Fecal Microbiota Transplantation With Immune Checkpoint Inhibitors in Lung Cancer

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.

Patient (Recipient) Inclusion Criteria:

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

Patient (Recipient) Exclusion Criteria:

• Severe or life-threatening food allergy (e.g. nuts, seafood)
• Allergy or other contraindication to omeprazole, investigational medicinal product.
• Treatment with pre- or probiotics in the four weeks prior to randomization.
• 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
• Swallowing disorder, oral-motor discoordination, inability to swallow capsules
• 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:

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

Donor Exclusion Criteria:

• Has not consumed any antimicrobials within the past 3 months
• No prior exposure to HIV or viral hepatitis or suffering from tuberculosis/latent tuberculosis
• 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
• 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)
• Has not received a live attenuated vaccine within the past 6 months
• 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)
• No acute diarrhea/gastrointestinal symptoms within the 2 weeks prior to donating
• No family history of any significant gastrointestinal conditions (e.g., family history of inflammatory bowel disease (IBD) or colorectal cancer)
• No history of atopy (e.g., asthma, eosinophilic disorders)
• Does not suffer from any systemic autoimmune conditions
• Does not start any new treatment regimens within 2 weeks of fecal collection
• No neurological or psychiatric conditions or known risk for prion disease
• No history of chronic pain syndromes, including chronic fatigue syndrome and fibromyalgia
• No history of receiving growth hormone, insulin from cows or clotting factor concentrates
• Has not received an experimental drug or vaccine within the past 6 months
• No history of travel to tropical countries within the past 6 months