A Phase I Clinical Trial to Evaluate the Safety and Tolerability of Mesothelin-Specific Chimeric Antigen Receptor-Positive T Cells in Patients With Metastatic Mesothelin-Expressing Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 186
- 试验地点
- 14
- 主要终点
- Maximum tolerated does (MTD)
研究概览
简要总结
The purpose of this study is to test the safety of different doses of specially prepared T cells collected from the blood. The investigators want to find a safe dose of these modified T cells for patients who have metastatic HER2-negative breast cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Patients aged ≥18 years with metastatic breast cancer
- •Karnofsky performance status ≥70%
- •Patients with breast cancer that is pathologically confirmed at MSKCC (pathology from outside institutions is acceptable for the screening phase of the protocol) and defined by the following:
- •HER2 negative (in cases of mixed HER2 results, the most recent pathology results considered reflective of the active cancer will be considered)
- •Previously treated with at least 1 chemotherapy regimen for metastatic disease and documented progression
- •Expression of mesothelin must be confirmed by meeting 1 of the following criteria:
- •Mesothelin expression (>10% of the tumor expressing mesothelin) by IHC
- •Elevated serum SMRP levels (>1.0 nM/L)
- •Presence of measurable or evaluable disease
- •Chemotherapy, targeted therapy (such as a tyrosine kinase inhibitor), or radiotherapy must have been completed at least 14 days before administration of T-cells. Prior immunotherapy with checkpoint blockade (i.e., PD1 inhibitor, PDL1 inhibitor, or CTL4-antagonist or similar agent) must have been completed more than 1 month before the T-cell infusion.
- •*Chemotherapy must have been completed at least 7 days prior to leukapheresis
- •Any major operation must have occurred at least 28 days before study enrollment.
- •All acute toxic effects of any previous radiotherapy, chemotherapy, or surgical procedures must have resolved to grade 1 or lower according to CTCAE
- •Lab requirements (hematology):
- •White blood cell (WBC) count ≥3000 cells/mm^3
- •Absolute neutrophil count ≥1500 neutrophils/mm^3
- •Platelet count ≥100,000 platelets/mm^3
- •Lab requirements (serum chemistry):
- •Bilirubin <1.5x upper limit of normal (ULN)
- •Serum alanine aminotransferase/serum aspartate aminotransferase (ALT/AST) <5x ULN
- •Serum creatinine <1.5x ULN or Cr >1.5x ULN, but calculated clearances of >60
- •Negative screen for human immunodeficiency virus (HIV), hepatitis B virus (HBV) antigen, and hepatitis C virus (HCV). If testing was performed during the previous 3 months, there is no need to repeat testing, as long as documentation of results is provided to the study site. Subjects must receive counseling and sign a separate informed consent form for HIV testing.
- •Subjects and their partners with reproductive potential must agree to use an effective form of contraception during the period of drug administration and for 4 weeks after completion of the last administration of the study drug. An effective form of contraception is defined as oral contraceptives plus 1 form of barrier or double-barrier method contraception (condom with spermicide or condom with diaphragm).
- •Subjects must be able to understand the potential risks and benefits of the study and must be able to read and provide written, informed consent for the study.
- •Availability of archival tumor tissues (FFPE tissue block or 10-15 unstained slides)
排除标准
- •Untreated or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control); patients with a history of treated CNS metastases are eligible, provided that all of the following criteria are met:
- •Presence of measurable or evaluable disease outside of the CNS;
- •Radiographic demonstration of improvement upon completion of CNS- directed therapy and no evidence of interim progression between completion of CNS-directed therapy and the screening radiographic study;
- •Completion of radiotherapy ≥8 weeks prior to the screening radiographic study;
- •Discontinuation of corticosteroids and anticonvulsants ≥4 weeks prior to the screening radiographic study.
- •History of seizure disorder
- •Patients currently receiving treatment for concurrent active malignancy. Prior immunotherapy with checkpoint blockade (i.e., PD1 inhibitor, PDL1 inhibitor, or CTL4-antagonist or similar agent) must have been completed more than 1 month prior to the T-cell infusion.
- •Autoimmune or antibody-mediated disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and temporal arteritis (patients with a history of hypothyroidism will not be excluded)
- •Clinically significant cardiac disease (New York Heart Association class III/IV) or severe debilitating pulmonary disease
- •Pregnant or lactating women
- •Known active infection requiring antibiotics within 7 days of the start of treatment (Day 0)
- •A requirement for daily systemic corticosteroids for any reason or a requirement for other immunosuppressive or immunomodulatory agents. Topical, nasal, and inhaled steroids are permitted.
- •Administration of live, attenuated vaccine within 8 weeks before the start of treatment (Day 0) and throughout the study
- •Any other medical condition that, in the opinion of the PI, may interfere with a subject's participation in or compliance with the study
- •Participation in a therapeutic research study or receipt of an investigational drug within 30 days of T-cell infusion
研究组 & 干预措施
T-cell infusion
A single blood volume leukapheresis for harvesting of PBMCs will be performed, As the transduced T cells will be frozen, the timing of leukapheresis is not defined & can vary from patient to patient. Subsequently, a single dose of mesothelin-targeted T cells will be infused via intravenous catheter or central line (i.e., mediport). Patients will be monitored in the hospital and discharged home after a minimum of 48 hours. Patients will be monitored closely as outpatients for the next 2 months. Patients will be followed weekly as outpatients for the first 8 weeks after treatment. All patients will be hydrated intravenously, premedicated with acetaminophen & diphenhydramine, & administered cyclophosphamide at 1.5 g/m2 2 to 7 days (Day -7 to Day -2) before administration of mesothelin-targeted T cells.
干预措施: Cyclophosphamide (Drug)
T-cell infusion
A single blood volume leukapheresis for harvesting of PBMCs will be performed, As the transduced T cells will be frozen, the timing of leukapheresis is not defined & can vary from patient to patient. Subsequently, a single dose of mesothelin-targeted T cells will be infused via intravenous catheter or central line (i.e., mediport). Patients will be monitored in the hospital and discharged home after a minimum of 48 hours. Patients will be monitored closely as outpatients for the next 2 months. Patients will be followed weekly as outpatients for the first 8 weeks after treatment. All patients will be hydrated intravenously, premedicated with acetaminophen & diphenhydramine, & administered cyclophosphamide at 1.5 g/m2 2 to 7 days (Day -7 to Day -2) before administration of mesothelin-targeted T cells.
干预措施: AP1903 (Drug)
T-cell infusion
A single blood volume leukapheresis for harvesting of PBMCs will be performed, As the transduced T cells will be frozen, the timing of leukapheresis is not defined & can vary from patient to patient. Subsequently, a single dose of mesothelin-targeted T cells will be infused via intravenous catheter or central line (i.e., mediport). Patients will be monitored in the hospital and discharged home after a minimum of 48 hours. Patients will be monitored closely as outpatients for the next 2 months. Patients will be followed weekly as outpatients for the first 8 weeks after treatment. All patients will be hydrated intravenously, premedicated with acetaminophen & diphenhydramine, & administered cyclophosphamide at 1.5 g/m2 2 to 7 days (Day -7 to Day -2) before administration of mesothelin-targeted T cells.
干预措施: Mesothelin-targeted T cells (Biological)
结局指标
主要结局
Maximum tolerated does (MTD)
时间窗: 2 years
We have designed the dose-escalation using a standard 3+3 design. In this design, patients will be treated in sequential groups of 3 to 6 patients per T cell dose. With 4 dose levels, the projected trial size for this study is a minimum of 4 and a maximum of 24 patients.
次要结局
未报告次要终点