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

Primary Purpose

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

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes
Cyclophosphamide
Fludarabine
Fludarabine Phosphate
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Castration-Resistant Prostate Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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)

Sites / Locations

  • City of Hope Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (PSCA CAR T cells)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
Number of Participants Experiencing a Dose-limiting Toxicity (DLT)
Defined by any grade 3 or NCI CTCAE toxicities and modified CRS grading as applicable.

Secondary Outcome Measures

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.
Expansion of CAR T Cells
Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid [DNA]) will be described.
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.
Overall Survival (OS)
Kaplan Meier methods will be used to estimate median OS, and graph the results.
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.
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.
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.

Full Information

First Posted
March 11, 2019
Last Updated
October 16, 2023
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT03873805
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 20, 2019 (Actual)
Primary Completion Date
August 20, 2022 (Actual)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (PSCA CAR T cells)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Grade 3 Toxicity Profile
Description
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.
Time Frame
Up to 32 months
Title
Number of Participants Experiencing a Dose-limiting Toxicity (DLT)
Description
Defined by any grade 3 or NCI CTCAE toxicities and modified CRS grading as applicable.
Time Frame
Up to 28 days post treatment
Secondary Outcome Measure Information:
Title
CAR T Cells Persistence
Description
Defined as CAR T cells > 0.1% of total CD3 cells by flow-cytometry. Maximum persistence (in days) will be described.
Time Frame
Up to 1 year post treatment
Title
Expansion of CAR T Cells
Description
Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid [DNA]) will be described.
Time Frame
Up to 1 year post treatment
Title
Disease Response
Description
Rates and associated 90% Clopper and Pearson binomial confidence limits will be estimated for response based on Prostate Cancer Working Group 3 (PCWG3) criteria.
Time Frame
Up to 1 year post treatment
Title
Overall Survival (OS)
Description
Kaplan Meier methods will be used to estimate median OS, and graph the results.
Time Frame
From CAR T cell infusion to the event date (death) or last contact date (censor date), assessed up to 15 years
Title
Progression-free Survival (PFS)
Description
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.
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
Title
PSCA Expression
Description
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.
Time Frame
Up to 1 year post treatment
Title
Serum Cytokine Profile
Description
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.
Time Frame
Up to 1 year post treatment
Other Pre-specified Outcome Measures:
Title
Phenotypes and Frequencies of Immune Cell Subsets in the Peripheral Blood Pre- and Post-therapy
Description
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.
Time Frame
Up to 1 year post treatment
Title
Phenotype of Tumor-infiltrating Lymphocytes
Description
Will provide descriptive statistics for exploratory studies.
Time Frame
Up to 1 year post treatment
Title
Gene Expression
Description
Assessed by ribonucleic acid sequencing (RNA-seq) of circulating tumor cells (CTCs). Will provide descriptive statistics for exploratory studies.
Time Frame
Up to 1 year post treatment
Title
Circulating Free DNA (cfDNA) in Peripheral Blood
Description
Assessed by whole exome sequencing. Will provide descriptive statistics for exploratory studies.
Time Frame
Up to 1 year post treatment
Title
CAR Immunogenicity
Description
Based on the presence of anti-PSCA CAR antibodies or T cell mediated immune responses. Will provide descriptive for statistics exploratory studies.
Time Frame
Up to 1 year post treatment

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tanya B Dorff
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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