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

A Phase I Trial of Intraperitoneal Mesothelin-Targeted CAR T-Cell Therapy in Patients With Mesothelin-Positive Esophagogastric Adenocarcinoma With Peritoneal Carcinomatosis

Participants will have a sample of their white blood cells, called T cells, collected using a procedure called leukapheresis. The collected T cells will be sent to a laboratory at Memorial Sloan Kettering to be changed (modified) to become MSLN-targeted CAR T cells, the CAR T-cell therapy that participants will receive during the study. Participant study therapy will take about 3-4 weeks.

Inclusion 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

Inclusion Criteria for Leukapheresis:

• 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 of signing the informed consent form

• Completion of systemic therapy at least 7 days before leukapheresis

  o Immune checkpoint inhibitor therapy must be completed at least 14 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

  o 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

• 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

Inclusion Criteria for lymphodepleting chemotherapy/CAR T cell infusion

• 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 lymphodepleting chemotherapy

  o Immune checkpoint inhibitor therapy must be completed at least 28 days before lymphodepleting chemotherapy

• 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

Participant Exclusion Criteria

Exclusion Criteria for Leukapheresis or Lymphodepleting chemotherapy/CAR T cell infusion: Participants are excluded from enrollment if any of the following criteria apply:

• 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)

  o 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

  o 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 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