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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: 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: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Fludarabine Phosphate; Biological: Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 or KPS ≥70%.

• 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) < 5 x ULN (to be performed within 42 days of signing the main study consent)
• Alanine aminotransferase (ALT) < 5 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]) without acute abnormalities requiring investigation or intervention (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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (PSCA CAR T cells); Patients may receive lymphodepleting regimen (either standard or modified) including fludarabine IV on days -5 to -3 and cyclophosphamide IV on days -5 to -3 or on days -4 and/or -3. The study PI and the protocol team will choose a chemotherapy regimen, for lymphodepletion prior to the PSCA-CAR T cell infusion (with the exception of cohorts 1 and -1 which will not receive lymphodepletion), based on the research participant's disease type and prior therapies. Patients then receive autologous anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T lymphocytes IV over 10-15 minutes at day 0.

Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Biological: Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes; Given IV; Other Names: Autologous Anti-PSCA(dCH2)BBz-CAR T-cells; Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-cells; PSCA(dCH2)BBzeta-CAR T-cells

What is the study measuring?

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
Percent of Participants With CAR T Cells Persistence at Day 28	Persistence is defined as CAR T cells comprising at least 7.5 copies/ug of DNA of total CD3 cells.	Days 28 post infusion
Expansion of CAR T Cells	Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid [DNA]) will be described.	Up to 28 days post treatment
Percent of Participants Achieving Stable Disease	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
Percent of Participants Alive at Six Months	Rates and associated 95% exact Clopper and Pearson binomial confidence intervals will be estimated.	From CAR T cell infusion to death from any cause or last contact date, assessed up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phenotypes and Frequencies of Immune Cell Subsets in the Peripheral Blood Pre- and Post-therapy	Analysis will include CD4:CD8 ratios, differentiation status (CD62L, CD27, CD45 RA/RO), and exhaustion markers (PD1, Tim3, LAG3),trafficking (CCR7, alpha4beta7), proliferation markers (ki67) and effector functions (cytotoxicity, Th1/Th2 cytokines, and CD107a degranulation) on endogenous and CAR+ T cells. Will provide descriptive statistics for exploratory studies.	Up to 1 year post treatment
Phenotype of Tumor-infiltrating Lymphocytes	Will provide descriptive statistics for exploratory studies.	Up to 1 year post treatment
Gene Expression	Assessed by ribonucleic acid sequencing (RNA-seq) of circulating tumor cells (CTCs). Will provide descriptive statistics for exploratory studies.	Up to 1 year post treatment
Circulating Free DNA (cfDNA) in Peripheral Blood	Assessed by whole exome sequencing. Will provide descriptive statistics for exploratory studies.	Up to 1 year post treatment
CAR Immunogenicity	Based on the presence of anti-PSCA CAR antibodies or T cell mediated immune responses. Will provide descriptive for statistics exploratory studies.	Up to 1 year post treatment

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tanya B Dorff, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2019
• Primary Completion (Actual): August 20, 2022
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: March 11, 2019
• First Submitted That Met QC Criteria: March 12, 2019
• First Posted (Actual): March 13, 2019

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Vidarabine
• Other Study ID Numbers: 17483 (Other Identifier: City of Hope Medical Center); NCI-2019-01264 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No