Mesothelin-Targeted CAR T-Cell Therapy for the Treatment of Patients with Mesothelin-Positive Recurrent or Metastatic Esophagogastric Cancer and Peritoneal Carcinomatosis

Inclusion Criteria

• AT SCREENING: Aged ≥ 18 years
• AT SCREENING: Diagnosis of pathologically confirmed EG adenocarcinoma
• AT SCREENING: Diagnosis of metastatic or recurrent disease
• AT SCREENING: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• AT SCREENING: Life expectancy of ≥ 4 months
• CRITERIA FOR LEUKAPHERESIS: Written informed consent for the study (from participant)
• CRITERIA FOR LEUKAPHERESIS: Life expectancy of ≥ 4 months
• CRITERIA FOR LEUKAPHERESIS: ECOG performance status of 0-1
• CRITERIA FOR LEUKAPHERESIS: Histologic diagnosis that > 25% of the tumor expresses MSLN by immunohistochemistry (IHC) analysis. Archival tissue obtained up to 2 years before study enrollment is acceptable. IHC testing of a cell block from cytology (e.g., ascitic fluid) is acceptable if approved by the study pathologist. If adequate archival tissue is not available at screening, a fresh tumor biopsy should be obtained
• CRITERIA FOR LEUKAPHERESIS: Stage IV disease with gross peritoneal carcinomatosis on imaging and/or microscopic peritoneal involvement by cytology or noted during diagnostic laparoscopy
• CRITERIA FOR LEUKAPHERESIS: Disease progression or treatment intolerance after receiving at least 1 treatment regimen in the metastatic setting; patients with disease recurrence within 6 months of completing curative systemic therapy (chemotherapy, chemoradiation or adjuvant immunotherapy) are also eligible
• CRITERIA FOR LEUKAPHERESIS: Patients with HER2 positive disease must have received ≥ 1 line of anti-HER2 based therapy
• CRITERIA FOR LEUKAPHERESIS: At least 1 measurable or evaluable lesion per RECIST 1.1. Screening imaging must be obtained within 6 weeks of signing the informed consent form
• CRITERIA FOR LEUKAPHERESIS: Completion of systemic therapy at least 7 days before leukapheresis * Immune checkpoint inhibitor therapy must be completed at least 14 days before leukapheresis
• CRITERIA FOR LEUKAPHERESIS: Absolute neutrophil count ≥ 1.0 K/mcL
• CRITERIA FOR LEUKAPHERESIS: Hemoglobin ≥ 9 gm/dL
• CRITERIA FOR LEUKAPHERESIS: Platelet count ≥ 75 K/mcL
• CRITERIA FOR LEUKAPHERESIS: Blood product transfusion or growth factor support cannot occur within 7 days of testing
• CRITERIA FOR LEUKAPHERESIS: Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• CRITERIA FOR LEUKAPHERESIS: Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level ≤ 3 x ULN
• CRITERIA FOR LEUKAPHERESIS: Calculated clearance of ≥ 50 mL/min by Cockcroft-Gault equation
• CRITERIA FOR LEUKAPHERESIS: Negative screen for infectious disease markers, including hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, HIV 1-2 antibody, human T cell lymphotropic virus (HTLV) antibody and syphilis antibody * Note: Patients with a history of hepatitis B virus infection are eligible if the hepatitis B viral load is undetectable. Patients with a history of hepatitis C virus infection who were treated for hepatitis C and cured are eligible if the hepatitis C viral load is undetectable
• CRITERIA FOR LEUKAPHERESIS: Serum pregnancy test with negative result at screening and preconditioning and must be willing to use effective and reliable contraception for at least 12 months after T cell infusion (for female participants of childbearing age)
• CRITERIA FOR LEUKAPHERESIS: Resolution of all acute toxic effects of any previous therapeutic or palliative chemotherapy, radiotherapy, or surgical procedures to grade ≤ 1 (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0), except for neuropathy and alopecia
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Life expectancy of ≥ 4 months
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: ECOG performance status of 0-1
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: At least 1 measurable or evaluable lesion per RECIST 1.1. Screening imaging must be obtained within 4 weeks before the date of lymphodepletion
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Completion of systemic therapy at least 14 days before lymphodepleting chemotherapy * Immune checkpoint inhibitor therapy must be completed at least 28 days before lymphodepleting chemotherapy
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Absolute neutrophil count ≥ 1.5 K/mcL
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Hemoglobin ≥ 8 gm/dL
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Platelet count ≥ 75 K/mcL
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level ≤ 3 x ULN
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Calculated clearance of ≥ 50 mL/min by Cockcroft-Gault equation
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Serum pregnancy test with negative result within 7 days of planned lymphodepletion date and must be willing to use effective and reliable contraception for at least 12 months after T cell infusion (for female participants of childbearing age)
• LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION: Resolution of all acute toxic effects of any previous therapeutic or palliative chemotherapy, radiotherapy, or surgical procedures to grade ≤ 1 (CTCAE v 5.0), except for neuropathy and alopecia

Exclusion Criteria

• FOR LEUKAPHERESIS OR LYMPHODEPLETING CHEMOTHERAPY/CAR T CELL INFUSION:
• Pregnant or lactating
• HIV, active hepatitis C virus, or active hepatitis B virus infection, as determined by quantitative PCR (patients who have undergone negative testing prior to leukapheresis do not require repeat testing)
• Receiving therapy for concurrent active malignancy * Note: Patients receiving treatment for in situ skin malignancies are not excluded * Patients with any malignancy diagnosed > 3 years before that is thought to be curatively treated and/or has a low risk of recurrence are eligible. Patients may continue to receive adjuvant therapy at the time of study enrollment (e.g., adjuvant hormonal therapy for curatively treated breast cancer)
• Known hematologic malignancy requiring treatment in the preceding 5 years or a known history of lymphoid malignancy
• Previous receipt of CAR T cell therapy or any other cellular therapy
• Previous mesothelin-directed therapy
• Any major abdominal surgery (laparotomy with resection of gastrointestinal tract or organ resection) that is completed < 28 days before study enrollment. Patients who have undergone diagnostic laparoscopy can be included in the study without regard to timing
• 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 if all of the following criteria are met: * 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 before the screening radiographic study
• Active autoimmune disease that has required systemic treatment within 1 year before leukapheresis (with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) * Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Receiving daily systemic corticosteroids ≥ 10 mg of prednisone daily or equivalent or receiving immunosuppressive or immunomodulatory treatment
• Any of the following cardiac conditions: * New York Heart Association stage III or IV congestive heart failure * Myocardial infarction ≤ 6 months before enrollment * History of myocarditis * Serious uncontrolled cardiac arrhythmia, unstable angina, or uncontrolled infection * Left ventricular ejection fraction ≤ 40%
• Active interstitial lung disease/pneumonitis or a history of interstitial lung disease/pneumonitis requiring treatment with systemic steroids
• Baseline pulse oximetry < 90% on room air at the screening time point
• Known active infection requiring antibiotic treatment 7 days before leukapheresis * Note: Treatment can be delayed at the discretion of the treating physician to allow the patient to recover from the infection
• Any other medical condition, e.g. fever > 38.0 °C, that, in the opinion of the principal investigator (PI), may interfere with the subject’s participation in or compliance with the study
• Receipt of live, attenuated vaccine within 8 weeks before the planned lymphodepleting chemotherapy date
• Deemed to be noncompliant by the study team for administration of a high-risk treatment agent and for close follow-up after treatment as required by the protocol