard care, suggesting a potentially more favorable treatment profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. Casak, SJ., Marcus, L., Fashoyin-Aje, L., et al.[2022]

Pembrolizumab is the first FDA-approved immune checkpoint inhibitor for gastric cancer, demonstrating significant effectiveness in the third-line treatment of advanced and metastatic cases.

Current research is exploring pembrolizumab's potential as an initial treatment combined with chemotherapy, while also investigating how molecular changes and the gut microbiome may influence the response to immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of gastric cancer. Kamath, SD., Kalyan, A., Benson, AB.[2019]

A 34-year-old woman with metastatic colorectal cancer (CRC) of the microsatellite stable, mismatch-repair-proficient (MSS-pMMR) phenotype showed a dramatic and durable response to pembrolizumab, an anti-PD-1 antibody, despite this phenotype typically being unresponsive to such treatments.

This case suggests that PD-L1 expression levels may serve as a predictor for response to immunotherapy, indicating that MSS-pMMR patients should not be excluded from receiving checkpoint inhibitors like pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable complete response to pembrolizumab in microsatellite stable colorectal cancer. Gomar, M., Najafi, M., Aghili, M., et al.[2022]

The annual guaiac or immunochemical fecal occult blood test (FOBT) is one of the recommended screening methods for colorectal cancer (CRC) by the American Cancer Society, highlighting its importance in early detection.

Stool-based DNA testing for CRC is emerging as a promising technology, suggesting advancements in noninvasive screening methods that could improve detection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of three stool tests for colorectal cancer screening. Greenwald, B.[2017]

Biennial faecal occult blood test (FOBT) screening significantly improves the detection of early-stage colorectal cancer, with 52% of FOBT-positive subjects diagnosed at an early stage compared to 38% in the unscreened control group.

Despite the benefits of FOBT screening, a concerning 27.3% of colorectal tumors in the screened population were interval cancers, indicating that some cancers may still develop between screenings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early detection of colorectal cancer with faecal occult blood test screening. Paimela, H., Malila, N., Palva, T., et al.[2010]

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NCT04951583 | Fecal Microbial Transplantation Non- ... ... non-small cell lung cancer (NSCLC) and melanoma. With the use of anti-PD-1 (Pembrolizumab), overall survival (OS) is now 45% at two years for patients with ...

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Safety and preliminary efficacy of different doses of fecal ... This preliminary study demonstrates that the combination of oral microbiota capsule and immunotherapy can open up a more economical, safe, and effective avenue