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

• ClinicalTrials.gov Identifier: NCT03873805
• Recruitment Status: Recruiting
• First Posted: March 13, 2019
• Last Update Posted: December 26, 2019
• Sponsor: City of Hope Medical Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): City of Hope Medical Center

Tracking Information

• First Submitted Date: March 11, 2019
• First Posted Date: March 13, 2019
• Last Update Posted Date: December 26, 2019
• Actual Study Start Date: May 23, 2019
• Estimated Primary Completion Date: February 21, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2019)

• Full toxicity profile [ Time Frame: Up to 15 years ]
  Full 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.
• Dose-limiting toxicity (DLT) [ Time Frame: Up to 28 days post treatment ]
  Defined by any grade 3 or NCI CTCAE toxicities and modified CRS grading as applicable. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for DLTs within 28 days of CAR T cell infusion at the recommended phase 2 dose (RP2D)

Original Primary Outcome Measures (submitted: March 12, 2019)

• Full toxicity profile [ Time Frame: Up to 15 years ]
  Full toxicity profile as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 post chimeric antigen receptor (CAR) T cell infusion.
• Dose-limiting toxicity (DLT) [ Time Frame: Up to 28 days post treatment ]
  Defined by any grade 3 or NCI CTCAE toxicities. Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for DLTs within 28 days of CAR T cell infusion at the recommended phase 2 dose (RP2D)

• Change History: Complete list of historical versions of study NCT03873805 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: March 12, 2019)

• CAR T cells persistence [ Time Frame: Up to 1 year post treatment ]
  Defined as CAR T cells > 0.1% of total CD3 cells by flow-cytometry. Maximum persistence (in days) will be described.
• Expansion of CAR T cells [ Time Frame: Up to 1 year post treatment ]
  Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid [DNA]) will be described.
• Disease response [ Time Frame: Up to 1 year post treatment ]
  Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for response based on Prostate Cancer Working Group 3 (PCWG3) criteria.
• Overall survival (OS) [ Time Frame: From CAR T cell infusion to the event date (death) or last contact date (censor date), assessed up to 15 years ]
  Kaplan Meier methods will be used to estimate median OS, and graph the results.
• Progression-free survival (PFS) [ Time Frame: 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 ]
  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.
• PSCA expression [ Time Frame: Up to 1 year post treatment ]
  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.
• Serum cytokine profile [ Time Frame: Up to 1 year post treatment ]
  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.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: March 12, 2019)

• Phenotypes and frequencies of immune cell subsets in the peripheral blood pre- and post-therapy [ Time Frame: Up to 1 year post treatment ]
  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.
• Phenotype of tumor-infiltrating lymphocytes [ Time Frame: Up to 1 year post treatment ]
  Will provide descriptive statistics for exploratory studies.
• Gene expression [ Time Frame: Up to 1 year post treatment ]
  Assessed by ribonucleic acid sequencing (RNA-seq) of circulating tumor cells (CTCs). Will provide descriptive statistics for exploratory studies.
• Circulating free DNA (cfDNA) in peripheral blood [ Time Frame: Up to 1 year post treatment ]
  Assessed by whole exome sequencing. Will provide descriptive statistics for exploratory studies.
• CAR immunogenicity [ Time Frame: Up to 1 year post treatment ]
  Based on the presence of anti-PSCA CAR antibodies or T cell mediated immune responses. Will provide descriptive for statistics exploratory studies.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

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

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
• Study Phase: Phase 1
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

• 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
• Drug: Cyclophosphamide
  Given IV
  Other Names:

  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
• Drug: Fludarabine
  Given IV
  Other Name: Fluradosa
• Drug: Fludarabine Phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • SH T 586

Study Arms

Experimental: Treatment (PSCA CAR T cells)

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.

Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 12, 2019): 33
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 21, 2021
• Estimated Primary Completion Date: February 21, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03873805
• Other Study ID Numbers: 17483; NCI-2019-01264 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 17483 ( Other Identifier: City of Hope Comprehensive Cancer Center )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Responsible Party: City of Hope Medical Center
• Study Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tanya B Dorff; City of Hope Medical Center

• PRS Account: City of Hope Medical Center
• Verification Date: December 2019