Phase 1 Trial of Human Chimeric Antigen Receptor Modified T Cells (huCART-meso) Administered in Combination With VCN-01 in Patients With Pancreatic and Serous Epithelial Ovarian Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Type, frequency, severity, and attribution of AEs/SAEs as assessed by CTCAE v 5.0
研究概览
简要总结
This is a single-center phase 1 study to evaluate the safety and feasibility of huCART-meso cells given in combination with VCN-01 in patients with unresectable or metastatic pancreatic adenocarcinoma and serous epithelial ovarian cancer.
详细描述
This is a Phase I study evaluating the safety and feasibility of lentiviral transduced huCARTmeso cells when given in combination with VCN-01.
Dose Finding Phase:
This study was initiated using a 3+3 dose (de)escalation design in order to explore the initial safety of these drugs when given in combination, as well as to establish the recommended expansion dose of VCN-01 in this setting.
Expansion Phase:
The trial was expanded to include two parallel treatment arms further exploring the dosing sequence and schedule of these two investigational products when given in combination.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Patients with one of the following diagnoses:
- •Histologically confirmed unresectable or metastatic pancreatic adenocarcinoma; OR
- •Persistent or recurrent serous epithelial ovarian cancer
- •Progression or intolerance to at least one prior standard of care chemotherapy for advanced stage disease.
- •Subjects must have measurable disease as defined by RECIST 1.1 criteria.
- •Patients ≥ 18 years of age.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Adequate organ and bone marrow function defined as:
- •Hemoglobin ≥ 9 g/dL
- •Platelets ≥ 75,000/µl
- •PT/INR and PTT ≤ 1.5 x ULN
- •Bilirubin ≤ 2.0 x ULN
- •Creatinine ≤ 1.5 x ULN
- •ALT/AST ≤ 5 x ULN (subjects with liver metastases) or ALT/AST ≤ 2.5 x ULN (subjects without liver metastases)
- •Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
- •Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
- •Provides written informed consent.
- •Subjects of reproductive potential must agree to use acceptable birth control methods, as described in the protocol
排除标准
- •Patients with known CNS metastases
- •Active invasive cancer other than the one of the two cancers targeted by this study. Patients with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder and prostate cancer with PSA level < 1.0) are not excluded.
- •Active hepatitis B or hepatitis C infection.
- •Chronic hepatitis C with a FibroScan score equivalent to fibrosis stage 2 (F2) or greater.
- •Patients with known cirrhosis.
- •Patients with ongoing or active infection.
- •Patients with a known history of Li Fraumeni syndrome or retinoblastoma protein pathway germinal deficiency.
- •Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
- •Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (≤ 10mg equivalent of prednisone). Use of inhaled steroids is allowable.
- •Patients requiring supplemental oxygen therapy.
- •History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
- •Any clinically significant pericardial effusion, Class II-IV cardiovascular disability according to the New York Heart Association Classification or other cardiovascular condition that would preclude assessment of mesothelin induced pericarditis or that may worsen as a result of toxicities expected for this study. This determination will be made by a cardiologist if cardiac issues are suspected.
- •Pregnant or breastfeeding women.
- •RETIRED WITH PROTOCOL VERSION
- •Patients with significant lung disease as follows:
- •Patients with radiographic evidence of greater than lobar lymphangitic pulmonary involvement, greater than lobar bronchial wall thickening suggestive of peribronchial lymphatic disease extension, and/or evidence of extensive bilateral parenchymal metastatic burden.
- •Patients with radiographic and/or clinical evidence of active radiation pneumonitis.
- •Patients with radiographic evidence of underlying interstitial lung disease, including evidence of unresolved drug toxicity from any agent (e.g. chemotherapy, targeted agents, amiodarone, nitrofurantoin, etc.)
- •Patients with prior/ongoing treatment that will not accommodate washout requirements for immune checkpoint inhibitors
研究组 & 干预措施
Expansion Arm B
Single dose of 5x10^7 huCART-meso cells on Day 0 via IV infusion followed by the recommended expansion dose of VCN-01 as a single IV infusion on Day 7 (+3d).
干预措施: huCART-meso Cells (Biological)
Cohort 2
Single dose of 1x10(13) vp of VCN-01 on Day 0, followed by a single dose of 5x10(7) of huCART-meso cells on Day 14.
干预措施: huCART-meso Cells (Biological)
Cohort 1
Single dose of 3.3x10(12) vp of VCN-01 on Day 0, followed by a single dose of 5x10(7) of huCART-meso cells on Day 14.
干预措施: VCN-01 (Biological)
Cohort 1
Single dose of 3.3x10(12) vp of VCN-01 on Day 0, followed by a single dose of 5x10(7) of huCART-meso cells on Day 14.
干预措施: huCART-meso Cells (Biological)
Cohort 2
Single dose of 1x10(13) vp of VCN-01 on Day 0, followed by a single dose of 5x10(7) of huCART-meso cells on Day 14.
干预措施: VCN-01 (Biological)
Cohort -1
In the event that 2 DLTs occur in Cohort 1, then enrollment in Cohort 1 will be stopped and Cohort -1 will be opened for evaluation. Enrolled subjects will receive a single dose of huCART-meso cells on Day 0 followed by a single dose of 3.3x10(12) vp of VCN-01 on Day 14.
干预措施: VCN-01 (Biological)
Cohort -1
In the event that 2 DLTs occur in Cohort 1, then enrollment in Cohort 1 will be stopped and Cohort -1 will be opened for evaluation. Enrolled subjects will receive a single dose of huCART-meso cells on Day 0 followed by a single dose of 3.3x10(12) vp of VCN-01 on Day 14.
干预措施: huCART-meso Cells (Biological)
Expansion Arm A
Recommended expansion dose of VCN-01 as a single IV infusion on Day 0, followed by a single dose of 5x10^7 huCART-meso cells on Day 7 (+3d) via IV infusion.
干预措施: VCN-01 (Biological)
Expansion Arm A
Recommended expansion dose of VCN-01 as a single IV infusion on Day 0, followed by a single dose of 5x10^7 huCART-meso cells on Day 7 (+3d) via IV infusion.
干预措施: huCART-meso Cells (Biological)
Expansion Arm B
Single dose of 5x10^7 huCART-meso cells on Day 0 via IV infusion followed by the recommended expansion dose of VCN-01 as a single IV infusion on Day 7 (+3d).
干预措施: VCN-01 (Biological)
结局指标
主要结局
Type, frequency, severity, and attribution of AEs/SAEs as assessed by CTCAE v 5.0
时间窗: 2 years
Occurrence of dose-limiting toxicities.
时间窗: 2 years
Recommended expansion dose of VCN-01 administered in combination with huCART-meso cells
时间窗: 42 days after Infusion #1 (huCART-meso cells or VCN-01 dependent on cohort assignment)
highest VCN-01 dose at which 0 or 1 DLT occurs in 6 DLT-evaluable subjects
Occurrence of treatment-limiting toxicities (TLTs)
时间窗: 28 days after Infusion #1 (huCART-meso cells or VCN-01 dependent on arm assignment)
Number of subjects who either a) receive huCARTmeso cells and VCN-01 as per their arm assignment, or b) have a TLT qualifying event after receipt of either VCN-01 or huCART-meso cells.
Comparison of the safety profiles of the two treatment arms via descriptive analysis
时间窗: Up to 15 years post infusion
次要结局
- Overall Survival (OS)(15 years)
- Overall Response Rate (ORR)(15 years)
- Duration of Response (DOR)(15 years)
- Progression Free Survival (PFS)(15 years)
- Best Overall Response (BOR)(15 years)
- Proportion of subjects enrolled who receive one or both of the intended study infusions(2 years)