T-Cell Therapy for Advanced Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer, Metastatic HER2-negative Breast

Intervention / Treatment
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* Drug: Cyclophosphamide
* Biological: Mesothelin-targeted T cells
* Drug: AP1903


Participation Criteria
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Eligibility Criteria
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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. *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) 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-cell infusion<br>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. | Drug: Cyclophosphamide<br> <br> Biological: Mesothelin-targeted T cells<br> <br> Drug: AP1903<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated does (MTD) | 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. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T-Cell, Chimeric antigen receptor (CAR), CAR T cells, Triple-negative breast cancer, Immunotherapy T-cell therapy, 16-040, immunotherapy, CAR