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

NCT02414269 | Active Not Recruiting Phase 1

• 1 other identifier: 15-007
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Malignant Pleural Disease; Mesothelioma; Metastases; Lung Cancer; Breast Cancer

Keywords

modified T cells; cyclophosphamide; CAR T cells; 15-007; CAR; immunotherapy

Outcome Measures

Primary Outcomes (2)

• Composite measure of severity and number of adverse events (AEs); changes in (clinical laboratory test findings (hematologic and chemistry); and physical examination. (Phase I)

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

  1 year

• clinical benefit rate (phase II)

  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.

  at 12 weeks following the first dose of pembrolizumab

Secondary Outcomes (1)

• Changes in serum levels of the biomarker soluble mesothelin related peptide (SMRP) (Phase I)

  60 days (+/-5 days) after treatment

Study Arms (3)

modified T cells alone (without chemotherapy)

EXPERIMENTAL

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.

Genetic: iCasp9M28z T cell infusions

modified T cells with cyclophosphamide

EXPERIMENTAL

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.

Genetic: iCasp9M28z T cell infusions; Drug: cyclophosphamide

CAR T cell and pembrolizumab

EXPERIMENTAL

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.

Drug: pembrolizumab

Interventions

iCasp9M28z T cell infusions GENETIC

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

modified T cells alone (without chemotherapy); modified T cells with cyclophosphamide

cyclophosphamide DRUG

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

modified T cells with cyclophosphamide

pembrolizumab DRUG

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

CAR T cell and pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with MPD aged ≥18 years
• Karnofsky performance status ≥70%
• Patients with malignant pleural disease (MPD), pathologically confirmed at MSKCC (radiographic confirmation is acceptable for screening phase eligibility), and defined as one of the following (patients who have not yet received treatment may enroll in the screening portion only):
• Malignant pleural mesothelioma - previously treated with at least one prior treatment regimen.
• Non-small cell lung cancer metastatic to the pleura-previously treated with at least one prior treatment regimen (chemotherapy or targeted agent) and documented progression of disease. Patients with disease outside of the pleura will be discussed among study PI and Co-PIs prior to considered eligible for the study. Disease outside of the pleura must not require any immediate therapy per PI's discretion.
• Breast cancer metastatic to the pleura- previously treated with at least one prior treatment regimen (chemotherapy or targeted agent) and documented progression of disease. Patients with disease outside of the pleura will be discussed among study PI and Co-PIs prior to be considered eligible for the study. Disease outside of the pleura must not require any immediate therapy per PI's discretion.
• Only patients with a diagnosis of malignant pleural mesothelioma will be included in cohort 9 and in the Phase II portion of the study
• Expression of mesothelin must be confirmed by meeting one of the following criteria.
• Mesothelin expression (\>10% of the tumor expressing mesothelin) by immunohistochemical (IHC) analysis
• Elevated serum SMRP levels (\>1.0 nM/L).
• Free flowing pleural effusion requiring management by placement of a pleural catheter. Patients with a functional pleural catheter already in place are eligible for the study, as long as there are no clinical concerns of infection.
• No free-flowing pleural effusion: an Interventional Radiologist has agreed that radiology-guided intrapleural or peritumoral injection of the CAR T cells is feasible.
• Chemotherapy, targeted therapy (such as a tyrosine kinase inhibitor) or therapeutic radiotherapy must have been completed at least 14 days prior to administration of T cells. Continuation of hormonal therapy (ie for breast cancer) is acceptable. Prior immunotherapy with checkpoint blockade (i.e. PD1 inhibitor, PDL1 inhibitor or CTL4-antagonist or similar agent) must have been completed more than 1 month1prior to the T cell infusion.
• Chemotherapy must have been completed at least 7 days prior to leukapheresis
• Palliative radiotherapy must be completed at least 2 days prior to administration of cyclophosphamide

You may not qualify if:

• Untreated or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control); patients with a history of treated CNS metastases are eligible, provided that all of 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 prior to the screening radiographic study;
• Discontinuation of corticosteroids and anticonvulsants ≥4 weeks prior to the screening radiographic study.
• Non-small cell lung cancer metastatic to the pleura that extends outside of the pleura requiring immediate therapy
• Breast cancer metastatic to the pleura that extends outside of the pleura requiring immediate therapy
• Prior history of seizure disorder
• Patients currently receiving treatment for concurrent active malignancy Continuation of hormonal therapy (i.e. for breast cancer) is acceptable. Prior immunotherapy with checkpoint blockade (i.e. PD1 inhibitor, PDL1 inhibitor or CTL4-antagonist or similar agent) must have been completed more than 1 month prior to the T cell infusion.
• Autoimmune or antibody-mediated disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and temporal arteritis (Patients with a history of hypothyroidism will not be excluded)
• History of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6 months prior to study entry
• Subjects with left ventricular ejection fraction (LVEF) less than 50%
• Patients with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids
• Baseline pulse oximetry is less than 92% on Room air
• Pregnant or lactating women

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• Bellicum Pharmaceuticals: collaborator
• United States Department of Defense: collaborator

Study Sites (6)

Memorial Sloan Kettering Basking Ridge (Consent and Follow-Up)

Basking Ridge, New Jersey, United States

Location

Memorial Sloan Kettering Monmouth (Consent and Follow-Up)

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Bergen (Consent and Follow-Up)

Montvale, New Jersey, 07645, United States

Location

Memorial Sloan Kettering Commack (Consent and Follow-Up)

Commack, New York, United States

Location

Memorial Sloan Kettering Westchester (Consent and Follow-Up)

Harrison, New York, 10604, United States

Location

Memorial Sloan Kettering Cancer Center (Consent and Follow-Up)

New York, New York, 10065, United States

Location

Related Publications (2)

• Barr T, Ma S, Li Z, Yu J. Recent advances and remaining challenges in lung cancer therapy. Chin Med J (Engl). 2024 Mar 5;137(5):533-546. doi: 10.1097/CM9.0000000000002991. Epub 2024 Feb 7.

  PMID: 38321811 DERIVED

• Ghosn M, Cheema W, Zhu A, Livschitz J, Maybody M, Boas FE, Santos E, Kim D, Beattie JA, Offin M, Rusch VW, Zauderer MG, Adusumilli PS, Solomon SB. Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial. Lung Cancer. 2022 Mar;165:1-9. doi: 10.1016/j.lungcan.2022.01.003. Epub 2022 Jan 6.

  PMID: 35045358 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Conditions

Mesothelioma; Neoplasm Metastasis; Lung Neoplasms; Breast Neoplasms

Interventions

Cyclophosphamide; pembrolizumab

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Roisin O'Cearbhaill, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 2, 2015
• First Posted: April 10, 2015
• Study Start: May 1, 2015
• Primary Completion: April 30, 2026
• Study Completion: April 30, 2026
• Last Updated: October 8, 2025

Record last verified: 2025-10

Locations

US (6)