T-Cell Therapy for Advanced Breast Cancer
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: 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. |
Drug: Cyclophosphamide
Biological: Mesothelin-targeted T cells
Drug: AP1903
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Outcome Measures
Primary Outcome Measures
- Maximum tolerated does (MTD) [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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients aged ≥18 years with metastatic breast cancer
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Karnofsky performance status ≥70%
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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:
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HER2 negative (in cases of mixed HER2 results, the most recent pathology results considered reflective of the active cancer will be considered)
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Previously treated with at least 1 chemotherapy regimen for metastatic disease and documented progression
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Expression of mesothelin must be confirmed by meeting 1 of the following criteria:
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Mesothelin expression (>10% of the tumor expressing mesothelin) by IHC
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Elevated serum SMRP levels (>1.0 nM/L)
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Presence of measurable or evaluable disease
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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
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Any major operation must have occurred at least 28 days before study enrollment.
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All acute toxic effects of any previous radiotherapy, chemotherapy, or surgical procedures must have resolved to grade 1 or lower according to CTCAE
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Lab requirements (hematology):
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White blood cell (WBC) count ≥3000 cells/mm^3
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Absolute neutrophil count ≥1500 neutrophils/mm^3
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Platelet count ≥100,000 platelets/mm^3
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Lab requirements (serum chemistry):
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Bilirubin <1.5x upper limit of normal (ULN)
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Serum alanine aminotransferase/serum aspartate aminotransferase (ALT/AST) <5x ULN
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Serum creatinine <1.5x ULN or Cr >1.5x ULN, but calculated clearances of >60
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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.
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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).
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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.
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Availability of archival tumor tissues (FFPE tissue block or 10-15 unstained slides)
Exclusion Criteria:
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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:
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Presence of measurable or evaluable disease outside of the CNS;
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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;
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Completion of radiotherapy ≥8 weeks prior to the screening radiographic study;
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Discontinuation of corticosteroids and anticonvulsants ≥4 weeks prior to the screening radiographic study.
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History of seizure disorder
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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.
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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)
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Clinically significant cardiac disease (New York Heart Association class III/IV) or severe debilitating pulmonary disease
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Pregnant or lactating women
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Known active infection requiring antibiotics within 7 days of the start of treatment (Day 0)
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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.
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Administration of live, attenuated vaccine within 8 weeks before the start of treatment (Day 0) and throughout the study
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Any other medical condition that, in the opinion of the PI, may interfere with a subject's participation in or compliance with the study
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Participation in a therapeutic research study or receipt of an investigational drug within 30 days of T-cell infusion
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Memoral Sloan Kettering Cancer Center (Consent and follow-up only) | Basking Ridge | New Jersey | United States | |
2 | Memorial Sloan Kettering Monmouth (Consent and follow-up only) | Middletown | New Jersey | United States | 07748 |
3 | Memorial Sloan Kettering Bergen (Consent and follow-up only) | Montvale | New Jersey | United States | 07645 |
4 | Memorial Sloan Kettering Cancer Center at Commack (Consent and follow-up only) | Commack | New York | United States | |
5 | Memorial Sloan Kettering Westchester (Consent and follow-up only) | Harrison | New York | United States | 10604 |
6 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
7 | Memorial Sloan Kettering Nassau (Consent and Follow-Up only) | Uniondale | New York | United States | 11553 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
- United States Department of Defense
Investigators
- Principal Investigator: Shanu Modi, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 16-040