Clinical Trials /

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

NCT03873805

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 17483
  • SECONDARY ID: NCI-2019-01264
  • SECONDARY ID: 17483
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT03873805

Conditions

  • 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
  • PSCA Positive

Interventions

DrugSynonymsArms
Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytesAutologous Anti-PSCA(dCH2)BBz-CAR T-cells, Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-cells, PSCA(dCH2)BBzeta-CAR T-cellsTreatment (PSCA CAR T cells)
Cyclophosphamide(-)-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- 138719Treatment (PSCA CAR T cells)
FludarabineFluradosaTreatment (PSCA CAR T cells)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (PSCA CAR T cells)

Purpose

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. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (PSCA CAR T cells)ExperimentalPatients 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.
  • Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes
  • Cyclophosphamide
  • Fludarabine
  • Fludarabine Phosphate

Eligibility Criteria

        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

          -  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

                    -  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 enrollment

          -  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)

          -  If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin
             (PT) =< 1.5 x ULN (to be performed within 42 days of signing the main study consent)).
             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 of signing the main study consent)). 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
             of signing the main study consent))

          -  Left ventricular ejection fraction > 40% (to be performed within 42 days of signing
             the main study consent)

          -  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 enrollment

          -  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 enrollment

          -  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 enrollment

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Full toxicity profile
Time Frame:Up to 15 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:CAR T cells persistence
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Defined as CAR T cells > 0.1% of total CD3 cells by flow-cytometry. Maximum persistence (in days) will be described.
Measure:Expansion of CAR T cells
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Peak expansion (max log10 copies/ug of genomic deoxyribonucleic acid [DNA]) will be described.
Measure:Disease response
Time Frame:Up to 1 year post treatment
Safety Issue:
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.
Measure: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
Safety Issue:
Description:Kaplan Meier methods will be used to estimate median OS, and graph the results.
Measure: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
Safety Issue:
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.
Measure:PSCA expression
Time Frame:Up to 1 year post treatment
Safety Issue:
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.
Measure:Serum cytokine profile
Time Frame:Up to 1 year post treatment
Safety Issue:
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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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