Phase I, Open-Label Study of Dually Armored Chimeric Antigen Receptor (CAR) T Cells (TmPSMA-02) in Patients With Metastatic Castrate-Resistant Prostate Cancer (mCRPC)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Incidence of Adverse Events as assessed by CTCAE v5.0
研究概览
简要总结
This is a Phase I, open-label dose finding study to assess the safety, tolerability, manufacturing feasibility, and preliminary efficacy of TmPSMA-02 CAR T cells in patients with metastatic castrate-resistant prostate cancer (mCRPC). Up to 4 total dose levels will be evaluated using a 3+3 dose escalation design.
详细描述
This is a Phase I, open-label dose finding study to assess the safety, tolerability, manufacturing feasibility, and preliminary efficacy of TmPSMA-02 CAR T cells in patients with metastatic castrate-resistant prostate cancer (mCRPC). Up to 4 total dose levels will be evaluated using a 3+3 dose escalation design as described below. Dose escalation will begin with Dose Level 1 as follows:
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Dose Level 1 (N = 3 to 6): Subjects will receive a single dose of 5 x 107 TmPSMA-02 CAR T cells via IV infusion administration on Day 0, following lymphodepletion with fludarabine and cyclophosphamide. This dose level will be evaluated as follows:
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If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level.
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If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level 2 (DL2).
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In the event that 2 or more DLTs occur at Dose Level 1 (DL1), enrollment at this dose level will be stopped and Dose Level -1 (DL-1) will be opened. In Dose Level -1, subjects will receive a de-escalated dose of 1 x 107 TmPSMA-02 CAR T cells following lymphodepletion.
If 0 DLT/3 or 1 DLT/3 subjects occurs at DL-1, the study will enroll an additional 3 subjects at this dose level.
If ≥ 2 DLTs occur at any time, enrollment at this dose level will be stopped.
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
- Male
- 接受健康志愿者
- 否
入选标准
- •Signed, written informed consent
- •Adult participants ≥ 18 years of age
- •Metastatic castrate-resistant prostate cancer (mCRPC)
- •Castrate levels of testosterone (<50 ng/dL) with/without the use of androgen-deprivation therapy
- •Received at least one prior standard therapy for systemic treatment in the mCRPC setting, including at least one second generation androgen receptor signaling inhibitor (e.g., enzalutamine, apalutamide, darolutamide, or abiraterone) or a taxane-based regimen (e.g., docetaxel, cabazitaxel, etc).
- •Adequate organ function within 4 weeks of eligibility confirmation by a physician-investigator defined as:
- •Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 50 cc/min per the Cockcroft-Gault Equation; Patient must not be on dialysis
- •ALT/AST ≤ 3 x ULN
- •Serum total bilirubin ≤ 1.5 mg/dL, unless the subject has Gilbert's syndrome (if so, serum total bilirubin must be ≤3.0 mg/dL)
- •Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO
- •Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
- •Patients must have adequate hematologic reserve within 4 weeks of eligibility confirmation by a physician-investigator and must not be dependent on transfusions to maintain these hematologic parameters. Adequate hematologic reserve is defined as:
- •Hemoglobin ≥ 8 g/dL
- •Absolute neutrophil count ≥ 1000/μL
- •Platelet count ≥ 75,000/μL
- •ECOG Performance Status that is either 0 or
- •Patients who have not undergone bilateral orchiectomy must be able to continue GnRH therapy during the study.
- •Participants of reproductive potential must agree to use acceptable birth control methods, as described in the protocol.
排除标准
- •Active hepatitis B or hepatitis C infection
- •Any other active, uncontrolled infection
- •Class III/IV cardiovascular disability according to the New York Heart Association Classification.
- •Severe, active co-morbidity that in the opinion of the physician-investigator would preclude participation in the study.
- •Active invasive cancer, other than the proposed cancer included in the study, within 2 years prior to eligibility confirmation by a physician-investigator. [Note: non-invasive cancers treated with curative intent (e.g., non-melanoma skin cancer) may still be eligible].
- •Patients requiring chronic treatment systemic steroids or immunosuppressant medications. Low-dose physiologic replacement therapy with corticosteroids equivalent to prednisone 10 mg/day or lower, topical steroids and inhaled steroids are acceptable. For additional details regarding use of steroid and immunosuppressant medications, please see Section 5.
- •Prior treatment with autologous T-cell therapy, with the exception of Sipuleucel-T.
- •Prior allogeneic stem cell transplant.
- •Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
- •History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
研究组 & 干预措施
Dose Level 3
After lymphodepleting chemotherapy subjects to receive 3x10(8) TmPSMA-02 CAR T Cells
干预措施: TmPSMA-02 CAR T Cells (Drug)
Dose Level 1
After lymphodepleting chemotherapy subjects to receive 5 x10(7) TmPSMA-02 CAR T Cells
干预措施: TmPSMA-02 CAR T Cells (Drug)
Dose Level 2
After lymphodepleting chemotherapy subjects to receive 1x10(8) TmPSMA-02 CAR T Cells
干预措施: TmPSMA-02 CAR T Cells (Drug)
Dose Level -1
After lymphodepleting chemotherapy subjects to receive 1x10(7) TmPSMA-02 CAR T Cells
干预措施: TmPSMA-02 CAR T Cells (Drug)
结局指标
主要结局
Incidence of Adverse Events as assessed by CTCAE v5.0
时间窗: Up to 15 years
Number of subjects with dose limiting toxicities (DLTs)
时间窗: 28 days after TmPSMA-02 CAR T cell infusion
Determination of maximum tolerated dose (MTD)
时间窗: 28 days after TmPSMA-02 CAR T cell infusion
次要结局
- Progression Free Survival (PFS)(Up to one year)
- Overall Survival (OS)(Up to one year)
- Percentage of manufacturing products that meet release criteria(Up to 3 years)
- Overall Response Rate (ORR)(Up to 3 months)
- Duration of Response (DOR)(up to one year)
- Percent Change in PSA from Baseline(Up to one year)