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

Официальное название

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

Обзор

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.

Вмешательства

• Биопрепарат M28z1XXPD1DNR CAR
  Participants with esophagastric adenocarcinoma will be treated with an intraperitoneal infusion of different doses of autologous T cells that have been genetically modified ex vivo to express the M28z1XXPD1DNR CAR. The CAR T cells will be manufactured in MSK's Center for Cell Engineering.

Первичные конечные точки

• Number of treatment-emergent adverse events [Срок оценки: 1 year]
• Maximum Tolerated Dose of M28z1XXPD1DNR CAR T cells [Срок оценки: Up to 1 year]

Критерии участия

Критерии включения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 7 центров

• Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities) — Basking Ridge
• Memorial Sloan Kettering Monmouth (Limited protocol activities) — Middletown
• Memorial Sloan Kettering Bergen (Limited Protocol Activities) — Montvale
• Memorial Sloan Kettering Suffolk - Commack (Limited Protocol Activities) — Commack
• Memorial Sloan Kettering Westchester (Limited Protocol Activities) — Harrison
• Memorial Sloan Kettering Cancer Center (All Protocol Activities) — New York
• Memorial Sloan Kettering Nassau (Limited Protocol Activities) — Uniondale

Идентификаторы

NCT: NCT06623396 · 24-214

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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