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
Overview
- Phase
- Phase 1
- Intervention
- Cyclophosphamide
- Conditions
- Breast Cancer
- Sponsor
- Memorial Sloan Kettering Cancer Center
- Enrollment
- 186
- Locations
- 7
- Primary Endpoint
- Maximum tolerated does (MTD)
- Status
- Active, not recruiting
- Last Updated
- 9 months ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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
Arms & Interventions
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.
Intervention: Cyclophosphamide
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.
Intervention: Mesothelin-targeted T cells
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.
Intervention: AP1903
Outcomes
Primary Outcomes
Maximum tolerated does (MTD)
Time Frame: 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.