Assessing the Safety of Modified T Cells for Mesothelioma
- Karnofsky performance status >= 70%
- Pathologically confirmed MPM: * Epithelioid or biphasic histologic diagnosis provided that >=10% of the tumor expresses MSLN by IHC analysis * Patients with peritoneal mesothelioma with pleural involvement are eligible only if there is radiographic and pathologic confirmation of mesothelioma in the pleural cavity and >=10% of the tumor expresses MSLN by IHC analysis
- Previously treated with at least 1 treatment regimen
- Measurable or evaluable disease (disease is considered evaluable but not measurable if it does not meet the eligibility criteria for mRECIST but is a manifestation of malignancy that can be followed qualitatively as an indicator of disease progression or treatment response)
- Chemotherapy, targeted therapy, or radiotherapy must be completed at least 7 days before leukapheresis * Checkpoint inhibitor (CPI) must be completed at least 21 days before leukapheresis
- Chemotherapy, targeted therapy, or therapeutic radiotherapy must be completed at least 14 days before administration of T cells * Palliative radiotherapy can be completed 2 days before lymphodepletion
- Immunotherapy with CPI must be completed at least 42 days before administration of T cells
- Any major thoracic (thoracotomy with lung or esophageal resection) or abdominal (laparotomy with organ resection) operation must have occurred at least 28 days before study enrollment. Patients who have undergone diagnostic videothoracoscopy (VATS) or laparoscopy can be included in the study
- All acute toxic effects of any previous therapeutic or palliative radiotherapy, chemotherapy, or surgical procedures must have resolved to grade 1 (Common Terminology Criteria for Adverse Events [CTCAE] v5.0)
- Absolute neutrophil count >= 1.5 K/mcL
- Platelet count >= 100 K/mcL
- Bilirubin =< 1.5 x upper limit of normal (ULN)
- Serum alanine aminotransferase and serum aspartate aminotransferase (ALT/AST) level =< 5 x ULN
- Serum creatinine level =< 1.5 x ULN or creatinine > 1.5 x ULN but calculated clearances of > 60 by Cockcroft-Gault Equation
- Negative screen for infectious disease markers including hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus (HIV) 1-2 antibody, human T-cell leukemia virus (HTLV) 1-2 and syphilis (rapid plasma regain profile)
- Life expectancy at the time of screening >= 4 months
- Patients receiving therapy for concurrent active malignancy * Patients receiving treatment for in situ skin malignancies are not excluded
- Patients who received prior CAR T-cell therapy
- 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 the following criteria are met: * Presence of measurable or evaluable disease outside of the CNS * 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 >= 8 weeks before the screening radiographic study * Discontinuation of corticosteroids and anticonvulsants >= 4 weeks before the screening radiographic study
- History of seizure disorder
- Active autoimmune disease that has required systemic treatment in the past year (with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) * 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
- Patients who are receiving daily systemic corticosteroids that are above physiological doses for any reason or who are under immunosuppressive or immunomodulatory treatment
- Patients with the below 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
- Patients with left ventricular ejection fraction =< 40%
- Patients with 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 timepoint
- Pregnant or lactating women * Subjects and their partners with reproductive potential must agree to use an effective form of contraception during treatment and for 1 year following treatment
- Known active infection requiring antibiotic treatment 7 days before the start of treatment (day 0). Note: treatment can be delayed at the discretion of the treating physician to allow the patient to recover from the infection
- Administration of live, attenuated vaccine within 8 weeks before the start of treatment (day 0) and for 100 days following treatment
- Any other medical condition that, in the opinion of the principal investigator (PI), may interfere with a subject’s participation in or compliance with the study
- Any patient 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
I. Assess the safety and maximum tolerated dose (MTD) of adoptive transfer of genetically modified, autologous mesothelin-specific CAR-T cells (autologous, mesothelin [MSLN]-targeted CAR T cells) using a novel costimulatory domain and cell-intrinsic checkpoint inhibition with a PD1DNR in patients with malignant pleural mesothelioma (MPM).
I. Evaluate overall response rate (ORR) as measured by modified Response Evaluation Criteria in Solid Tumors (mRECIST) (v1.0).
II. Evaluate duration of response (DOR) as measured by mRECIST (v1.0).
III. Evaluate disease control rate (DCR) at 12 weeks as measured by mRECIST (v1.0).
I. Summarize time to next treatment.
II. Summarize progression-free survival (PFS).
III. Summarize overall survival (OS).
IV. Evaluate changes in body mass index (BMI).
V. Assess for correlation between response by positron emission tomography/computed tomography (PET/CT) using PET Response Criteria in Solid Tumors (PERCIST) (v1.0) and other clinically relevant endpoints.
VI. Evaluate changes in the absolute value of megakaryocyte-potentiating factor (SMRP) in the serum before and after adoptive transfers of T cells.
VII. Evaluate the persistence of adoptively transferred T cells in the peripheral blood.
VIII. Evaluate the persistence of adoptively transferred T cells in tissue from patients undergoing procedures after receiving T cells.
IX. Evaluate the cytokine profile of serum and pleural effusions before and after adoptive transfer of T cells.
X. Evaluate the expansion of T-cell clones as measured by immunosequencing (immunoSEQ) assay.
XI. Identify and quantify new antibody epitopes as measured by proteomics assay.
OUTLINE: This is a dose-escalation study of autologous mesothelin-specific CAR-T cells.
Patients receive cyclophosphamide intravenously (IV) 2-7 days before T-cell infusion. 30-60 minutes before T-cell infusion, patients receive acetaminophen orally (PO) and diphenhydramine PO or IV. Patients then receive autologous mesothelin-specific CAR-T cells via intrapleural infusion over 5-30 minutes on day 0.
After completion of study treatment, patients are followed up weekly for 1 month, every 6 weeks for 6 months, every 12 weeks for 2 years, and annually for up to 15 years.
Trial Phase Phase I
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
Roisin Eilish O'Cearbhaill
- Primary ID 20-328
- Secondary IDs NCI-2020-08021
- Clinicaltrials.gov ID NCT04577326