Fecal Microbiota Transplantation With Immune Checkpoint Inhibitors in Lung Cancer

Phase 2

Recruiting

• Conditions: Metastatic Lung Cancer
• Interventions: Drug: Antibiotics; Other: FMT (Fecal Microbiota Transplantation)

• Registration Number: NCT05502913
• Lead Sponsor: Soroka University Medical Center

Brief Summary

Immunotherapy has recently become a main-stream treatment option in cancer care, with improved clinical outcomes in many malignancies, especially that of lung cancer. The long-term benefits of this treatment however are limited. There is therefore a critical need to distinguish predictive biomarkers of response from those of resistance, and to develop synergistic strategies for improved therapeutic response. Strong emerging evidence indicates that the gut microbiome has the ability to influence response to immunotherapy. Unlike tumor genomics, the gut microbiome is modifiable, and thus its modulation to enhance response to immunotherapy is an attractive therapeutic strategy.

Working hypothesis: Fecal Microbiota Transplant (FMT) treatment in conjunction with standard (chemo-)immunotherapy as a first-line treatment for metastatic lung cancer enhances disease control rate.

The main objective of this study is to evaluate the safety and efficacy of Fecal Microbiota Transplant (FMT) in altering response to immunotherapy in patients with metastatic lung cancer. The overall goal is to determine microbiome compositional and gene-content changes in patients who respond more efficiently to immunotherapy subsequent to FMT. This understanding may lead to future microbiome-based treatments in combination with immunotherapy to significantly increase lung cancer treatment efficacy. In this prospective clinical and molecular study, we will perform an in-depth analysis of the potential role of FMT in the context of immunotherapy.

Detailed Description

Only a small subset of tumor types benefit from immune checkpoint inhibitor therapy, where most responders eventually develop resistance. Oral administration of Fecal Microbiota Transplantation (FMT) from treatment-responsive patients has been found to considerably improve Programmed death-ligand 1 (PD-L1)-based immunotherapy outcomes as well as inhibit tumor growth through augmented dendritic cell and T cell responses.

This study aims to investigate the safety and efficacy of FMT treatment combined with first-line (chemo-)immunotherapy in metastatic lung cancer. The study will include a thorough microbiome composition analysis of FMT donors and recipients to be correlated to clinical outcomes. In addition, blood samples will be analyzed using a novel commensal antigen microarray for rapid serum profiling.

Patients with metastatic malignancy who completely respond to immunotherapy will serve as the fecal implant donors. Dr. Arik Segal's Lab will produce capsules with one donor/capsule. In an open-label approach, patients will receive FMT on the first day of (chemo-)immunotherapy cycle one and every 3-4 weeks based on the specific (chemo-)immunotherapy protocol. Before FMT treatment, participants will receive active antibiotics. The second arm will receive standard-of-care treatment only. Study participants will be evaluated throughout the study using imaging, laboratory, vital signs, and disease status assessments until the end of the study.

Stool samples from study participants will be collected before the start of treatment during the (chemo-)immunotherapy cycle and at the end of treatment for sequencing and bioinformatics analysis of the microbiome. Blood samples will be collected from all donors at the study start and from all recipients at recruitment, on the day of each FMT administration, and at the end of treatment.

Statistics:

A one-sided test for differences in proportions and type I error of 0.05 will have a power of 88% to detect a 30% difference in response between the FMT and placebo group, for a total of 80 randomized patients, 40 in each treatment group stratified by PD-L1 status.

Study Timeline

• Study First Submitted: 2022-08-08
• Study First Submitted QC: 2022-08-14
• Study First Posted: 2022-08-16
• Status Verified: 2023-09
• Study Start: 2023-09-01
• Last Update Submitted: 2023-09-27
• Last Update Posted: 2023-10-02
• Primary Completion: 2025-06-30
• Study Completion: 2028-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. A histologically confirmed diagnosis of malignancy.
2. Patients over the age of 18.
3. Patients planning to be treated with chemotherapy, immune checkpoint inhibitors and/or targeted therapy.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
5. Able to provide written informed consent.

Patient (Recipient)

Exclusion Criteria

1. Severe or life-threatening food allergy (e.g. nuts, seafood)

2. Allergy or other contraindication to omeprazole, investigational medicinal product.

3. Treatment with pre- or probiotics in the four weeks prior to randomization.

4. Severe immunodeficiency:

   • Systemic chemotherapy <30 days from baseline
   • Known neutropenia with absolute neutrophils <1.0x109 cells/µL
   • Prolonged treatment with corticosteroids (equivalent to prednisone >60mg daily for >30 days) within 8 weeks of randomization

5. Swallowing disorder, oral-motor discoordination, inability to swallow capsules

6. Pregnant or breastfeeding or expecting to conceive or father children within the trial's projected duration, starting from the pre-screening or screening visit through to 120 days after the last dose of trial treatment.

Donor Inclusion Criteria:

1. A histologically confirmed diagnosis of malignancy.
2. Over the age of 18.
3. Treated with immune checkpoint inhibitors and with a full response.
4. Currently attending medical follow-ups

Donor Exclusion Criteria:

1. Has not consumed any antimicrobials within the past 3 months
2. No prior exposure to HIV or viral hepatitis or suffering from tuberculosis/latent tuberculosis
3. No risk factors for blood-borne viruses, including high-risk sexual behavior, use of illicit drugs, any tattoo/body piercing/needlestick injury/blood transfusion/acupuncture, all within the past 6 months
4. No signs or symptoms consistent with Coronavirus disease 19 (COVID-19) or a nose/throat and/or stool sample with detectable Coronavirus disease 2 (CoV-2)
5. Has not received a live attenuated vaccine within the past 6 months
6. No underlying gastrointestinal conditions/symptoms (e.g., history of IBD, irritable bowel syndrome (IBS), chronic diarrhea, chronic constipation, coeliac disease, bowel resection or bariatric surgery)
7. No acute diarrhea/gastrointestinal symptoms within the 2 weeks prior to donating
8. No family history of any significant gastrointestinal conditions (e.g., family history of inflammatory bowel disease (IBD) or colorectal cancer)
9. No history of atopy (e.g., asthma, eosinophilic disorders)
10. Does not suffer from any systemic autoimmune conditions
11. Does not start any new treatment regimens within 2 weeks of fecal collection
12. No neurological or psychiatric conditions or known risk for prion disease
13. No history of chronic pain syndromes, including chronic fatigue syndrome and fibromyalgia
14. No history of receiving growth hormone, insulin from cows or clotting factor concentrates
15. Has not received an experimental drug or vaccine within the past 6 months
16. No history of travel to tropical countries within the past 6 months

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
standard of care (SoC) (IO±CTX) + FMT	Antibiotics	Subjects assigned to Arm 1 will be required to swallow FMT capsules in a regimen of ten capsules in the morning and ten capsules in the afternoon on day 1 of the first (chemo-)immunotherapy cycle, and then every three weeks. abbreviation: Immuno-Oncology (IO) Chemotherapy (CTX)
standard of care (SoC) (IO±CTX) + FMT	FMT (Fecal Microbiota Transplantation)	Subjects assigned to Arm 1 will be required to swallow FMT capsules in a regimen of ten capsules in the morning and ten capsules in the afternoon on day 1 of the first (chemo-)immunotherapy cycle, and then every three weeks. abbreviation: Immuno-Oncology (IO) Chemotherapy (CTX)

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	up to 2 years	PFS is defined as the time passed from screening until the date of progressive disease (PD) or death from any cause. Imaging will be performed using computed tomography (CT) and/or Positron emission tomography (PET).

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	up to 4 years	OS is defined as the time passed from randomization until death from any cause.
Safety and feasibility	up to 2 years	Number of adverse events and serious adverse events related definitely to fecal microbiota transplantation (FMT).
Objective response rate (ORR)	From randomization (Day 0) until end of study	ORR is defined as the percentage of subjects who had a complete response (CR) or partial response (PR), as defined by ir-RECIST v1.1, and is based on the best response obtained.
Rate of Disease Control	up to 2 years	Rate of Disease Control is defined as the percentage of subjects who had a complete response (CR), partial response (PR), or stable disease (SD), as defined by ir-RECIST v1.1.
Microbiome analysis	up to 2 years	Microbiome analysis of the stool of donors and recipients (before and after FMT) to reveal the optimum microbiome-based components to significantly increase cancer immunotherapy efficacy
Serum antibody levels and lymphocyte subpopulation distribution	up to 2 years	Analysis of serum antibodies and blood lymphocyte repertoires to be correlated to gut microbes and yeasts via blood samples of donors and recipients at several timepoints prior and post FMT induction

Trial Locations

Locations (2)

Soroka Medical Center; 🇮🇱 Beer sheva, Israel

Rabin Medical Center; 🇮🇱 Petah Tikva, Israel