A Phase 1b Clinical Trial of Anti-BCMA Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Proportion of participants who experience a dose-limiting toxicity (DLT) (Dose Escalation)
研究概览
简要总结
This is an open-label study to determine the safety of anti-B-cell maturation antigen (BCMA) Chimeric antigen receptor T-cell (CAR T) therapy in participants with Relapsed or Refractory Multiple Myeloma (RRMM).
详细描述
PRIMARY OBJECTIVE:
- To evaluate the safety of administering chimeric antigen receptor (CAR)-T cells targeting BCMA to participants with RRMM (Dose Escalation).
- To determine the maximum tolerated dose (MTD) for anti-BCMA CAR-T cells (Dose Escalation).
- Determine whether administering chimeric antigen receptor T cells targeting BCMA to participants with RRMM increases the overall response rate (ORR) in RRMM compared with historical data for non-CAR agents per International Myeloma Working Group (IMWG) response criteria (Dose Expansion).
SECONDARY OBJECTIVES:
Dose Expansion Only:
- To describe the efficacy of CAR-T cells targeting BCMA in participants with RRMM defined by ORR using IMWG criteria.
- To evaluate the feasibility of manufacturing anti-BCMA CAR-T cells locally and ability to produce adequate quantities of vector positive T-cells.
- To evaluate the safety and toxicity of CAR-T cells targeting BCMA to participants with RRMM.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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
- •Eligibility for enrollment:
- •Inclusion Criteria:
- •Voluntarily sign informed consent form.
- •>=18 years of age at the time of signing informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •Diagnosis of MM with relapsed or refractory disease and have had at least 3 different prior lines of therapy including proteasome inhibitor (PI) (e.g., bortezomib or carfilzomib) immunomodulatory therapy (IMiD) (e.g., lenalidomide or pomalidomide), and anti-CD38 antibody therapy.
- •Participants must have measurable disease, including at least one of the criteria below:
- •Serum M-protein greater or equal to 0.5 g/dL.
- •Urine M-protein greater or equal to 200 mg/24 hours (h).
- •Serum free light chain (FLC) assay: involved FLC level of >= 100 mg/L.
- •Adequate organ function, defined as:
- •Hemoglobulin >8 gm/dl (transfusions allowed).
- •Platelets >50,000/microliter (uL) (in the absence of platelet transfusion within 7 days of apheresis, but transfusion permitted prior to lymphodepleting chemotherapy).
- •Absolute neutrophil count (ANC) > 1000/uL in the absence of growth factor support (filgrastim within 7 days or pegfilgrastim within 14 days of apheresis, but growth factor permitted prior to lymphodepleting chemotherapy).
- •Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x institutional upper limit of normal (ULN).
- •Total bilirubin =< 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome.
- •Serum creatinine clearance (CrCl) >= 45 mL/min using Cockcroft-Gault formula.
- •Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) >= 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA).
- •Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-BCMA CAR-T cells.
- •Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method.
排除标准
- •Autologous transplant within 6 weeks of planned CAR-T cell infusion.
- •Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast). Any fully treated malignancies or indolent, clinically insignificant malignancies can be discussed among the study team to determine eligibility.
- •HIV seropositivity.
- •Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded).
- •Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, pulmonary abnormalities, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test.
- •Patients with currently symptomatic central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia, and Parkinson's disease.
- •History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months.
- •Eligibility for Infusion of Investigational Product:
- •Participants will undergo an evaluation of eligibility on day -1 or 1 prior to infusion of anti-BCMA CAR-T cell product. This eligibility criteria will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions:
- •Hematologic function parameters will not be included as a pre-infusion eligibility criterion (because lymphodepletive chemotherapy is expected to cause pancytopenia).
- •Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition.
- •Exclusion criteria additions:
- •Use of anti-multiple myeloma therapy, including systemic corticosteroids within 14 days prior to lymphodepletive chemotherapy.
- •Neurologic symptoms suggestive of an active central nervous system condition.
研究组 & 干预措施
Dose Escalation (150 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the starting dose of 150 x 10^6 flat dose will then be given on Day 1.
干预措施: Manufactured Anti-BCMA CAR-T cells (Biological)
Dose Escalation (150 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the starting dose of 150 x 10^6 flat dose will then be given on Day 1.
干预措施: Fludarabine (Drug)
Dose Escalation (150 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the starting dose of 150 x 10^6 flat dose will then be given on Day 1.
干预措施: Cyclophosphamide (Drug)
Dose Escalation (450 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 450 x 10^6 flat dose will then be given on Day 1.
干预措施: Manufactured Anti-BCMA CAR-T cells (Biological)
Dose Escalation (450 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 450 x 10^6 flat dose will then be given on Day 1.
干预措施: Fludarabine (Drug)
Dose Escalation (450 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 450 x 10^6 flat dose will then be given on Day 1.
干预措施: Cyclophosphamide (Drug)
Dose Escalation (600 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 600 x 10^6 flat dose will then be given on Day 1.
干预措施: Manufactured Anti-BCMA CAR-T cells (Biological)
Dose Escalation (600 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 600 x 10^6 flat dose will then be given on Day 1.
干预措施: Fludarabine (Drug)
Dose Escalation (600 x 10^6 CAR + T cells/ infusion)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the next highest dose of 600 x 10^6 flat dose will then be given on Day 1.
干预措施: Cyclophosphamide (Drug)
Dose Expansion: Maximum Tolerated Dose (MTD)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the MTD will then be given on Day 1.
干预措施: Manufactured Anti-BCMA CAR-T cells (Biological)
Dose Expansion: Maximum Tolerated Dose (MTD)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the MTD will then be given on Day 1.
干预措施: Fludarabine (Drug)
Dose Expansion: Maximum Tolerated Dose (MTD)
Participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. After successful generation of the anti-BCMA CAR-T cells, and no dose limiting toxicities were reported for the previous dose level, participants will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-BCMA CAR-T cells at the MTD will then be given on Day 1.
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
Proportion of participants who experience a dose-limiting toxicity (DLT) (Dose Escalation)
时间窗: From initiation of study treatment (day 1) to 29 days following CAR-T infusion
The DLT evaluable analysis set includes all participants in the dose-finding part of the study who have received the anti-BCMA CAR-T cell product, and who have either experienced a DLT or were followed for the full DLT evaluation period (within 28 days following infusion of CAR-T cells targeting BCMA). The MTD is defined as the dose level immediately below that in which \>=2/6 participants experience a DLT and will be used to determine the recommended Phase 2 dose for future studies.
Proportion of participants with treatment-emergent adverse events (AE) (Dose Escalation)
时间窗: From initiation of study treatment (day 1) to 29 days following CAR-T infusion
Proportion of participants with treatment-emergent adverse events of CAR-T as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, revised cytokine release syndrome (CRS) grading criteria (for CRS), and American Society of Transplantation and Cellular Therapy (ASTCT) Immune Effector Cell Associated Neurotoxicity (ICANS) Consensus Grading for Adults (for neurotoxicity grading). Analyses will be performed for all participants having received at least one dose of study drug and employ a modified criteria for hematologic adverse events.
Overall Response Rate (ORR) (Dose Expansion)
时间窗: Up to 12 months following CAR- T infusion
Overall response rate includes participants with a demonstrated Stringent Complete Response (sCR), Complete Response (CR), Partial Response (PR), or Very Good Partial Response (VGPR) per International Myeloma Working Group (IMWG) criteria reported as proportion with 90% binomial confidence interval for the expansion cohort including the patients on MTD in the dose escalation cohort.
次要结局
- Proportion of participants who complete study treatment(From initiation of CAR T-cell manufacturing to end of infusion, up to 21 days)
- Duration of response(Up to 12 months following CAR- T infusion)
- Overall Survival(Up to 15 years)
- Proportion of participants for whom BCMA CAR T-cell therapy is manufactured successfully(From initiation of CAR T-cell manufacturing to end of infusion, up to 21 days)
- Overall Response Rate (ORR)(Up to 15 years)
- Progression-free Survival (PFS)(Up to 15 years)
- Percentage of participants with minimal residual disease, negative (MRD-)(Up to 15 years)
- Percentage of participants with sustained MRD-(Up to 15 years)
- Proportion of participants with treatment-emergent adverse events (AE)(From initiation of CAR T-cell manufacturing to end of long-term follow-up, approximately 15 years)
研究者
Thomas Martin, MD
Principal Investigator
University of California, San Francisco