A Seamless Phase 1/2 Study to Evaluate the Safety and Efficacy of Mesothelin-Targeting Autologous Logic-gated Tmod™ CAR T Products, in Heterozygous HLA-A*02 Adults With Recurrent Unresectable, Locally Advanced, or Metastatic Solid Tumors That Express MSLN and Have Lost HLA-A*02 Expression
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 474
- 试验地点
- 24
- 主要终点
- Phase 1: Rate of adverse events and dose limiting toxicities (DLTs) by dose level
研究概览
简要总结
The goal of this study is to test autologous logic-gated Tmod™ CAR T-cell products in subjects with solid tumors including colorectal cancer (CRC), pancreatic cancer (PANC), non-small cell lung cancer (NSCLC), ovarian cancer (OVCA), mesothelioma (MESO), and other solid tumors that express mesothelin (MSLN) and have lost HLA-A*02 expression.
The main questions this study aims to answer are:
Phase 1: What is the recommended dose that is safe for patients
Phase 2: Does the recommended dose kill solid tumor cells and protect the patient's healthy cells
Participants will be required to perform study procedures and assessments, and will also receive the following study treatments:
Enrollment and Apheresis in BASECAMP-1 (NCT04981119)
Preconditioning Lymphodepletion (PCLD) Regimen
Tmod CAR T cells at the assigned dose
详细描述
This is a seamless phase 1/2, multi-center, open-label study that enrolls adults with recurrent unresectable, locally advanced, or metastatic (considered non-curative) CRC, NSCLC, PANC, OVCA, MESO or other solid tumors with MSLN expression. Subjects must be germline HLA-A*02 heterozygous, with tumors that express MSLN and have lost HLA-A*02 expression. This study has two arms: Arm 1 is a study of A2B694 and Arm 2 is a study of A2B543.
The purpose of Phase 1 of this study is to determine the safety and the optimal dose of the Tmod products (after PCLD) in participants with solid tumor disease. The purpose of Phase 2 of this study is to determine the further safety and efficacy (how well it treats the solid tumor disease) of the Tmod products.
The treatment available for these cancers and other solid tumors can be toxic, debilitating, and fatal. In the recurrent unresectable, locally advanced, or metastatic setting, the intent of standard of care treatment is typically palliative rather than curative, and has not changed significantly in several decades. A2 Bio hypothesizes that Tmod CAR T-cell therapy will enable the killing of tumor target cells (those cells that express MSLN and have loss of heterozygosity [LOH] for HLA-A*02 protein). Additionally, normal healthy cells that maintain HLA-A*02 expression and co-express MSLN (eg, lung tissue) will not be targeted due to the blocker portion of the Tmod CAR T cell that acts as a self-regulated safety switch that protects normal tissue from damage. A2 Bio believes this will provide a therapeutic safety window compared to previous solid tumor targeting therapies. This hypothesis will be explored in the study.
Participants for this study must enroll and have their T cells collected (apheresis) in the pre-screening BASECAMP-1 study (NCT04981119). T cells are collected, processed and stored for each participant. Upon disease progression the participant may screen for this study (EVEREST-2) and the participant's T cells are manufactured and then infused following PCLD regimen. There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to EVEREST-2 based on their own disease course.
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
- •Appropriately enrolled in the BASECAMP-1 A2 Biotherapeutics, Inc. study, with tissue demonstrating LOH of HLA-A*02 by NGS (whenever possible from the primary site), successful apheresis and PBMC processing, and with sufficient stored cells available for Tmod CAR T-cell therapy
- •Histologically confirmed recurrent unresectable, locally advanced, or metastatic CRC, NSCLC, PANC, OVCA, MESO, or other solid tumors with MSLN expression. Measurable disease is required with lesions of ≥1.0 cm by CT.
- •Received previous required therapy for the appropriate solid tumor disease as described in the protocol
- •Has adequate organ function as described in the protocol
- •ECOG performance status of 0 to 1
- •Life expectancy of ≥3 months
- •Willing to comply with study schedule of assessments including long term safety follow up
排除标准
- •Has disease that is suitable for local therapy or able to receive standard of care therapy that is therapeutic and not palliative
- •Prior allogeneic stem cell transplant
- •Prior solid organ transplant
- •MESO with pleural involvement extending into the peritoneum
- •Cancer therapy within 3 weeks or 3 half lives of infusion
- •Radiotherapy within 28 days of infusion
- •Unstable angina, arrhythmia, myocardial infarction, or any other significant cardiac disease within the last 6 months
- •Any new symptomatic pulmonary embolism (PE) or a deep vein thrombosis (DVT) within 3 months of enrollment. Therapeutic dosing of anticoagulants is allowed for history of PE or DVT if greater than 3 months from time of enrollment, and adequately treated
- •History of interstitial lung disease including drug-induced interstitial lung disease and radiation pneumonitis that requires treatment with prolonged steroids or other immune suppressive agents within 1 year
- •Requires supplemental home oxygen
- •Females of childbearing potential who are pregnant or breastfeeding
- •Subjects, both male and female, of childbearing potential who are not willing to practice birth control from the time of consent through 6 months post infusion
研究组 & 干预措施
Arm 2: A2B543
Patients receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B543 intravenously on day 0
干预措施: xT CDx with HLA-LOH Assay (Diagnostic Test)
Arm 2: A2B543
Patients receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B543 intravenously on day 0
干预措施: A2B543 (Biological)
Arm 1: A2B694
Patients receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B694 intravenously on day 0
干预措施: A2B694 (Biological)
Arm 1: A2B694
Patients receive preconditioning lymphodepletion (PCLD) regimen followed by a single dose of A2B694 intravenously on day 0
干预措施: xT CDx with HLA-LOH Assay (Diagnostic Test)
结局指标
主要结局
Phase 1: Rate of adverse events and dose limiting toxicities (DLTs) by dose level
时间窗: From the time of Informed consent until 24 months (2 years) post infusion
Adverse Events and toxicity will be evaluated according to the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 (or current version). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) events will be graded according to the criteria described in the current protocol.
Phase 1: Recommended Phase 2 Dose (RP2D)
时间窗: 21 days post infusion
The RP2D will be identified utilizing a BOIN study design in addition to considering safety and biomarker analysis.
Phase 2: The Overall Response Rate (ORR) for patients
时间窗: 24 months post infusion
The ORR will be evaluated per RECIST v1.1 and assessed by independent central review.
次要结局
- Persistence of Tmod product(up to 24 months post infusion)
- Cytokine analysis(up to 24 months post infusion)