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

Trial Summary

What is the purpose of this trial?

This study is to determine if Healthy Donor FMT (hdFMT) improves the body's ability to fight cancer in patients with relapsed/refractory PD-L1 Positive NSCLC.

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.

What data supports the effectiveness of the treatment FMT + Pembrolizumab for Non-Small Cell Lung Cancer?

Pembrolizumab, a drug used in this treatment, has shown effectiveness in treating various cancers, including colorectal and gastric cancer, by improving survival rates and being approved by the FDA for certain cancer types. Although specific data for non-small cell lung cancer is not provided, its success in other cancers suggests potential benefits. ^{1 2 3 4 5}

Is FMT combined with Pembrolizumab safe for humans?

Fecal microbiota transplantation (FMT) is generally considered safe for treating recurrent Clostridioides difficile infection and is being explored for other conditions, though there are concerns about infectious risks, especially in immunocompromised patients. Pembrolizumab, an immune checkpoint inhibitor, can cause immune-related side effects, but FMT has been used to manage some of these side effects, like colitis, in certain cases. ^{6 7 8 9 10}

What makes the FMT + Pembrolizumab treatment unique for non-small cell lung cancer?

FMT (Fecal Microbiota Transplant) combined with Pembrolizumab is unique because it uses a combination of stool transplant to alter gut bacteria and an immunotherapy drug (Pembrolizumab) to boost the immune system's ability to fight cancer, which is different from traditional chemotherapy or radiation treatments. ^{11 12 13 14 15}

Research Team

Diwakar Davar, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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) 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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[MSI Status in Colorectal Cancer]. [2019]

2. United States 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of gastric cancer. [2019]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Durable complete response to pembrolizumab in microsatellite stable colorectal cancer. [2022]

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

Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer. [2022]

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

Use of Fecal Microbial Transplantation for Immune Checkpoint Inhibitor Colitis. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Fecal microbiota transplantation for refractory diarrhea in immunocompromised diseases: a pediatric case report. [2020]

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

Faecal microbiota transplantation: establishment of a clinical application framework. [2022]

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

Current Evidence for the Management of Inflammatory Bowel Diseases Using Fecal Microbiota Transplantation. [2020]

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

Safety and tolerability of frozen, capsulized autologous faecal microbiota transplantation. A randomized double blinded phase I clinical trial. [2023]

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

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

12. United States 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. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Early detection of colorectal cancer with faecal occult blood test screening. [2010]

14. Canada pubmed.ncbi.nlm.nih.gov

Endoscopic follow-up of positive fecal occult blood testing in the Ontario FOBT Project. [2022]

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

Advances in Fecal Occult Blood Tests: the FIT revolution. [2022]