Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03873805
Recruitment Status : Recruiting
First Posted : March 13, 2019
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

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. 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.

Condition or disease Intervention/treatment Phase
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 Biological: Autologous Anti-PSCA-CAR-4-1BB/TCRzeta-CD19t-expressing T-lymphocytes Drug: Cyclophosphamide Drug: Fludarabine Drug: Fludarabine Phosphate Phase 1

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study to Evaluate PSCA-Targeting Chimeric Antigen Receptor (CAR)-T Cells for Patients With Metastatic Castration Resistant Prostate Cancer
Actual Study Start Date : May 23, 2019
Estimated Primary Completion Date : February 21, 2021
Estimated Study Completion Date : February 21, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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.

  2. 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)


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.


Other Outcome Measures:
  1. 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.

  2. Phenotype of tumor-infiltrating lymphocytes [ Time Frame: Up to 1 year post treatment ]
    Will provide descriptive statistics for exploratory studies.

  3. 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.

  4. 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.

  5. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03873805


Locations
Layout table for location information
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Tanya B. Dorff    626-218-8231    tdorff@coh.org   
Principal Investigator: Tanya B. Dorff         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Tanya B Dorff City of Hope Medical Center

Layout table for additonal information
Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT03873805     History of Changes
Other Study ID Numbers: 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 )
First Posted: March 13, 2019    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: March 2019

Layout table for additional information
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Prostatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents