A Study of TmPSMA-02 Chimeric Antigen Receptor (CAR) T-cells in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Study Overview
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Brief Summary
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An open-label, multi-center, Phase 1/2 study to determine the safety, tolerability, and feasibility of dosing adult patients with mCRPC with genetically modified autologous T-cells (TmPSMA-02) engineered to express a CAR capable of recognizing the tumor antigen prostate-specific membrane antigen (PSMA) and activating the T-cell.

Detailed Description
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This is a Phase 1/2 single-arm study designed to identify the dose and regimen of TmPSMA-02 that can be safely administered intravenously following the lymphodepletion (LD) regimen to patients with mCRPC. The Phase 1 dose escalation portion of the study will employ a Bayesian Optimal Interval (BOIN) Design to define the Maximum Tolerated Dose (MTD) and determine the Recommended Phase 2 Dose (RP2D). Dose-limiting toxicities (DLTs) will be assessed from the start of LD regimen through 28-days post infusion of TmPSMA-02. The Phase 2 portion will employ a Simon's 2-stage design and include a single-arm of adult patients with mCRPC treated with the TmPSMA-02 at the RP2D. It is anticipated that up to 30 patients will enroll in the Phase 1 portion of the study and up to 84 patients will enroll in the Phase 2 portion of the study.

Official Title
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A Phase 1/2, Open-label, Multi-Center Study of Dually Armored Chimeric Antigen Receptor (CAR) T-cells (TmPSMA-02) in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Biological: TmPSMA-02


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults at least 18 years of age. A confirmed histologic diagnosis of prostate cancer. Castrate levels of testosterone (< 50 ng/dL). Measurable disease (radiographic or Prostate Specific Antigen [PSA]) per PCWG3 criteria (see Appendix 3) Received at least 2 prior lines of systemic therapy for prostate cancer, including at least one second generation androgen receptor inhibitor (e.g., enzalutamide or apalutamide) or CYP17α inhibitor (e.g., abiraterone/ prednisone) and a taxane based regimen (e.g., docetaxel, cabazitaxel, etc). At least one line of prior therapy must be in the mCRPC setting. Note: Androgen deprivation therapy (ADT) with gonadotropin- releasing hormone (GnRH) agonist/antagonist does not count as a line of therapy nor does a first-generation nonsteroidal antiandrogen (e.g., bicalutamide, flutamide, etc.). Adequate vital organ function as defined by: (A) Estimated glomerular filtration rate (eGFR) eGFR ≥ 50 mL/min by Modification of Diet in Renal Disease criteria, (B) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x the upper limit of normal (ULN); patients with hepatic metastases ALT and AST ≤ 3.0 ULN. (C) Serum total bilirubin < 1.5 × ULN unless patient has known Gilbert's; if so, then serum bilirubin ≤ 3 mg/dL, or (D) Left ventricular ejection fraction ≥ 45%. Patients must have adequate hematologic reserve and must not be dependent on transfusions to maintain these hematologic parameters. Adequate hematologic reserve is defined as: (A) Hemoglobin ≥ 8 g/dL, (B) absolute neutrophil count ≥ 1000/ μL, or (C) Platelet count ≥ 75,000/μL. Patients who have not undergone bilateral orchiectomy must be able to continue GnRH therapy during the study. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Toxicities from any previous therapy must have recovered to Grade 1 or to the baseline. Exceptions include non-clinically significant toxicities as a result of previous therapy (e.g., alopecia, hormonal changes, weight loss, etc). Patients of reproductive potential agree to use protocol-specified highly effective contraceptive methods Exclusion Criteria: Active invasive cancer, other than the proposed cancer included in the study, within 2 years prior to screening. [Note: non-invasive cancers treated with curative intent (e.g., non-melanoma skin cancer may still be eligible], unless treated with curative intent, i.e., non-melanoma skin cancer. Prior treatment with autologous T-cell therapy. Note: Prior treatment with Sipuleucel-T is allowed. Patients who require chronic treatment with systemic corticosteroids (defined as a dose greater than the equivalent of prednisone 10 mg/day). Low-dose physiologic replacement therapy with corticosteroids equivalent to prednisone 10 mg/day or lower, topical steroids and inhaled steroids are acceptable. Prior allogeneic stem cell transplant. Active autoimmune disease (including, but not limited to, connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease or multiple sclerosis) or a history of severe autoimmune disease requiring prolonged immunosuppressive therapy. Patients should have stopped any immunosuppressive therapy within 6 weeks prior to Screening. Current infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV). Viral testing at Screening is required in all patients to rule out subclinical infections. Patients who are hepatitis B core antibody positive and hepatitis B surface antigen negative should have quantitative viral load measured. If viral load is undetectable, the patient may enroll and be monitored as per ASCO Guidelines. Seizure disorder requiring anti-epileptic medications. History of severe infusion reaction to monoclonal antibodies or biological therapies, or to study product excipients (e.g., human serum albumin, dimethyl sulfoxide [DMSO], dextran 40) that would preclude the patient safely receiving TmPSMA-02. History of or known predisposition to hemophagocytosis lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) Any active infection currently being treated with antibiotics, anti-virals or anti-fungal. Prophylactic anti-microbials are not exclusionary. Active or recent (within the past 6 months prior to leukapheresis) cardiovascular disease, defined as (1) New York Heart Association Class III or IV heart failure, (2) unstable angina or (3) a history of recent (within 6 months) myocardial infarction or sustained (> 30 second) ventricular tachyarrhythmias, (4) cerebrovascular accident. Active or uncontrolled medical or psychiatric condition that would preclude participation in the opinion of the Sponsor, Principal Investigator (PI) and/or their designee. Have inadequate venous access for or contraindications for the leukapheresis procedure. Central venous access is acceptable.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TmPSMA-02<br> | Biological: TmPSMA-02<br>* Intravenous administration of genetically modified autologous T-cells engineered to express a protein capable of recognizing the tumor antigen prostate-specific membrane antigen (PSMA) with a lentiviral vector to express anti-PSMA scFv, CD2 co-stimulatory domain and dually armored with a dominant negative TGFβ receptor and PD1.CD28 switch, will be infused intravenously on Day 0 as a single flat dose following standard lymphodepleting (LD) regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: To evaluate the safety of TmPSMA-02 in adult patients with mCRPC | Type, frequency, and severity of adverse events (AEs) and serious adverse events (SAEs) | Up to 5 years | 
| Phase 1: To identify the recommended Phase 2 dose of TmPSMA-02 administered in combination with LD chemotherapy | Frequency of DLTs and/or determination of the maximum tolerated dose (MTD) | Up to 5 years | 
| Phase 2: To evaluate the objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 | Objective Response Rate (ORR) by RECIST v1.1. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: To evaluate the preliminary antitumor activity of TmPSMA-02 according to RECIST v1.1 and the PCWG3 criteria | Objective Response Rate (ORR), Duration of Response (DOR), PSA percent change from baseline at 12-weeks and maximal, change calculated at any timepoint Progression Free Survival (PFS) Radiographic progression free survival (rPFS) Overall Survival (OS) | Up to 5 years | 
| Phase 1: To assess the clinical and manufacturing feasibility of TmPSMA-02 | Clinical: proportion of patients enrolled on this protocol who do not receive TmPSMA-02 cells for any reasons not related to manufacturing (see below) Manufacturing: Proportion of patients whose leukapheresis product results in manufacturing failure for any reason | Up to 5 years | 
| Phase 2: To evaluate the safety and tolerability of TmPSMA-02 in adult patients with mCRPC | Type, frequency, severity of AEs, SAEs | Up to 5 years | 
| Phase 2: Evaluate the anti-tumor activity of TmPSMA-02 according to Prostate Cancer Working Group 3 (PCWG3). | Duration of Response (DOR), PSA percent change from baseline at 12-weeks and maximal change calculated at any timepoint, Progression Free Survival (PFS), Radiographic progression free survival (rPFS), Overall Survival (OS) | Up to 5 years | 
| Phase 2: Describe pharmacokinetic factors of TmPSMA-02 in peripheral blood | Expansion and persistence of CAR T-cells by molecular detection of CAR-specific sequences in peripheral blood | Up to 5 years | 
| Phase 2: Evaluate changes in patient reported health-related outcomes following treatment with TmPSMA-02 | Evaluate changes in health-related outcomes following treatment with TmPSMA-02 using the Functional Assessment of Cancer Therapy - Prostate Cancer (FACT-P) | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chimeric Antigen Receptor (CAR), T-Cells, Prostate-Specific Membrane Antigen (PSMA), Prostate Cancer