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Immune Checkpoint Inhibitors

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Antibiotics, Antitubercular

Rifaximin

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)

Subjects will receive standard-of-care treatment only.

Recipients will undergo bowel preconditioning with antibiotics (Rifaximin) following randomization.

Antibiotics

FMT involves the transplantation of fecal bacteria from a screened donor to a recipient. This will be achieved per os in the form of a capsule containing freeze-dried stool obtained from the donor.

FMT (Fecal Microbiota Transplantation)

Ismaell Massalha, M.D.

Amichay Meirovitz, Prof.

Mor Moskovitz, MD

Ismaell Massalha, MD

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.

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.

Fecal Microbiota Transplantation With Immune Checkpoint Inhibitors in Lung Cancer

Fecal Microbiota Transplantation to Improve Efficacy of Immune Checkpoint Inhibitors in Metastatic Lung Cancer

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).

OS is defined as the time passed from randomization until death from any cause.

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 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 of the stool of donors and recipients (before and after FMT) to reveal the optimum microbiome-based components to significantly increase cancer immunotherapy efficacy

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

Number of adverse events and serious adverse events related definitely to fecal microbiota transplantation (FMT).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Fecal Microbiota Transplantation With Immune Checkpoint Inhibitors in Lung Cancer	NCT05502913	Metastatic Lung...	Antibiotics FMT (Fecal Micr...	18 Years -	Soroka University Medical Center
Fecal Microbiota Transplantation With Immune Checkpoint Inhibitors in Lung Cancer	NCT05502913	Metastatic Lung...	Antibiotics FMT (Fecal Micr...	18 Years -	Soroka University Medical Center

Spots Global Cancer Trial Database for fmt (fecal microbiota transplantation)