A Study of CART-PSMA-TGFβRDN in Patients With Metastatic Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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Multi-center, open-label, Phase 1 study of the safety, tolerability and feasibility of dosing patients harboring metastatic castration resistant prostate cancer (mCRPC) with genetically modified autologous T cells (CART-PSMA-TGFβRDN cells) engineered to express a chimeric antigen receptor (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 single-arm study designed to identify the dose and regimen of CART-PSMA- TGFβRDN cells that can be safely administered intravenously following the lymphodepletion (LD) regimen to patients with metastatic castration resistant prostate cancer (mCRPC). Following Dose Escalation, a Cohort Expansion will enroll patients to further explore the safety and tolerability of the selected dose and schedule. It is anticipated that up to 50 patients will enroll in this study in both dose escalation and cohort expansion.

Official Title
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A Phase 1 Open-Label, Multi-Center Study of PSMA Targeted Genetically Modified Chimeric Antigen Receptor T Cells in Patients With Metastatic Castration Resistant Prostate Cancer

Conditions
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Metastatic Castration-resistant Prostate Cancer

Intervention / Treatment
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* Biological: CART-PSMA-TGFβRDN
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Anakinra


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed histologic diagnosis of prostate cancer and have mCRPC, with castrate levels of testosterone (<50 ng/mL) PSA measurable disease per Prostate Working Group 3 (PCWG3) criteria Prior therapies defined as at least 2 prior lines of systemic therapy for prostate cancer, including at least one second generation androgen receptor inhibitor and/or CYP17α inhibitor. At least one line of prior therapy must be in the mCRPC setting Estimated estimated glomerular filtration rate ≥ 60 mL/min by Modification of Diet in Renal Disease criteria Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x the upper limit of normal (ULN); patients with hepatic metastases ALT and AST ≤ 3.0 x ULN Serum total bilirubin < 1.5 mg/dL unless patient has known Gilbert's Syndrome, then serum bilirubin ≤3 mg/dL Serum albumin ≥ 3.0 g/dL Left ventricular ejection fraction (LVEF) ≥ 50%. LVEF assessment must have been performed within 8 weeks of enrollment Hemoglobin ≥ 8 g/dL Absolute neutrophil count ≥ 1000/μL Platelet count ≥ 75,000/μL Patients who have not undergone bilateral orchiectomy must be able to continue gonadotropin-releasing hormone (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 baseline Patients of reproductive potential agree to use of approved highly effective contraceptive methods Exclusion Criteria: Active invasive cancer, other than the proposed cancer included in the study, within 2 years prior to screening, unless treated with curative intent Current treatment with systemic corticosteroids (defined as a dose greater than the equivalent of prednisone 10 mg/day) Active autoimmune disease (including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease or multiple sclerosis) or a history of severe autoimmune disease requiring prolonged immunosuppressive therapy (any immunosuppressive therapy within 6 weeks prior to screening visit) Current human immunodeficiency virus (HIV), hepatitis C virus, hepatitis B virus infections; Patients who are hepatitis B core antigen positive, hepatitis B surface antigen negative, should have a quantitative viral load measured; If viral load is undetectable, the patient will not be excluded if hey are able to be treated with anti-viral medication for at least 7 days prior to lymphodepletion until at least 6 months after infusion with viral load and ALT monitoring Active or uncontrolled medical or psychological condition that would preclude participation History of seizure disorder Prior allogeneic stem cell transplant Central nervous system malignancy History of severe infusion reaction to monoclonal antibodies or biological therapies, or to study product excipients that would preclude the patient safely receiving CART-PSMA-TGFβRDN cells History of being previously treated with a J591 antibody-based therapy Ferritin levels ≥ 4x the upper limit of normal prior to apheresis or prior to the start of lymphodepleting chemotherapy Active or recent (within the past 6 months prior to apheresis or lymphodepletion) cardiovascular disease, defined as (1) New York Heart Association Class III or IV heart failure, (2) unstable angina, (3) a history of recent (within 6 months) myocardial infarction or sustained (> 30 second) ventricular tachyarrhythmias, or (4) cerebrovascular accident Any active infection currently being treated or any infection within the last 6 weeks that required 7 days or more of IV antibiotics or any active infection within the last 4 weeks that requires use of oral antibiotics. Patients may be eligible once these timeframes elapse and with evidence that the infection has completely resolved Have inadequate venous access for or contraindications for the apheresis procedure Must agree not to participate in a conception process or must agree to a highly effective method of contraception

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
Interventional Model Description: Sequential dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Dose escalation of intravenous CART-PSMA-TGFβRDN cells for patients with metastatic castration resistant prostate cancer | Biological: CART-PSMA-TGFβRDN<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), as well as a dominant negative TGFβ receptor<br>Drug: Cyclophosphamide<br>* Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-PSMA-TGFβRDN genetically modified T cells<br>Drug: Fludarabine<br>* Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-PSMA-TGFβRDN genetically modified T cells<br>Drug: Anakinra<br>* In applicable cohorts, patients will receive anakinra prophylactically starting on the day of administration of investigational product, CART-PSMA-TGFβRDN genetically modified T cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Dose Identification of CART-PSMA-TGFβRDN | Incidence of Dose Limiting Toxicity (DLT) | Up to 2 years | 
| Cohort Expansion: Safety of CART-PSMA-TGFβRDN | Percentage of patients experiencing adverse events (AEs), including serious and severe AEs overall, by dose level, and severity grade | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary efficacy of CART-PSMA-TGFβRDN as assessed by biochemical Objective Response Rate (ORR) | ORR defined as the proportion of patients with maximal prostate-specific antigen (PSA) decline of greater than or equal to 50% at 12 weeks post infusion | Up to 2 years | 
| Feasibility of CART-PSMA-TGFβRDN | Proportion of patients who did not receive CART-PSMA-TGFβRDN cells | Up to 2 years | 
| Peripheral expansion and persistence of CART-PSMA-TGFβRDN | Quantitative polymerase chain reaction (qPCR) | Up to 15 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