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

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ClinicalTrials.gov Identifier: NCT03873805
Recruitment Status : Not yet recruiting
First Posted : March 13, 2019
Last Update Posted : March 13, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE March 11, 2019
First Posted Date  ICMJE March 13, 2019
Last Update Posted Date March 13, 2019
Estimated Study Start Date  ICMJE August 1, 2019
Estimated Primary Completion Date February 21, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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)
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE 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  ICMJE PSCA-CAR T Cells in Treating Patients With Metastatic Castration Resistant Prostate Cancer
Official Title  ICMJE A Phase I Study to Evaluate PSCA-Targeting Chimeric Antigen Receptor (CAR)-T Cells for Patients With 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 castration resistant prostate cancer that has spread to other places in the body. 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 metastatic castration resistant prostate cancer (mCRPC).

II. Define the recommended phase 2 dose (RP2D) of PSCA-CAR T cells in 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Castration Levels of Testosterone
  • Castration-Resistant Prostate Carcinoma
  • Metastatic Prostate Carcinoma
  • PSA Progression
  • Stage IV Prostate Cancer AJCC v8
  • Stage IVA Prostate Cancer AJCC v8
  • Stage IVB Prostate Cancer AJCC v8
Intervention  ICMJE
  • 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
    • 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  ICMJE 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 12, 2019)
33
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 21, 2021
Estimated Primary Completion Date February 21, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • All subjects 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 Karnofsky performance status (KPS) performance status of 70% or greater
  • 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)

    • 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
      • 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 3 months must have elapsed since completion of therapy
  • Prior radiotherapy is allowed provided it was not administered to the only evaluable site of disease and was > 14 days prior to screening
  • No known contraindications to leukapheresis, steroids or tocilizumab
  • Total serum bilirubin =< 2.0 mg/dL (to be performed within 42 days prior to day 1 of protocol therapy)

    • 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 prior to day 1 of protocol therapy)
  • Alanine aminotransferase (ALT) < 3 x ULN (to be performed within 42 days prior to day 1 of protocol therapy)
  • Creatinine clearance of >= 50 mL/min per the Cockcroft-Gault formula (to be performed within 42 days prior to day 1 of protocol therapy)
  • If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN (to be performed within 42 days prior to day 1 of protocol therapy). If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
  • If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (to be performed within 42 days prior to day 1 of protocol therapy). If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
  • Cardiac function (12 lead-electrocardiography [ECG]) (to be performed within 42 days prior to day 1 of protocol therapy)
  • Left ventricular ejection fraction > 40% (to be performed within 42 days prior to day 1 of protocol therapy)
  • Pulmonary function tests (diffusing capacity of the lung for carbon monoxide [DLCO] of 40% of best predicted) (to be performed within 42 days prior to day 1 of protocol therapy)
  • Subjects of reproductive potential must agree to use acceptable birth control methods throughout therapy and for 3 months after final study treatment

Exclusion Criteria:

  • Taxane chemotherapy or radium223 within 3 months of study screening
  • Concurrent use of systemic corticosteroids or chronic use of immunosuppressant medications above physiologic replacement doses (prednisone =< 7.5 mg /day, or hydrocortisone =< 20 mg /day is allowed). Recent or current use of inhaled steroids is not exclusionary
  • Subjects with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of screening
  • Subjects 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 screening
  • 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  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03873805
Other Study ID Numbers  ICMJE 17483
NCI-2019-01264 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17483 ( Other Identifier: City of Hope Medical Center )
P30CA033572 ( U.S. NIH Grant/Contract )
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  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Tanya B Dorff City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP