A Study of Mesothelin-Targeted CAR T-Cell Therapy in People With Esophagogastric Cancer

Eligibility Criteria

• * Aged ≥18 years
• * Diagnosis of pathologically confirmed EG adenocarcinoma
• * Diagnosis of metastatic or recurrent disease
• * ECOG performance status of 0-1
• * Life expectancy of ≥4 months
• * Written informed consent for the study (from participant)
• * Life expectancy of ≥4 months
• * ECOG performance status of 0-1
• * Histologic diagnosis that \>25% of the tumor expresses MSLN by 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
• * Stage IV disease with gross peritoneal carcinomatosis on imaging and/or microscopic peritoneal involvement by cytology or noted during diagnostic laparoscopy
• * 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
• * Patients with Her2 positive disease must have received ≥1 line of anti-Her2 based therapy
• * At least 1 measurable or evaluable lesion per RECIST 1.1. Screening imaging must be obtained within 6 weeks before the informed consent form signing date
• * Completion of systemic therapy at least 7 days before leukapheresis
• * Lab requirements (hematology):
• * Absolute neutrophil count ≥1.0 K/mcL
• * Hemoglobin ≥9 gm/dL
• * Platelet count ≥75 K/mcL
• * Blood product transfusion or growth factor support cannot occur within 7 days of testing
• * Lab requirements (serum chemistry):
• * Bilirubin ≤1.5× upper limit of normal (ULN)
• * Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level ≤3× ULN
• * Calculated clearance of ≥50 mL/min by Cockcroft-Gault equation
• * Negative screen for infectious disease markers, including hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, HIV 1-2 antibody, HTLV antibody and syphilis antibody
• * 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)
• * Resolution of all acute toxic effects of any previous therapeutic or palliative chemotherapy, radiotherapy, or surgical procedures to grade ≤1 (CTCAE v5.0), except for neuropathy and alopecia
• * Life expectancy of ≥4 months
• * ECOG performance status of 0-1
• * At least 1 measurable or evaluable lesion per RECIST 1.1. Screening imaging must be obtained within 4 weeks before the date of lymphodepletion
• * Completion of systemic therapy at least 14 days before leukapheresis
• * Lab requirements (hematology):
• * Absolute neutrophil count ≥1.5 K/mcL
• * Hemoglobin ≥8 gm/dL
• * Platelet count ≥75 K/mcL
• * Lab requirements (serum chemistry):
• * Bilirubin ≤1.5× upper limit of normal (ULN)
• * Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level ≤3× ULN
• * Calculated clearance of ≥50 mL/min by Cockcroft-Gault equation
• * 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)
• * Resolution of all acute toxic effects of any previous therapeutic or palliative chemotherapy, radiotherapy, or surgical procedures to grade ≤1 (CTCAE v5.0), except for neuropathy and alopecia
• * 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)
• * 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
• * Any other medical condition, e.g. fever \>38.0 degrees C, that, in the opinion of the 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