Anti-Mesothelin TNaive/SCM hYP218 (TNhYP218) CAR T Cells in Participants With Mesothelin-Expressing Solid Tumors Including Mesothelioma

Brief summary public domain (ClinicalTrials.gov)

Background: Mesothelioma is an aggressive cancer that grows in the linings of the body; this can include the membranes that line the heart, lungs, and internal organs. Mesothelin (MSLN) is a protein that appears in high numbers in many tumors, including mesothelioma. Researchers are developing a new treatment that collects a person s own immune cells (T cells); the T cells are genetically modified to target and kill tumor cells with high levels of MSLN. Objective: To test a new treatment (TNhYP218 CAR T cells) in people with solid tumors including mesothelioma. Eligibility: People aged 18 and older with solid tumors including mesothelioma that returned or spread after standard treatment. Design: Participants will be screened. A small piece of tissue will be cut from a tumor (biopsy). The sample will be tested to see if it has enough MSLN. Participants will undergo leukapheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. Participant s T cells will be modified in a lab to produce TNhYP218 CAR T cells. Participants will enter the hospital. For 7 days, they will receive drugs to prepare their bodies for the study treatment. TNhYP218 CAR T cells will be administered into a vein. Participants will remain in the hospital for at least 7 more days. After discharge, participants will have follow-up visits for 5 years. These visits may include imaging scans, blood and heart tests, and a new biopsy. Long-term follow-up will continue another 10 years....

Detailed description public domain (ClinicalTrials.gov)

Background: * Mesothelin (MSLN), a cell surface glycoprotein, normally expressed on the mesothelial cells lining the pleura, peritoneum, and pericardium, is highly expressed in many cancers including mesothelioma, ovarian, lung, thymic, colorectal, pancreatic, and gastric cancers, making it an attractive target for immunotherapy. * Adoptive cell therapy using CAR T cells exploits the ability of these modified T cells to recognize and kill their target. Several mesothelin directed CAR T cell therapies have been evaluated in clinical trials, but thus far have not resulted in significant anti-tumor efficacy. * Many antibodies used to make anti-mesothelin CAR T cells bind to the immunogenic distal region of mesothelin, away from the cell membrane. * hYP218 CAR T cells target membrane-proximal region of mesothelin and in pre-clinical studies have shown increased tumor killing and persistence compared to CAR T cells binding to membrane distal region of mesothelin. * Naive/SCM T cells have stem cell like properties and have increased persistence and decreased exhaustion in tumors. * We hypothesize that TNaive/SCM anti-mesothelin, TNhYP218 CAR T cells will have enhanced anti-tumor activity and increased persistence in participants with mesothelioma and other mesothelin expressing cancers. Objectives: * Part 1- Dose escalation: Establish the recommended phase 2 dose (RP2D) of TNhYP218 CAR T cells based on dose-limiting toxicity (DLT) of defined adverse events (AEs). * Part 2- Dose expansion: Determine the preliminary objective response rate of TNhYP218 CAR T cells in a limited number of participants with mesothelioma treated at the RP2D. Eligibility: * Age 18 or older * Must have unresectable, histologically confirmed, recurrent, locally advanced, or metastatic mesothelioma, and other mesothelin expressing solid tumors. * Tumor must be positive for mesothelin in more than half of the cancer cells. * Participants must have an ECOG performance status of 0 or 1. * Participants must have adequate organ function. Design: * Phase 1 dose-escalation study of TNhYP218 CAR T cells, with a small expansion cohort. * Participants will undergo leukapheresis for cell manufacture, followed by lymphodepletion with chemotherapeutic drugs, followed by infusion of TNhYP218 CAR T cells. * Participants will be followed for safety for up to 15 years per FDA requirement.

Intervention public domain (ClinicalTrials.gov)

Drug: cyclophosphamide. 600 mg/m\^2 IV infusion. Daily x 3 doses on Day -6, -5, -4

Intervention public domain (ClinicalTrials.gov)

Drug: fludarabine. 30 mg/m\^2 IV infusion administered followed by cyclophosphamide on days both are given. Daily x 4 doses on Day -7, -6, -5 and -4

Intervention public domain (ClinicalTrials.gov)

Biological: TNhYP218 CAR T Cells. Variable doses, administered intravenously on Day 0

Intervention public domain (ClinicalTrials.gov)

Device: mesothelin expression testing. Assay done at screening to determine mesothelin expression levels

Arm public domain (ClinicalTrials.gov)

1/Dose Escalation (experimental): Participants with mesothelin expressing tumors will undergo lymphodepletion and will receive TNhYP218 CAR T cells at escalating doses

Arm public domain (ClinicalTrials.gov)

2/Dose Expansion (experimental): Participants with mesothelioma will undergo lymphodepletion and will receive TNhYP218 CAR T cells at the RP2D determined in Arm 1

Primary outcome public domain (ClinicalTrials.gov)

Establish the recommended phase 2 dose (RP2D) of TNhYP218 CAR T cells based on dose-limiting toxicity (DLT) of defined adverse events (AEs).. The highest dose level below the maximum administered dose at which no more than 1 of 6 participants experience DLT from the initiation of CAR-T cell infusion (day 0) through day 28 after infusion (day 28). Time frame: DLT assessment will occur in participants in the dose escalation cohort daily on days 0-4, on day 7, on day 21 and during week 4..

Primary outcome public domain (ClinicalTrials.gov)

Determine the preliminary objective response rate of TNhYP218 CAR T cells in a limited number of participants with mesothelioma treated at the recommended phase 2 dose.. The proportion of mesothelioma participants with partial response or complete response at the recommended phase 2 dose. Time frame: assessed based on imaging studies at weeks 4, 8, 12 then every 12 weeks through disease progression or week 108, whichever occurs first..

Secondary outcome public domain (ClinicalTrials.gov)

Near term safety of autologous genetically modified TNhYP218 CAR T cells in adult study participants with mesothelin expressing unresectable, metastatic, or recurrent mesothelioma and other mesothelin expressing solid tumors.. Time frame: Assessments will occur daily during lymphodepletion, on day of cell infusion (D0), D10, D21, every 2 weeks from W4 to W8, then every 4 weeks through W 24 or disease progression..

Secondary outcome public domain (ClinicalTrials.gov)

Long term safety of autologous genetically modified TNhYP218 CAR T cells in adult study participants with mesothelin expressing unresectable, metastatic, or recurrent mesothelioma and other mesothelin expressing solid tumors.. Time frame: Monitored at baseline, weeks 4, 12, 24 and 48 after cell infusion and annually thereafter for up to 15 years if positive during year 1 or warranted based on clinical history collected annually during15 year follow-up..

Secondary outcome public domain (ClinicalTrials.gov)

Determine the objective response rate of TNhYP218 CAR T cells in participants with mesothelin expressing solid tumors treated at doses other than the RP2D. Time frame: assessed based on imaging studies at weeks 4, 8, 12 then every 12 weeks through disease progression or week 108, whichever occurs first..

Secondary outcome public domain (ClinicalTrials.gov)

Determine progression free survival in participants with mesothelin expressing solid tumors. Time frame: Assessed based on imaging studies at weeks 4, 8, 12 then every 12 weeks through disease progression or week 108, whichever occurs first..

Secondary outcome public domain (ClinicalTrials.gov)

Determine duration of response in participants with mesothelin expressing solid tumors. Time frame: Assessed based on imaging studies at weeks 4, 8, 12 then every 12 weeks through disease progression or week 108, whichever occurs first..

Secondary outcome public domain (ClinicalTrials.gov)

Determine overall survival in participants with mesothelin expressing solid tumors. Time frame: Assessed from physical exams performed on D10, D21, W4, W6, W8, then every 4 weeks through W 24, and with semiannual remote assessments following active follow up through year 5..

Eligibility public domain (ClinicalTrials.gov)

* INCLUSION CRITERIA: In order to be eligible to participate in this study, an individual must meet all of the following criteria. For this protocol, treatment initiation is defined as the first day of lymphodepleting chemotherapy. * Participant must have unresectable, locally advanced, or metastatic, or recurrent mesothelioma and other mesothelin expressing solid tumors. For participants with mesothelioma only those with epithelioid or biphasic histology (with \>80% epithelioid component) will be eligible. The diagnosis will be confirmed by the Laboratory of Pathology, CCR, NCI. * Participant must have progressed on at least one FDA-approved systemic therapy considered standard of care for their tumor type. There is no limit on the number of prior treatment regimens. Note: Given the aggressive nature of pancreatic cancer, otherwise eligible individuals with this cancer type can undergo leukapheresis before or while they are getting their frontline treatment as long as they meet all other inclusion criteria. However, TNhYP218 CAR T cells will only be administered after progression on first line standard of care therapy. * Participant must have at least 1 measurable lesion by RECIST version 1.1. * Tumor must have MSLN positivity of 2+ to 3+ in \>= 50% cancer cells by immunohistochemistry on freshly collected biopsy or archival tissue. * Age \>= 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Participants must have adequate organ and marrow function as defined below: System: Laboratory Value Hematological * Hemoglobin: \>=9 g/dL(a) * absolute neutrophil count: \>=1,500/mcL * platelets: \>=100,000/mcL Hepatic * total bilirubin: \<=2.5 X institutional ULN OR direct bilirubin \<= ULN for participants with total bilirubin levels \>1.5 X ULN * AST and ALT \<= 2.5 X institutional ULN (\<= 5 X ULN for participants with liver metastases) Renal * Creatinine OR: \<=1.5 X ULN OR * Calculated(b) creatinine clearance (GFR can also be used in place of creatinine or CrCl) \>= 50 mL/min for participant with creatinine levels \> 1.5 X institutional ULN Coagulation * International normalized ratio (INR) OR prothrombin time (PT): \<=1.5 X ULN unless participant is receiving anticoagulant therapy if PT or aPTT is within therapeutic range of intended use of anticoagulants * Activated partial thromboplastin time (aPTT): \<=1.5 X ULN unless participant is receiving anticoagulant therapy if PT or aPTT is within therapeutic range of intended …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 120 participants (estimated).