A Phase 2 Randomized Trial of Remodeling Intestinal Microbiota Using Fecal Microbiome Transplant (FMT) Among Recipients of Chimeric Antigen Receptor T Cells (CAR T)

Summary

This phase II trial tests how well fecal microbiome transplantation works to remodel intestinal microbiota for patients with lymphoma that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory) with exposure to high-risk antibiotics who are receiving chimeric antigen receptor (CAR) T cells. Fecal microbiome transplantation consists of fecal microbiota from healthy donors with healthy gut microbiota that allows re-population of the patient's microbiome with diverse protective microorganisms. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Part of the treatment for CAR T therapy involves high doses of chemotherapy. This, along with prior exposure to high strength antibiotics, can damage patient's intestinal microbiota. Giving fecal microbiome transplantation may improve clinical response by repairing intestinal microbiota for patients with relapsed or refractory lymphoma who had exposure to high-risk antibiotics.

Detailed description

PRIMARY OBJECTIVE: I. Evaluate the efficacy of fecal microbiome transplant (FMT) by measuring changes in gut microbiome diversity (as assessed by Shannon alpha diversity Index) at day 0 (day of CAR T infusion). SECONDARY OBJECTIVES: I. Estimate rates of complete response (CR) at days +30, +90 or 1 year after CAR T therapy in each arm. (Key secondary objective) II. Determine the safety and tolerability/feasibility of fecal microbiota transplant (FMT) until 28 days post last dose by adverse events: type, frequency, severity, attribution, time course, duration. III. Quantify engraftment of bacterial strains that are definitely attributable to FMT product. IV. Estimate incidence and severity of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in each arm. V. Shannon index at each fecal sampling timepoint after day 0 to assess overtime changes in microbiome diversity in each cohort after CAR T infusion. VII. Estimate rates of overall response (ORR) at 30 days, 90 days and 1 year after CAR T therapy in each arm. VIII. Determine the number of bacterial infection rate post 30 days of last FMT last dose. IX. Estimate rate of overall survival (OS), relapse/progression and non-relapse mortality (NRM) at 30 days, 90 days and 1 year after CAR T therapy in each arm. X. Estimate time to neutropenia recovery at each arm. EXPLORATORY OBJECTIVES: I. Compare quality of manufactured CAR T products in patients treated or not treated with FMT. II. Characterize and correlate FMT treatment with the following biologic endpoints. IIa. Plasma and stool metabolites with a focus on butyrate-related pathways (metabolomics analysis); IIb. T cell phenotype (multicolor flow cytometry at Immuno-Oncology Core) and cytokines assay (30-multiplex plate using Luminex); IIc. CAR T cell persistence (using standard polymerase chain reaction \[PCR\] assays) on days +30, +90, 6 months and 1 year after CAR T therapy. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive FMT orally (PO) once daily (QD) on day -10 and -7 before leukapheresis, day -10 and -7 before CAR T cell infusion, within 3 days of neutrophil recovery and 2 days after first neutrophil recovery dose. Treatment given in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. ARM II: Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive placebo PO QD on day -10 and -7 before leukapheresis, day -10 and -7 before CAR T cell infusion, within 3 days of neutrophil recovery and 2 days after first neutrophil recovery dose. Treatment given in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up at day 28, 90 and 1 year post CAR T cell therapy.

Arms & interventions

• BiologicalAxicabtagene Ciloleucel

  Given CAR-T cells

• ProcedureBiospecimen Collection

  Undergo blood sample collection

• DrugChemotherapy

  Receive chemotherapy

• ProcedureFecal Microbiota Transplantation

  Given PO

• ProcedureLeukapheresis

  Undergo leukapheresis

• DrugPlacebo Administration

  Given PO

Outcome measures

Eligibility criteria