Trial-in-progress: A phase 2 randomized trial of remodeling intestinal microbiota using fecal microbiome transplant (FMT) among recipients of chimeric antigen receptor T cells (CAR T) Free

Background: CAR T cell therapy has been transformative in the treatment of B cell lymphomas, with overall response rates (ORR) reaching (PMID: 36821768, 34895487). Yet, recent evidence suggests that treatment efficacy may be compromised by microbiome injury due to high-risk antibiotic exposure prior to receiving cell therapy, leading to reduced progression free survival (PMID: 35288695,36914893, 39441941). Hence, restoration of microbiome diversity after antibiotic treatment may improve CAR T treatment responses.

Fecal Microbiota Transplants (FMT) were initially shown to be effective in treating recurrent C. difficile infections and multidrug resistant bacterial infections. Recently, FMT has also been tested for treatment of graft-vs-host disease in hematopoietic cell transplant patients and reproducibly demonstrated improvements in gut microbiome diversity in leukemia and transplant patients. In this study, we hypothesize that, in B-cell lymphoma patients undergoing commercial CD19 CAR T therapy with recent antibiotic exposure, reshaping gastrointestinal microbiome using FMT will improve microbiome diversity and clinical response rates.

Study design: This single center, double blind, randomized, placebo-controlled Phase 2a study (NCT07042438) is currently approved by FDA and institutional IRB. We will enroll 56 patients randomized 1:1 to FMT or placebo arms. FMT and placebo capsules are both provided by the University of Minnesota Microbiota Therapeutics Program. FMT capsules contain purified and lyophilized microbiota from the stool of healthy donors. Recipients will receive microbiota from a single donor. Visually and organoleptically identical placebo capsules contain sterile trehalose and carboxymethylcellulose.

Eligible patients are aged ≥ 18 years, with a confirmed diagnosis of relapsed/refractory CD19 B-cell lymphoma, including Diffuse Large B Cell Lymphoma, transformed Follicular Lymphoma, or Double-Hit Lymphoma, and scheduled to receive CAR T treatment, YESCARTA®. In addition, patients must be exposed to high-risk antibiotics within 90 days of consent. High-risk broad-spectrum antibiotics include carbapenems, anti-pseudomonal antibiotics or anaerobic antibiotics. Randomization will be stratified based on time from antibiotic exposure (<45 or ≥45 days) and age group (≤60 or >60 years old).

Patients will receive a total of 6 doses of FMT or placebo across 3 timepoints: i) 7 and 10 days before leukapheresis, ii) 7 and 10 days before CAR T infusion, and iii) 3 and 6 days after neutrophil recovery (absolute neutrophil count > 1 × 10⁹/L) and at least 2 days after antibiotic treatment is completed, but no later than 10 weeks after CAR T infusion. Each dose of FMT or placebo will be 4 capsules.

Our primary endpoint is the efficacy of FMT in changing gut microbiome diversity from pre-treatment to the day of CAR T infusion (Day 0). Microbiome diversity will be measured by the Shannon Index using serial stool samples collected before and after each set of FMT dose. Our sample size calculation is based on detecting a mean difference of 0.4 in the change in Shannon index from baseline to Day 0 between the FMT and control group, with an estimated standard deviation of 0.5. The engraftment of strains attributable to the FMT product will also be quantified from the stool samples using source tracking algorithms.

Safety will be assessed as a secondary objective until 28 days post-last dose of FMT. Toxicity will be evaluated according to the NCI CTCAE v5.0. Unacceptable toxicity is defined as the occurrence of any grade 3 or higher gastrointestinal toxicity or primary bloodstream infection (BSI) within 7 days post-FMT.

A key secondary endpoint is assessing treatment response according to Lugano Response Criteria at days 30, 90 and 1 year after CAR T therapy. Incidence and severity of bacterial infections and toxicities related to CAR T treatment, such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), will also be assessed in patients on each arm. Clinical endpoints of ORR, relapse/progression, non-relapse mortality (NRM) and overall survival (OS) at days 30, 90 and 1 year after CAR T will be assessed. As patients receive FMT doses prior to leukapheresis, we will also compare the quality of manufactured CAR T products, including purity, potency and durability, from patients who received FMT or not.

The study is currently open to accrual and will accrue patients at City of Hope.