T-Cell Therapy for Advanced Breast Cancer

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase: Active, not recruiting; Phase 1

Conditions: Breast Cancer; Metastatic HER2-negative Breast

Treatments: Drug: AP1903; Biological: Mesothelin-targeted T cells; Drug: Cyclophosphamide

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT02792114

16-040

Details and patient eligibility

About

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.

Enrollment: 186 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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186 participants in 1 patient group

T-cell infusion

Experimental group

Description:

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.

Treatment:

Drug: Cyclophosphamide

Biological: Mesothelin-targeted T cells

Drug: AP1903