T-Cell Therapy for Advanced Breast Cancer

• ClinicalTrials.gov Identifier: NCT02792114
• Recruitment Status: Active, not recruiting
• First Posted: June 7, 2016
• Last Update Posted: March 24, 2023
• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

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
Breast Cancer; Metastatic HER2-negative Breast	Drug: Cyclophosphamide; Biological: Mesothelin-targeted T cells; Drug: AP1903	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 186 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 2016
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm

Intervention/treatment

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

Outcome Measures

Primary Outcome Measures :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

  *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

Contacts and Locations

Locations

United States, New Jersey

Memoral Sloan Kettering Cancer Center (Consent and follow-up only)

Basking Ridge, New Jersey, United States

Memorial Sloan Kettering Monmouth (Consent and follow-up only)

Middletown, New Jersey, United States, 07748

Memorial Sloan Kettering Bergen (Consent and follow-up only)

Montvale, New Jersey, United States, 07645

United States, New York

Memorial Sloan Kettering Cancer Center at Commack (Consent and follow-up only)

Commack, New York, United States

Memorial Sloan Kettering Westchester (Consent and follow-up only)

Harrison, New York, United States, 10604

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

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

More Information

Additional Information:

Memorial Sloan Kettering Cancer Center 

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT02792114
• Other Study ID Numbers: 16-040
• First Posted: June 7, 2016
• Last Update Posted: March 24, 2023
• Last Verified: March 2023

Keywords provided by Memorial Sloan Kettering Cancer Center:

T-Cell; Chimeric antigen receptor (CAR); CAR T cells; Triple-negative breast cancer; Immunotherapy T-cell therapy; 16-040; immunotherapy; CAR

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Cyclophosphamide; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists