Neoplasms

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Skin and Connective Tissue Diseases

Rare Diseases

Lung Neoplasms

Neoplasm Metastasis

Breast Neoplasms

Pleural Diseases

Mesothelioma

Mesothelioma, Malignant

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Respiratory Tract Diseases

Malignant Mesothelioma

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Antipyretics

Analgesics

Antiemetics

Gastrointestinal Agents

Anti-Allergic Agents

Central Nervous System Depressants

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Cyclophosphamide

Acetaminophen

Pembrolizumab

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Diphenhydramine

Promethazine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Following enrollment, leukapheresis product will be obtained in the blood donor facility at MSKCC and cryopreserved in the Cell Therapy and Cell Engineering Facility (CTCEF). Before protocol treatment, the leukapheresis product will be thawed, and T cell isolation, transduction, and expansion of iCasp928z T cells will be performed in the MSKCC CTCEF Facility. It is estimated that it will take approximately 3 to 6 weeks to generate T cells for treatment.

Patients will receive cyclophosphamide intravenously (at 1.5 g/m\^2) , 2 - 7 (Day (-7) -(-2) days before T cell infusion. On Day 1 , patients will be admitted to the MSKCC Inpatient Service (if not already inpatients) for intravenous hydration, clinical monitoring, and blood work for immune monitoring. Standard MSKCC antiemetic therapy will be administered prior to chemotherapy to prevent nausea/vomiting. Administration of corticosteroids will be avoided as steroids may impede the efficacy of CAR T cells.

Pembrolizumab 4 weeks (+3/-1 week window) after completing CAR T cell administration. Patients will receive 3 doses of pembrolizumab given on a recurring schedule followed by reassessment. Those responding or deriving clinical benefit, without unacceptable toxicity, will continue pembrolizumab. Patients will be followed weekly for the first four weeks. Patients in cohorts 9 and in Phase II will receive pembrolizumab 4 weeks(+3/- 1 week window) following CAR T cell administration.

Administration through the pleural catheter- On day 0 patients will be treated with genetically modified T cells. Thirty to 60 minutes before T cell infusion, patients will be given 650 mg of acetaminophen orally and 25- 50 mg of diphenhydramine orally or intravenously, to prevent infusion-related reactions. The genetically modified T cells will be infused for at least 15 minutes and no more than 2 hours through the indwelling pleural catheter depending on the volume of the T cells. A physician will be available during the infusion. Please note, during formulation of iCasp9M28z T cells, under or over estimation of CAR modified T Cells may occur. Patient may receive an altered fractionation of the total dose or up to 35% over or under total cell dose with approval of the PI. Patients who do not have enough cells to match the current dose cohort will be treated in the cohort in which they have cells available

iCasp9M28z T cell infusions

Patients will receive cyclophosphamide intravenously (at 1.5 g/m\^2)

cyclophosphamide

Pembrolizumab will be given as 200 mg flat dose infusion intravenously.

pembrolizumab

Roisin O'Cearbhaill, MD

The purpose of this Phase I study is to test the safety of different doses of specially prepared immune cells (called "T cells") collected from blood. The Investigators want to find a safe dose of these modified T cells for patients who have malignant pleural disease. They want to find out what effects these T cells have on the patient and the cancer (MPD).

Phase 2 part of the study, the investigators will test the dose in combination with another drug, pembrolizumab, to see what effects the study treatment has on malignant pleural mesothelioma.

This is an open-label, dose-escalating, non randomized, single-center, phase I/II study of mesothelin-targeted T cells administered intrapleurally as an infusion in patients with a diagnosis (histologically or cytologically documented) of MPD from mesothelioma, lung cancer, or breast cancer. Patients receiving pembrolizumab in cohort 9 only includes patients with a diagnosis of mesothelioma. The total number of patients studied will depend on the number of dose levels tested, up to a maximum dose of 6×10\^7 mesothelin-targeted T cells/kg or until the maximum tolerated dose (MTD) is reached. In Phase I of this study, we anticipate infusing a minimum of 4 and a maximum of 54 evaluable patients. The total number of enrolled patients in Phase II of this study depends on the number of observed responses and ranges from 13-21 evaluable patients, including 6 patients treated at the final dose in Phase I.

For patients who were treated and were removed from study, duplicate enrollment is permitted if it is determined the patients could receive benefit. If the patients meet all eligibility criteria, they may receive treatment in a higher dose level cohort. Patients who are re-treated with CAR T cell therapy will not be considered new accruals. Outcomes of re-treated patients will be analyzed separately.

Patients may receive palliative radiotherapy for symptom management prior to or following the CAR T cell infusion. If a patient receives palliative radiotherapy, the study PI, treating Radiation Oncologist, and treating Medical Oncologist will decide whether to proceed with the infusion. Palliative radiotherapy must be completed at least 2 days prior to the administration of cyclophosphamide.

Patients in cohort 9 and in the Phase II portion of the study will begin treatment with pembrolizumab 4 weeks (+3/-1 week window) after completing CAR T cell administration. Patients will receive 3 doses of pembrolizumab given on a recurring schedule followed by reassessment. Patients responding or deriving clinical benefit, without unacceptable toxicity, will be followed for up to 6 months after the first dose of pembrolizumab and may continue pembrolizumab. Patients who cannot receive all 6 doses of pembrolizumab at MSK will be followed and medical records including images will be obtained from the treating physician.

Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin

A Phase I/II Clinical Trial of Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin

All AEs and laboratory toxicities will be graded using version 4 of the CTCAE.

rate will be defined as the proportion of patients with a response of complete response (CR), partial response (PR), and stable disease (SD) as measured by mRECIST criteria.

Mesothelin is an immunogenic cell surface antigen, that is expressed at high levels in MPD and mesothelioma pleural fluid will be drained from the chest by thoracentesis or through a pleural catheter and will be preserved for analysis .

Bellicum Pharmaceuticals

United States Department of Defense

Memorial Sloan Kettering Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin	NCT02414269	Malignant Pleur... Mesothelioma Metastases Lung Cancer Breast Cancer	iCasp9M28z T ce... cyclophosphamid... pembrolizumab	18 Years -	Memorial Sloan Kettering Cancer Center
Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin	NCT02414269	Malignant Pleur... Mesothelioma Metastases Lung Cancer Breast Cancer	iCasp9M28z T ce... cyclophosphamid... pembrolizumab	18 Years -	Memorial Sloan Kettering Cancer Center

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