Phase I Study of CART-PSMA-TGFβRDN Cells in Patients With Advanced Castrate Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Occurrence of study related adverse events, laboratory toxicities and clinical events that are possibly, likely, or definitely related to study participation.
研究概览
简要总结
This is a single center, single arm Phase I study to establish the safety and feasibility of intravenously administered lentivirally transduced dual PSMA-specific/TGFβ-resistant CAR modified autologous T cells (CART-PSMA-TGFβRDN cells) in patients with metastatic castrate resistant prostate cancer.
详细描述
This is a Phase I study evaluating the safety and feasibility of lentivirally transduced PSMA-TGFβRDN autologous CAR T cells administered with and without cyclophosphamide/fludarabine lymphodepleting chemotherapy in a 3+3 dose escalation design. Subjects must receive the dose of CART-PSMA-TGFβRDN cells as per their cohort assignment in order to be considered evaluable for DLT assessments at that dose level. Subjects who do not receive CART-PSMA-TGFβRDN cells as per their cohort assignment will not be evaluable for DLT assessments/MTD determination, however they will still be followed per protocol and will be included in the overall safety analysis, as well as the analysis of secondary and exploratory endpoints. Subjects who enroll but do not receive CART-PSMA-TGFβRDN cells will be removed from the study and replaced.
Up to 5 dosing cohorts will be explored as follows:
- Cohort 1 subjects (N=3 or 6): will receive a single dose of 1-3 x 107/m2 lentivirally transduced CART-PSMA-TGFβRDN cells on day 0 without any conditioning chemotherapeutic regimen. If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance to Cohort 2. If 2 DLT/3 subjects occurs at dose of 1-3 x 107/m2 cells, then enrollment in this Cohort will be stopped and the dose will be de-escalated by 10-fold to 1-3 x 106 cells/m2 (Cohort -1). In this situation, up to 6 subjects will be enrolled in Cohort -1.
- Cohort 2 subjects (N=3 or 6): will receive a single dose of 1-3 x 108/m2 lentivirally transduced CART-PSMA-TGFβRDN cells on day 0 without any conditioning chemotherapeutic regimen. If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance toIf 2 DLT/3 subjects occur, then the study will stop and declare maximum tolerated dose (MTD).
Cohorts 1 and 2 were originally designed to identify the MTD of CART-PSMA-TGFβRDN cells. The highest dose level where only 0/3 or 1/6 DLTs were observed in a given cohort will be defined as the MTD for evaluation in Cohort 3.
COHORT 3 CLOSED WITH PROTOCOL V10
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
- •Metastatic castrate resistant prostate cancer
- •RETIRED WITH PROTOCOL VERSION 15
- •Radiographic evidence of osseous metastatic disease and/or measurable, non-osseous metastatic disease (nodal or visceral)
- •Patients ≥ 18 years of age
- •ECOG performance status of 0 - 1
- •Adequate organ function, as defined by:
- •Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min
- •Serum total bilirubin < 1.5x ULN
- •Serum ALT/AST < 2x ULN
- •Adequate hematologic reserve within 4 weeks of eligibility confirmation by physician-investigator as defined by:
- •Hgb > 10 g/dl
- •PLT > 100 k/ul
- •ANC > 1.5 k/ul Note: Subjects must not be transfusion dependent
- •Evidence of progressive castrate resistant prostate adenocarcinoma, as defined by:
- •Castrate levels of testosterone (< 50 ng/ml) with or without the use of androgen-deprivation therapy AND
- •Evidence of one of the following measures of progressive disease in the 12 weeks preceding eligibility confirmation by physician:
- •i. soft tissue progression by RECIST 1.1 criteria ii. osseous disease progression with 2 or more new lesions on bone scan (as per PCWG2 criteria) iii. increase in serum PSA of at least 25% and an absolute increase of 2 ng/ml or more from nadir (as per PCWG2 criteria)
- •Prior therapy with at least one standard initial therapy for the treatment of metastatic castrate resistant prostate cancer (i.e. docetaxel chemotherapy, 17α lyase inhibitor, or second-generation anti-androgen therapy)
- •Provides written informed consent
- •Subjects of reproductive potential must agree to use acceptable birth control methods
排除标准
- •RETIRED WITH PROTOCOL V16
- •History of an active non-curative non-prostate primary malignancy within the prior 3 years
- •RETIRED WITH PROTOCOL VERSION 6
- •Subjects who require the chronic use of systemic corticosteroid therapy. Patients may be on a low dose of steroids (≤10mg equivalent of prednisone).
- •RETIRED WITH PROTOCOL V13
- •Subjects with Class III/IV cardiovascular disability according to the New York Heart Association Classification
- •Subjects with symptomatic vertebral metastases affecting spinal cord function (as determined by clinical history, physical exam, or MRI imaging)
- •Active autoimmune disease, including connective tissue disease, uveitis, inflammatory bowel disease, or multiple sclerosis; or a history of severe (as judged by the physician-investigator) autoimmune disease requiring prolonged immunosuppressive therapy
- •Patients with ongoing or active infection.
- •History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
- •Active hepatitis B, hepatitis C or HIV infection.
- •Active medical condition that, in the opinion of the physician-investigator, would substantially increase the risk of uncontrollable CRS or CAR Neurotoxicity.
研究组 & 干预措施
Cohort 4
CART-PSMA-TGFβRDN cells 0.70-1.00 x 10^8 Day 0
干预措施: CART-PSMA-TGFβRDN cells (Biological)
Cohort 1
CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0
干预措施: CART-PSMA-TGFβRDN cells (Biological)
Cohort 2
CART-PSMA-TGFβRDN cells 1-3x10^8 Day 0
干预措施: CART-PSMA-TGFβRDN cells (Biological)
Cohort -3
CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0
干预措施: CART-PSMA-TGFβRDN cells (Biological)
Cohort -3
CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0
干预措施: Cyclophosphamide (Drug)
Cohort -3
CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0
干预措施: Fludarabine (Drug)
Cohort 4
CART-PSMA-TGFβRDN cells 0.70-1.00 x 10^8 Day 0
干预措施: Cyclophosphamide (Drug)
Cohort 4
CART-PSMA-TGFβRDN cells 0.70-1.00 x 10^8 Day 0
干预措施: Fludarabine (Drug)
Cohort 3
CART-PSMA-TGFβRDN cells at the MTD (established by Cohorts 1-2) on day 0
干预措施: CART-PSMA-TGFβRDN cells (Biological)
Cohort 3
CART-PSMA-TGFβRDN cells at the MTD (established by Cohorts 1-2) on day 0
干预措施: Cyclophosphamide (Drug)
Cohort 3
CART-PSMA-TGFβRDN cells at the MTD (established by Cohorts 1-2) on day 0
干预措施: Fludarabine (Drug)
结局指标
主要结局
Occurrence of study related adverse events, laboratory toxicities and clinical events that are possibly, likely, or definitely related to study participation.
时间窗: 15 years
using CTCAE v 4.03
Clinical feasibility is defined as the frequency of subjects enrolled on this protocol who do not receive CART-PSMA-TGFβRDN cells.
时间窗: 30 days
Manufacturing feasibility is determined by the frequency of product release failures and the occurrence of dose failures (inability to meet target dose).
时间窗: 30 days
次要结局
- Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by RECIST(6 months)
- Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by overal survival (OS).(15 Years)
- Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by PCWG2(6 months)
- Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by number of subjects with progression free survival (PFS).(15 Years)
- Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by serum PSA measurement(6 months)