Mesothelin-Targeted T-Cells after Cyclophosphamide in Treating Patients with Metastatic, Mesothelin-Expressing, HER2 Negative Breast Cancer
- Patients with metastatic breast cancer
- Karnofsky performance status >= 70%
- Patients with breast cancer that is pathologically confirmed at Memorial Sloan Kettering Cancer Center (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 immunohistochemistry (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 Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0)
- White blood cell (WBC) count >= 3000 cells/mm^3
- Absolute neutrophil count >= 1500 neutrophils/mm^3
- Platelet count >= 100,000 platelets/mm^3
- Bilirubin < 1.5 x upper limit of normal (ULN)
- Serum alanine aminotransferase/serum aspartate aminotransferase (ALT/AST) < 5 x ULN
- Serum creatinine < 1.5 x ULN or creatinine (Cr) > 1.5 x 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 (formalin-fixed paraffin-embedded [FFPE] tissue block or 10-15 unstained slides)
- Untreated or active central nervous system (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 >= 4 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 principal investigator (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
I. To evaluate the safety of adoptive transfer of genetically modified, autologous, intravenously delivered anti-mesothelin iCasp9M28z chimeric antigen receptor (CAR)-transduced autologous T lymphocytes (mesothelin-targeted T cells) in patients with mesothelin-expressing metastatic HER2-negative breast cancer following the administration of cyclophosphamide, as well as to establish the maximum tolerated dose (MTD) for this treatment.
I. Changes in the absolute value of the biomarker serum soluble mesothelin related peptide (SMRP) in serum before and after adoptive transfer of T cells.
II. The pattern of change in SMRP levels from before to after adoptive transfer of T cells.
III. The persistence of adoptively transferred T cells in peripheral blood, assessed by quantitative molecular techniques.
IV. The persistence and targeting efficiency of adoptively transferred T cells in tumor tissue from patients after receiving T cells.
V. The cytokine profile of serum before and after adoptive transfer of T cells.
VI. The capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered mesothelin-targeted T cells and resolve toxicity.
VII. The clinical response to adoptively transferred T cells, as measured by week-12 radiographic response (by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), in patients with measurable disease at baseline.
OUTLINE: This is a dose-escalation study of anti-mesothelin iCasp9M28z CAR-transduced autologous T lymphocytes.
Patients receive cyclophosphamide intravenously (IV) followed by anti-mesothelin iCasp9M28z CAR-transduced autologous T lymphocytes IV over 15-120 minutes 2 to 7 days later.
After completion of study treatment, patients are followed up within 3 days, weekly for 8 weeks, monthly for 6 months, at 12 months, and then periodically for up to 15 years.
Trial Phase Phase I
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
- Primary ID 16-040
- Secondary IDs NCI-2016-01307
- Clinicaltrials.gov ID NCT02792114