PSCA-CAR T Cells in Treating Patients With PSCA+ Metastatic Castration Resistant Prostate Cancer

Study Overview
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Brief Summary
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This phase I trial studies side effects and best dose of PSCA-chimeric antigen receptor (CAR) T cells in treating patients with prostate stem cell antigen positive (PSCA+) castration resistant prostate cancer that has spread to other places in the body (metastatic). PSCA-CAR T cells are immune cells that have been engineered in the laboratory to kill tumor cells. This is done by using a virus to insert a piece of deoxyribonucleic acid (DNA) into the immune cells that allows them to recognize prostate tumor cells. It is not yet known how well PSCA-CAR T cells works in killing tumor cells in patients with metastatic castration resistant prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Define the safety and tolerability of autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes (PSCA-CAR T cells) in patients with PSCA+ metastatic castration resistant prostate cancer (mCRPC). II. Define the recommended phase 2 dose (RP2D) of PSCA-CAR T cells in patients with PSCA+ mCRPC. SECONDARY OBJECTIVES: I. Assess the expansion and persistence of PSCA-CAR T cells. II. Assess clinical response based on Prostate Cancer Working Group 3 (PCWG3) criteria. III. Assess survival outcomes (including biochemical progression free survival [PFS], radiographic PFS and overall survival [OS]). IV. Assess serum cytokine profiles in peripheral blood pre- and post-therapy. V. Describe the PSCA expression level on tumor cells prior to CAR T cell infusion, and the relationship it may have with disease response and observed toxicities. EXPLORATORY OBJECTIVES: I. Characterize the phenotypes and frequencies of immune cell subsets in the peripheral blood pre- and post-therapy. II. Enumerate and characterize tumor-infiltrating lymphocytes (TILs) pre- and post-therapy. III. Enumerate and analyze gene expression of circulating tumor cells (CTC) pre- and post-therapy. IV. Analyze circulating cell-free DNA (cfDNA). V. Determine the immunogenicity of PSCA-CAR T cells. OUTLINE: This is a dose-escalation study. Patients may receive lymphodepleting regimen at the discretion of the treating physician including fludarabine intravenously (IV) on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0. After completion of study treatment, patients are followed up at day 1, every 2 days for up to 14 days, weekly for up to 1 month, every month for up to 1 year, and then annually for up to 15 years.

Official Title
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A Phase I Study to Evaluate PSCA-Targeting Chimeric Antigen Receptor (CAR)-T Cells for Patients With PSCA+ Metastatic Castration Resistant Prostate Cancer

Conditions
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Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8

Intervention / Treatment
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* Biological: Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Fludarabine Phosphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants must have the ability to understand and the willingness to sign a written informed consent Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. Documented castration resistant prostate cancer (mCRPC) (Note: castration will be defined by a testosterone < 50 ng/dL achieved by orchiectomy or luteinizing hormone-releasing hormone [LHRH] agonist/antagonist therapy) Documented PSCA+ tumor expression as evaluated by City of Hope (COH) Pathology Care Progression of disease manifest by one of the following means during treatment with at least one advanced androgen targeted therapy (e.g., abiraterone or enzalutamide) Rising PSA documented on 2 occasions at least 7 days apart, with absolute increase > 2 ng/dL despite testosterone < 50 OR Radiographic evidence of new metastatic foci on computed tomography (CT) or bone scan, or soft tissue progression by Response Evaluation Criteria in Solid Tumors (RECIST) Prior chemotherapy with cabazitaxel and/or docetaxel is allowed but not required. If there has been prior chemotherapy, at least 2 weeks must have elapsed prior to leukapheresis Prior radiotherapy is allowed provided it was not administered to the only evaluable site of disease and was > 14 days prior to leukapheresis No known contraindications to leukapheresis, steroids or tocilizumab Total serum bilirubin =< 2.0 mg/dL (to be performed within 42 days of signing the main study consent) Patients with Gilbert syndrome may be included if their total bilirubin is =< 3.0 x upper limit of normal (ULN) and direct bilirubin =< 1.5 x ULN Aspartate aminotransferase (AST) < 3 x ULN (to be performed within 42 days of signing the main study consent) Alanine aminotransferase (ALT) < 3 x ULN (to be performed within 42 days of signing the main study consent) Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula (to be performed within 42 days of signing the main study consent) Cardiac function (12 lead-electrocardiography [ECG]) (to be performed within 42 days of signing the main study consent) Left ventricular ejection fraction > 40% (to be performed within 42 days of signing the main study consent) Participants of reproductive potential must agree to use acceptable birth control methods throughout study therapy and for 3 months after final dose of study treatment Exclusion Criteria: Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of signing the main consent Participants with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system, including seizure disorder History of allergic reactions attributed to compounds of similar chemical or biologic composition or other agents used in this study Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia History of stroke or intracranial hemorrhage within 6 months prior to signing the main consent History of other malignancies, except for malignancy surgically resected (or treated with other modalities) with curative intent, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; non-muscle invasive bladder cancer; malignancy treated with curative intent with no known active disease present for >= 3 years Uncontrolled active infection Active hepatitis B or hepatitis C infection Human immunodeficiency virus (HIV) infection Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (PSCA CAR T cells)<br>Patients may receive lymphodepleting regimen including fludarabine IV on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0. | Biological: Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes<br>* Given IV<br>* Other names: PSCA(dCH2)BBzeta-CAR T-cells;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine<br>* Given IV<br>* Other names: Fluradosa;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 Toxicity Profile | Grade 3 toxicity profile as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 and modified Cytokine Release Syndrome (CRS) grading as applicable post chimeric antigen receptor (CAR) T cell infusion. | Up to 32 months | 
| Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Defined by any grade 3 or NCI CTCAE toxicities and modified CRS grading as applicable. | Up to 28 days post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAR T Cells Persistence | Defined as CAR T cells > 0.1% of total CD3 cells by flow-cytometry. Maximum persistence (in days) will be described. | Up to 1 year post treatment | 
| Expansion of CAR T Cells | Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid [DNA]) will be described. | Up to 1 year post treatment | 
| Disease Response | Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for response based on Prostate Cancer Working Group 3 (PCWG3) criteria. | Up to 1 year post treatment | 
| Overall Survival (OS) | Kaplan Meier methods will be used to estimate median OS, and graph the results. | From CAR T cell infusion to the event date (death) or last contact date (censor date), assessed up to 15 years | 
| Progression-free Survival (PFS) | Defined as survival without biochemical (PSA) or radiographic evidence of disease progression or relapse from the date of CAR T cell infusion. Kaplan Meier methods will be used to estimate median PFS, and graph the results. | From CAR T cell infusion to event date (progression/relapse or death) the censor date: off protocol therapy date (required disallowed treatment or withdrawal of consent for further therapy) or last contact date, assessed up to 15 years | 
| PSCA Expression | PSCA expression on tumor cells by immunohistochemistry (IHC) and/or flow cytometry. Linear regression will be used to assess the relationship between PSCA expression and disease response and toxicities experienced. | Up to 1 year post treatment | 
| Serum Cytokine Profile | Serum cytokine profile before and after CAR T cell infusion: to assess potential cytokine release syndrome (CRS) toxicity and CAR T cell effector function, sequential serum samples will be analyzed for Th1/Th2 cytokines (e.g., IL-2, IFNgamma, TNFalpha, IL-10, GMCSF, IL-6, MIP-1alpha) by bead array. | Up to 1 year post treatment |