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

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase

Enrolling

Phase 1

Conditions

Mesothelin Positive

Diabetes Mellitus

Esophageal Adenocarcinomas

Breast Neoplasms

Esophagogastric Adenocarcinoma

Esophageal Adenocarcinoma

Peritoneal Carcinomatosis

Mesothelin-Expressing Tumors

Treatments

Biological: M28z1XXPD1DNR CAR

Study type

Interventional

Funder types

Other

Identifiers

NCT06623396

24-214

Details and patient eligibility

About

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.

Enrollment

18 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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