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CART-PSMA-TGFβRDN Cells for Castrate-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: NCT03089203
Recruitment Status : Recruiting
First Posted : March 24, 2017
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
This is a single center, single arm Phase I study to establish the safety and feasibility of intravenously administered lentivirally transduced dual PSMA-specific/ TGFβ-resistant CAR modified autologous T cells (CART-PSMA-TGFβRDN cells) in patients with metastatic castrate resistant prostate cancer.

Condition or disease Intervention/treatment Phase
Prostate Cancer Biological: CART T cells Drug: Cyclophosphamide 1g/m^2 Phase 1

Detailed Description:

This is a Phase I study evaluating the safety and feasibility of lentivirally transduced PSMA-TGFβRDN autologous CAR T cells administered with and without cyclophosphamide in a 3+3 dose escalation design. Cohort 1 subjects (N=3 or 6) will receive a single dose of 1-3 x 107/m2 lentivirally transduced CART-PSMA-TGFβRDN cells on day 0 without any conditioning chemotherapeutic regimen. If the number of manufactured CAR T cells does not meet the pre-specified minimum infused dose of 1 x 107/m2 cells, then dose will not be administered, and the subject will be replaced in the study. If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance to Cohort 2.

If 2 DLT/3 subjects occurs at dose of 1-3 x 107/m2 cells, then enrollment in this Cohort will be stopped and the dose will be de-escalated by 10-fold to 1-3 x 106 cells/m2 (Cohort -1). In this situation, up to 6 subjects will be enrolled in Cohort

-1. Cohort 2 subjects (N=3 or 6) will receive a single dose of 1-3 x 108/m2 lentivirally transduced CART-PSMA-TGFβRDN cells on day 0 without any conditioning chemotherapeutic regimen. If the number of manufactured CAR T cells does not meet the protocol-specified minimum of 1 x 108/m2 cells, but does meet the minimum dose requirement of at least 1 x 107/m2 cells, then the subject may receive the dose and will not be included in the DLT assessment for Cohort 2. This subject would be replaced for DLT assessment. If, however, the number of manufactured CAR T cells does not meet the pre-specified minimum infused dose as outlined for Cohort 1, then no dose will be administered, and the subject will be replaced in the study. If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. If 0 DLT/3 subjects or 1 DLT/6 subjects occurs, the study will advance to Cohort 3. If 2 DLT/3 subjects occur, then the study will stop and declare maximum tolerated dose (MTD). Cohorts 1 and 2 will serve to identify the MTD of CART-PSMA-TGFβRDN cells. The maximum tolerated dose is defined as the highest dose at which 0/3 or 1/6 DLTs occur. Cohort 3 subjects (N=3 or 6) will receive a single infusion at the MTD of lentivirally transduced CART-PSMA-TGFβRDN cells on day 0, following a single dose of 1.0 gram/m2 of cyclophosphamide administered up to 4 days prior to the CAR T cells (day -3 ± 1 day). If 0 DLT /3 subjects occur, the study will enroll an additional 3 patients to confirm tolerability. If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. If two of the initial three subjects experience a DLT, three additional patients will be accrued with a dose reduction in the lymphodepleting chemotherapy to 500 mg/m2 administered up to 4 days prior to the CAR T cells (day -3 ± 1 day). The DLT observation period will be 28 days. The highest dose level where only 0/3 or 1/6 DLTs were observed in a given cohort will be defined as the MTD. Adverse event reporting will begin on Day 0 (Cohorts 1 and 2) or Day -3 ±1 day (Cohort 3) and continue through 2 years after the infusion or until subjects begin an alternative cancer-related treatment, whichever comes first. While on study, subjects will be continually reassessed for evidence of acute and cumulative toxicities.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PHASE I STUDY OF PSMA-TGFβRDN CAR MODIFIED T CELLS IN PATIENTS WITH ADVANCED CASTRATE RESISTANT PROSTATE CANCER
Actual Study Start Date : March 8, 2017
Estimated Primary Completion Date : September 8, 2020
Estimated Study Completion Date : September 8, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Cohort 1
CART T cells 1-3x10^7 Day 0
Biological: CART T cells
1-3x10^7

Biological: CART T cells
1-3 x 10^8

Biological: CART T cells
MTD given in Cohort 3 only

Experimental: Cohort 2
Cart T cells 1-3x10^8 Day 0
Biological: CART T cells
1-3x10^7

Biological: CART T cells
1-3 x 10^8

Biological: CART T cells
MTD given in Cohort 3 only

Experimental: Cohort -3
Cyclophosphamide 300 mg/m^2/day and fludarabine 30 mg/m^2/day Day -3 CART T cells 1-3x10^7 Day 0
Biological: CART T cells
1-3x10^7

Biological: CART T cells
1-3 x 10^8

Drug: Cyclophosphamide 1g/m^2
day -3 of cohort 3 subjects only

Biological: CART T cells
MTD given in Cohort 3 only




Primary Outcome Measures :
  1. I. Adverse Events experienced by subjects infused with CART-PSMA- TGFβRDN cells [ Time Frame: week -8 through end of study approximately 24 months after infusion ]
    using CTCAE v 4.03


Secondary Outcome Measures :
  1. II. Assess the clinical anti-tumor effect of CART-PSMA- TGFβRDN cells [ Time Frame: Week -2, day 28. month 3 and 6 ]
    using RECIST 1.1

  2. III. Assess the clinical anti-tumor effect of CART-PSMA- TGFβRDN cells [ Time Frame: Week -2, day 28. month 3 and 6 ]
    PCWG2 criteria for bone disease

  3. IV. Assess the clinical anti-tumor effect of CART-PSMA- TGFβRDN cells [ Time Frame: Week -2, day 28. month 2, 3 and 6 ]
    Serum PSA measurements



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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Metastatic castrate resistant prostate cancer

    ≥10% tumor cells expressing PSMA as demonstrated by immunohistochemistry analysis on fresh tissue.

  • Radiographic evidence of osseous metastatic disease and/or measurable, non-osseous metastatic disease (nodal or visceral)
  • Patients > 18 years of age
  • ECOG performance status of 0 - 1
  • Adequate organ function, as defined by:
  • Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min
  • Serum total bilirubin < 1.5x ULN
  • Serum ALT/AST < 2x ULN
  • Adequate hematologic reserve within 4 weeks of study enrollment as defined by:
  • Hgb > 10 g/dl
  • PLT > 100 k/ul
  • ANC > 1.5 k/ul
  • Note: Subjects must not be transfusion dependent
  • Evidence of progressive castrate resistant prostate adenocarcinoma, as defined by:
  • Castrate levels of testosterone (< 50 ng/ml) with or without the use of androgen deprivation therapy AND
  • Evidence of one of the following measures of progressive disease in the 12 weeks preceding study enrollment: soft tissue progression by RECIST 1.1 criteria, osseous disease progression with 2 or more new lesions on bone scan(as per PCWG2 criteria), increase in serum PSA of at least 25% and an absolute increase of 2ng/ml or more from nadir (as per PCWG2 criteria)
  • Prior therapy with at least one standard 17α lyase inhibitor or second-generation anti-androgen therapy for the treatment of metastatic castrate resistant prostate cancer
  • Provides written informed consent
  • Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion Criteria:

  • Prior treatment with an immune-based therapy for the treatment of prostate cancer, including cancer vaccine therapies (such as SipuleucelT, PROSTVAC), immune checkpoint inhibitors,radium-223 and immunoconjugate therapies
  • History of an active non-curative non-prostate primary malignancy within the prior 5 years
  • Subjects with a rising PSA, but who have never had radiologic evidence of metastatic disease(i.e. 'biochemical recurrence')
  • Subjects who require the chronic use of systemic corticosteroid therapy
  • Subjects who have received > 3 prior therapies for the treatment of castrate resistant prostate cancer (excluding luteinizing hormone-releasing hormone agonists or antagonists, or first generation anti-androgen therapies). This includes subjects who received Taxotere in noncastrate setting.
  • Subjects with Class III/IV cardiovascular disability according to the New York Heart Association Classification
  • Subjects with symptomatic vertebral metastases affecting spinal cord function (as determined by clinical history, physical exam, or MRI imaging)
  • History of active autoimmune disease requiring immunosuppressive therapy
  • Patients with ongoing or active infection.
  • History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO,and Dextran 40)
  • Active hepatitis B, hepatitis C or HIV infection.

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): NCT03089203


Contacts
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Contact: Naomi Haas, MD 855-216-0098 CancerTrials@emergingmed.com

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Naomi Haas, MD    855-216-0098    CancerTrials@emergingmed.com   
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Naomi Haas, MD Universtiy of Pennsylvania
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03089203    
Other Study ID Numbers: UPCC 32816, 826250
First Posted: March 24, 2017    Key Record Dates
Last Update Posted: February 11, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists