Clinical Trial: NCT03089203 - My Cancer Genome

NCT03089203

Description:

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.

Related Conditions:

Prostate Adenocarcinoma

Recruiting Status:

Active, not recruiting

Phase:

Phase 1

URL:

https://clinicaltrials.gov/show/NCT03089203

Trial Eligibility

Document

Title

Brief Title: CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer
Official Title: PHASE I STUDY OF PSMA-TGFβRDN CAR MODIFIED T CELLS IN PATIENTS WITH ADVANCED CASTRATE RESISTANT PROSTATE CANCER

Clinical Trial IDs

ORG STUDY ID: UPCC 32816, 826250
NCT ID: NCT03089203

Conditions

Prostate Cancer

Interventions

Drug	Synonyms	Arms
CART T cells		Cohort -3
CART T cells		Cohort -3
Cyclophosphamide 1g/m^2		Cohort -3
CART T cells		Cohort -3

Purpose

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.

Trial Arms

Name	Type	Description	Interventions
Cohort 1	Experimental	CART T cells 1-3x10^7 Day 0	CART T cells CART T cells CART T cells
Cohort 2	Experimental	Cart T cells 1-3x10^8 Day 0	CART T cells CART T cells CART T cells
Cohort -3	Experimental	Cyclophosphamide 300 mg/m^2/day and fludarabine 30 mg/m^2/day Day -3 CART T cells 1-3x10^7 Day 0	CART T cells CART T cells Cyclophosphamide 1g/m^2 CART T cells

Eligibility 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 > or = 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) are allowable.
             Under protocol-specified conditions, immune checkpoint inhibitors,radium-223 and
             immunoconjugate therapies are also allowable.

          -  History of an active non-curative non-prostate primary malignancy within the prior 5
             years

          -  Subjects who require the chronic use of systemic corticosteroid therapy. Patients may
             be on a low dose of steroids (≤10mg equivalent of prednisone).

          -  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 or severe 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.

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

Primary Outcome Measures

Measure:	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
Safety Issue:
Description:	using CTCAE v 4.03

Secondary Outcome Measures

Measure:	II. Assess the clinical anti-tumor effect of CART-PSMA- TGFβRDN cells
Time Frame:	Week -2, day 28. month 3 and 6
Safety Issue:
Description:	using RECIST 1.1

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

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

Details

Phase:	Phase 1
Primary Purpose:	Interventional
Overall Status:	Active, not recruiting
Lead Sponsor:	University of Pennsylvania

Last Updated

January 14, 2021

Clinical Trials /

CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer