Phase I Clinical Trial of Adoptive Transfer of Autologous Folate Receptor - Alpha Redirected T Cells for Recurrent High Grade Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0
研究概览
简要总结
Phase I study to establish safety and feasibility of intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy
详细描述
This is a Phase I study evaluating the safety and feasibility of intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells in 4 cohorts with or without cyclophosphamide + fludarabine in a 3+3 dose escalation design.
The DLT observation period is 28 days post CAR T cell infusion. The Maximum Tolerated Dose (MTD) is defined as the dose at which 0 or 1 DLT occurs in 6 evaluable subjects tested within the dose range of this study.
Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy.
Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed persistent or recurrent stage II to IV high grade serous epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Disease can be platinum-sensitive or platinum-resistant.
- •Failure of at least two prior chemotherapy regimens for advanced stage disease. Prior therapies against PD-1 or PDL-1 are permissible.
- •Confirmation of tumor aFR expression (≥70% of tumor cells with ≥2+ aFR staining).
- •Subjects must have measureable disease as defined by RECIST 1.1 criteria.
- •Patients with asymptomatic CNS metastases that have been treated and are off steroids are allowed. They must meet the following at the time of eligibility confirmation by physician-investigator:
- •No concurrent treatment for the CNS disease
- •No progression of CNS metastasis on brain MRI at screening
- •No evidence of leptomeningeal disease or cord compression
- •Patients ≥ 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Satisfactory organ and bone marrow function as defined by the following:
- •i. Absolute neutrophil count ≥ 1,000/μl ii. Platelets ≥75,000/μl iii. Hemoglobin ≥ 9 g/dL iv. Total bilirubin ≤ 2.0x the institutional normal upper limit unless secondary to bile duct obstruction by tumor v. Creatinine ≤ 1.5x the institutional normal upper limit vi. Albumin ≥2 vii. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5x the institutional normal upper limit viii. Cardiac ejection fraction of ≥40%
- •Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤ 1.5 and a PTT ≤ 1.2 time the upper limit of normal unless the patient is therapeutically anti-coagulated for history of cancer-related thrombosis and has stable coagulation parameters.
- •Provides written informed consent.
- •Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.
排除标准
- •High grade serous ovarian, fallopian, or primary peritoneal cancer that is platinum refractory, defined as disease that has clinical or radiographic progression on platinum-based chemotherapy, as per the discretion of the treating physician.
- •Patients with symptomatic CNS metastases are excluded.
- •Participation in a therapeutic investigational study within 4 weeks prior to eligibility confirmation by physician-investigator, or anticipated treatment with another investigational product while on study. This refers to non-commercially approved investigational drugs different than those used in this protocol.
- •Active invasive cancer other than ovarian cancers. Patients with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder cancer) are not excluded.
- •HIV infection
- •Hepatitis B or hepatitis C infection
- •Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to >/= 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as multiple sclerosis) will be excluded.
- •Patients with active and uncontrolled infection.
- •Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (<10 mg daily equivalent of prednisone). Corticosteroids treatment as anti-emetic prophylaxis on the day of lymphodepleting chemotherapy administration is allowed per institutional guidance. The use of topical and/or inhaled steroids are not exclusionary.
- •Patients requiring supplemental oxygen therapy.
- •Prior therapy with lentiviral gene modified cells.
- •History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
- •Any ascites requiring therapeutic drainage within 4 weeks prior to eligibility confirmation by physician-investigator.
- •Pregnant or breastfeeding women.
- •Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the physician-investigator, would make the patient inappropriate for entry into the study.
研究组 & 干预措施
Cohort 1: MOv19-BBz CAR T cells without chemo
Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy.
干预措施: MOv19-BBz CAR T cells (Drug)
Cohort 1: MOv19-BBz CAR T cells without chemo
Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy.
干预措施: Alpha Folate Receptor expression test (Device)
Cohort 2: MOv19-BBz CAR T cells after chemo
Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
干预措施: MOv19-BBz CAR T cells (Drug)
Cohort 2: MOv19-BBz CAR T cells after chemo
Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
干预措施: Alpha Folate Receptor expression test (Device)
Cohort 3: MOv19-BBz CAR T cells after chemo
Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
干预措施: MOv19-BBz CAR T cells (Drug)
Cohort 3: MOv19-BBz CAR T cells after chemo
Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
干预措施: Alpha Folate Receptor expression test (Device)
Cohort-1: without chemo;only if dose de-escalation required
Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.
干预措施: MOv19-BBz CAR T cells (Drug)
Cohort-1: without chemo;only if dose de-escalation required
Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.
干预措施: Alpha Folate Receptor expression test (Device)
结局指标
主要结局
Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0
时间窗: Up to 34 months
For this study, collection of adverse events will begin at the time of apheresis and will continue until the subject is off-study.
Manufacturing Feasibility
时间窗: 8 weeks
Manufacturing feasibility is determined based on the "manufacturing failures" products. The number of manufactured products that do not meet release criteria for vector transduction efficiency, CART+ cell number, T cell purity, viability, and sterility will be determined and defined as "manufacturing failures".
Clinical Feasibility
时间窗: 8 weeks
Clinical feasibility is defined as the proportion of subjects enrolled on this protocol who do not receive MOv19-BBz CAR T cells. Reasons for this occurrence include rapid clinical deterioration or death, and subject withdrawal.
次要结局
- Progression-free Survival (PFS)(Up to 33 months)
- Overall Response Rates (ORR)(Up to 33 months)
- Overall Survival (OS)(Up to 33 months)