Clinical trial NCT06623396: A Study of Mesothelin-Targeted CAR T-Cell Therapy in People With Esophagogastric Cancer
Official title: A Phase I Trial of Intraperitoneal Mesothelin-Targeted CAR T-Cell Therapy in Patients With Mesothelin-Positive Esophagogastric Adenocarcinoma With Peritoneal Carcinomatosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Mesothelin Positive
Mesothelin-Expressing Tumors
Esophageal Adenocarcinoma
Esophageal Adenocarcinomas
Esophagogastric Adenocarcinoma
Peritoneal Carcinomatosis
Breast Neoplasms
Diabetes Mellitus
Keywords: mesothelin positive
mesothelin-expressing tumors
esophageal adenocarcinoma
esophageal adenocarcinomas
esophagastric adenocarcinoma
peritoneal carcinomatosis
CAR T-Cell Therapy
24-214
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
First posted: 2024-10-02
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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 \&gt;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 \&lt;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 \&lt;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 \&gt;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

Primary outcomes:
measure: Number of treatment-emergent adverse events
timeFrame: 1 year
measure: Maximum Tolerated Dose of M28z1XXPD1DNR CAR T cells
timeFrame: Up to 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth (Limited protocol activities)
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen (Limited Protocol Activities)
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Suffolk - Commack (Limited Protocol Activities)
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester (Limited Protocol Activities)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center (All Protocol Activities)
state: New York
city: Uniondale
country: United States
facility: Memorial Sloan Kettering Nassau (Limited Protocol Activities)
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Geoffrey Ku, MD
role: PRINCIPAL_INVESTIGATOR
References: