A Phase 2 Randomized Trial of Remodeling Intestinal Microbiota Using Fecal Microbiome Transplant (FMT) Among Recipients of Chimeric Antigen Receptor T Cells (CAR T)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Changes in gut microbiome diversity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
This single center, double-blind, phase 2a clinical trial
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented informed consent of the participant and/or legally authorized representative.
- •Assent, when appropriate, will be obtained per institutional guidelines
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies
- •If unavailable, exceptions may be granted with study principal investigator (PI) approval
- •Age: ≥ 18 years
- •Karnofsky performance status (KPS) ≥ 60
- •Confirmed diagnosis of relapsed/refractory CD19 B-cell lymphomas of diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), or double-hit lymphoma (DHL) and scheduled to receive commercial CAR T treatment of YESCARTA ® for their diagnosis
- •Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
- •Exposure to high-risk antibiotics within 90 days of consent. High-risk broad-spectrum antibiotics include carbapenems (meropenem, imipenem, doripenem), anti-pseudomonal antibiotics (cefepime, piperacillin-tazobactam, ceftazidime) or anaerobic antibiotics including metronidazole, clindamycin, amoxicillin-sulbactam, and vancomycin
- •Clinical laboratory and organ function criteria per standard of care to CAR T patients at City of hope: (To be performed within 30 days prior to leukapheresis)
- •Seronegative for HIV antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative)
- •HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
- •Meets other institutional and federal requirements for infectious disease titer requirements
- •Note: Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
- •Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
- •If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- •Agreement by females and males of childbearing potential* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 12 months after the last dose of protocol therapy.
- •Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
排除标准
- •Major surgery in 4 months preceding enrollment
- •No live vaccine in 30 days prior to enrollment
- •Inability to swallow capsules or history of disorder with Inability to swallow FMT capsules
- •History of inflammatory bowel disorder, irritable bowel disorder
- •Severe food allergies
- •History of chronic aspiration
- •History of behavioral disorders including substance abuse disorders which per discretion of primary investigator will interfere with safe conduct and compliance to study treatment
- •History neurocognitive disorder which per discretion of primary investigator will interfere with safe conduct and compliance to study treatment
- •Diagnosis of primary immunodeficiency
- •Active second malignancy requiring treatment except non-melanoma skin cancer or carcinoma in situ-cervix, bladder or to non-metastatic prostate cancer which does not require treatment
- •Uncontrolled bacterial, fungal, or viral infection confirmed using clinical, laboratory and radiological findings requiring administration of intravenously (IV) antimicrobials
- •Any clinical, laboratory or radiologic findings per discretion of primary investigator will interfere with safe conduct of study treatment and compliance with study procedures
- •Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
- •Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
研究组 & 干预措施
Arm I (FMT)
Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive FMT 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.
干预措施: Axicabtagene Ciloleucel (Biological)
Arm I (FMT)
Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive FMT 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.
干预措施: Biospecimen Collection (Procedure)
Arm I (FMT)
Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive FMT 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.
干预措施: Chemotherapy (Drug)
Arm I (FMT)
Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive FMT 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.
干预措施: Fecal Microbiota Transplantation (Procedure)
Arm I (FMT)
Patients undergo standard of care leukapheresis and receive standard of care chemotherapy and CAR T cells. Patients receive FMT 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.
干预措施: Leukapheresis (Procedure)
Arm II (Placebo)
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.
干预措施: Biospecimen Collection (Procedure)
Arm II (Placebo)
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.
干预措施: Chemotherapy (Drug)
Arm II (Placebo)
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.
干预措施: Fecal Microbiota Transplantation (Procedure)
Arm II (Placebo)
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.
干预措施: Leukapheresis (Procedure)
Arm II (Placebo)
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.
干预措施: Placebo Administration (Drug)
结局指标
主要结局
Changes in gut microbiome diversity
时间窗: From baseline to day 0
Assessed using the Shannon alpha diversity index. For comparisons at a timepoint of most interest, a t-test (or Wilcoxon rank-sum test if assumptions are not met) will be used to compare the Shannon index between the fecal microbiome transplant (FMT) and placebo groups. For over-time comparisons, linear mixed models will be used to assess longitudinal changes in microbiome diversity between treatment (FMT) and control (placebo) groups, accounting for within-subject correlations over multiple measurement points.
次要结局
- Incidence and severity of immune effector cell associated neurotoxicity syndrome(Up to 1 year post CAR T cell therapy)
- Feasibility of Rx administration(Up to 30 days before CAR T cell infusion)
- Rate of complete response(At day +30, +90 and 1 year after chimeric antigen receptor t cell (CAR T) therapy)
- Incidence of adverse events(Up to 1 year post CAR T cell therapy)
- Quantify engraftment of bacterial strains that are definitely attributable to FMT product(Up to 1 year post CAR T cell therapy)
- Incidence and severity of Cytokine Release Syndrome(Up to 1 year post CAR T cell therapy)
- Overall response rate(At day +30, +90 and 1 year after CAR T therapy)
- Bacterial infection rate(Post 30 days of last FMT last dose)
- Rate of overall survival(At day +30, +90 and 1 year after CAR T therapy)
- Rate of relapse/progression(At day +30, +90 and 1 year after CAR T therapy)
- Rate of non-relapse mortality(At day +30, +90 and 1 year after CAR T therapy)