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

• ClinicalTrials.gov Identifier: NCT03089203
• Recruitment Status: Recruiting
• First Posted: March 24, 2017
• Last Update Posted: March 21, 2022
• Sponsor: University of Pennsylvania
• Information provided by (Responsible Party): University of Pennsylvania

Tracking Information

• First Submitted Date: March 20, 2017
• First Posted Date: March 24, 2017
• Last Update Posted Date: March 21, 2022
• Actual Study Start Date: March 8, 2017
• Estimated Primary Completion Date: September 8, 2038 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2022)

• Occurrence of study related adverse events, laboratory toxicities and clinical events that are possibly, likely, or definitely related to study participation. [ Time Frame: 15 years ]
  using CTCAE v 4.03
• Clinical feasibility is defined as the frequency of subjects enrolled on this protocol who do not receive CART-PSMA-TGFβRDN cells. [ Time Frame: 30 days ]
• Manufacturing feasibility is determined by the frequency of product release failures and the occurrence of dose failures (inability to meet target dose). [ Time Frame: 30 days ]

Original Primary Outcome Measures (submitted: March 20, 2017)

Adverse Events experienced by subjects infused with PSMATGFβRDN autologous CAR T cells [ Time Frame: week -8 through end of study approximately 24 months after infusion ]

using CTCAE v 4.03

Current Secondary Outcome Measures (submitted: March 17, 2022)

• Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by RECIST [ Time Frame: 6 months ]
  RECIST 1.1 criteria for soft tissue disease
• Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by PCWG2 [ Time Frame: 6 months ]
  PCWG2 criteria for osseous disease
• Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by serum PSA measurement [ Time Frame: 6 months ]
  serum PSA measurement
• Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by overal survival (OS). [ Time Frame: 15 Years ]
• Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by number of subjects with progression free survival (PFS). [ Time Frame: 15 Years ]

Original Secondary Outcome Measures (submitted: March 20, 2017)

• 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
• 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
• 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer
• Official Title: Phase I Study of CART-PSMA-TGFβRDN Cells in Patients With Advanced Castrate Resistant Prostate Cancer
• 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.

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/fludarabine lymphodepleting chemotherapy in a 3+3 dose escalation design. Subjects must receive the dose of CART-PSMA-TGFβRDN cells as per their cohort assignment in order to be considered evaluable for DLT assessments at that dose level. Subjects who do not receive CART-PSMA-TGFβRDN cells as per their cohort assignment will not be evaluable for DLT assessments/MTD determination, however they will still be followed per protocol and will be included in the overall safety analysis, as well as the analysis of secondary and exploratory endpoints. Subjects who enroll but do not receive CART-PSMA-TGFβRDN cells will be removed from the study and replaced.

Up to 5 dosing cohorts will be explored as follows:

• 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 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 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 toIf 2 DLT/3 subjects occur, then the study will stop and declare maximum tolerated dose (MTD).

Cohorts 1 and 2 were originally designed to identify the MTD of CART-PSMA-TGFβRDN cells. The highest dose level where only 0/3 or 1/6 DLTs were observed in a given cohort will be defined as the MTD for evaluation in Cohort 3.

COHORT 3 CLOSED WITH PROTOCOL V10

• Cohort 3 subjects (N=3 to 9): will receive a single dose of lentivirally transduced CART-PSMA-TGFβRDN cells at the MTD (established by Cohorts 1-2) on day 0, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days; lymphodepleting chemotherapy will be scheduled such that the last day of chemotherapy is 3 days (± 1 day) prior to the infusion of CART-PSMA-TGFβRDN cells. This treatment regimen will be evaluated as follows:

  • If 0 DLT /3 subjects occur, the study will enroll an additional 6 patients to confirm further evaluate the safety of this treatment regimen.
  • If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level to further evaluate safety. If 1 DLT/6 subjects and the safety of this treatment regimen is established, another 3 subjects may be enrolled to further evaluate the safety of this treatment regimen.
  • If 2 DLT/3 subjects or 2 DLT/6 subjects occurs, then enrollment into this cohort will be stopped and the CART-PSMA-TGFβRDN dose will be de-escalated to 1x107/m2 CART-PSMA-TGFβRDN cells with lymphodepleting chemotherapy (Cohort -3). At least 3 subjects would be treated in the Cohort -3 de-escalation cohort.
• Cohort -3 subjects (N=3 to 6): will open in the event of unacceptable toxicity in Cohort 3. Subjects enrolled into this cohort will receive a single dose of 1-3 x 107/m2 lentivirally transduced CART-PSMA-TGFβRDN cells on day 0, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days; lymphodepleting chemotherapy will be scheduled such that the last day of chemotherapy is 3 days (± 1 day) prior to the infusion of CART-PSMA-TGFβRDN cells. Up to 6 subjects will be treated in this dose de-escalated cohort to demonstrate the safety of this regimen.

Once the safety of the Cohort -3 dosing regimen has been established, a new dose escalation Cohort 4 will be opened to enrollment. The 1st three infusions in Cohort 4 will be staggered by 28 days to allow for the assessment of DLTs. If no safety concerns are identified in the first three subjects within this cohort, subsequent infusions within Cohort 4 will be staggered by at least 14 days.

• Cohort 4 subjects (N=3 to 6): Subjects enrolled into this cohort will receive a single dose of 0.70-1.00 x 108 lentivirally transduced CART-PSMA-TGFβRDN cells on Day 0, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days. Lymphodepleting chemotherapy will be scheduled such that the last day of chemotherapy is 3 days (± 1 day) prior to the infusion of CART-PSMA-TGFβRDN cells.

• If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level. If 1 DLT/6 subjects occurs, this dose level will be established as safe; and the safety of the CART-PSMA-TGFβRDN cells may continue to be further explored as part of a subsequent expansion amendment.
• If 0 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this dose level to further evaluate safety. If 0 DLT/6 subjects or 1 DLT/6 subjects occurs, this dose level will be established as safe; and the safety of the CART-PSMA-TGFβRDN cells may continue to be further explored as part of a subsequent expansion amendment. .
• If 2 DLTs occur at any time, enrollment in this cohort will be stopped and the study will be paused for additional investigation.

At the investigator's discretion, subjects may receive "retreatment" with CART-PSMA-TGFβRDN cells at any point after Day 28, provided that safety of the cohort-defined treatment regimen has been established.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• Biological: CART-PSMA-TGFβRDN cells
  autologous CAR T cells
• Drug: Cyclophosphamide
  300 mg/m2/day given over 3 days
• Drug: Fludarabine
  30 mg/m2/day given over 3 days

Study Arms

• Experimental: Cohort 1
  CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0
  Intervention: Biological: CART-PSMA-TGFβRDN cells
• Experimental: Cohort 2
  CART-PSMA-TGFβRDN cells 1-3x10^8 Day 0
  Intervention: Biological: CART-PSMA-TGFβRDN cells
• Experimental: Cohort -3
  CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0
  Interventions:

  • Biological: CART-PSMA-TGFβRDN cells
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Experimental: Cohort 4
  CART-PSMA-TGFβRDN cells 0.70-1.00 x 10^8 Day 0
  Interventions:

  • Biological: CART-PSMA-TGFβRDN cells
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
• Experimental: Cohort 3
  CART-PSMA-TGFβRDN cells at the MTD (established by Cohorts 1-2) on day 0
  Interventions:

  • Biological: CART-PSMA-TGFβRDN cells
  • Drug: Cyclophosphamide
  • Drug: Fludarabine

• Publications *: Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, Maus MV, Fraietta JA, Zhao Y, June CH. Dominant-Negative TGF-β Receptor Enhances PSMA-Targeted Human CAR T Cell Proliferation And Augments Prostate Cancer Eradication. Mol Ther. 2018 Jul 5;26(7):1855-1866. doi: 10.1016/j.ymthe.2018.05.003. Epub 2018 May 8.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 17, 2022): 19
• Original Estimated Enrollment (submitted: March 20, 2017): 18
• Estimated Study Completion Date: December 8, 2038
• Estimated Primary Completion Date: September 8, 2038 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Metastatic castrate resistant prostate cancer
2. ≥10% tumor cells expressing PSMA as demonstrated by immunohistochemistry analysis on biopsied tissue. RETIRED WITH PROTOCOL VERSION 15
3. Radiographic evidence of osseous metastatic disease and/or measurable, non-osseous metastatic disease (nodal or visceral)
4. Patients ≥ 18 years of age
5. ECOG performance status of 0 - 1

6. Adequate organ function, as defined by:

   1. Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min
   2. Serum total bilirubin < 1.5x ULN
   3. Serum ALT/AST < 2x ULN

7. Adequate hematologic reserve within 4 weeks of eligibility confirmation by physician-investigator as defined by:

   1. Hgb > 10 g/dl
   2. PLT > 100 k/ul
   3. ANC > 1.5 k/ul Note: Subjects must not be transfusion dependent

8. Evidence of progressive castrate resistant prostate adenocarcinoma, as defined by:

   1. Castrate levels of testosterone (< 50 ng/ml) with or without the use of androgen-deprivation therapy AND
   2. Evidence of one of the following measures of progressive disease in the 12 weeks preceding eligibility confirmation by physician:

   i. soft tissue progression by RECIST 1.1 criteria ii. osseous disease progression with 2 or more new lesions on bone scan (as per PCWG2 criteria) iii. increase in serum PSA of at least 25% and an absolute increase of 2 ng/ml or more from nadir (as per PCWG2 criteria)

9. Prior therapy with at least one standard initial therapy for the treatment of metastatic castrate resistant prostate cancer (i.e. docetaxel chemotherapy, 17α lyase inhibitor, or second-generation anti-androgen therapy)
10. Provides written informed consent
11. Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion Criteria:

1. Treatment with immune checkpoint inhibitors and immunoconjugate therapies, including nivolumab, pembrolizumab, atezolizumab, ipilimumab, and/or durvalumab, within 2 months prior to eligibility confirmation by physician-investigator. Cancer vaccine therapies (such as Sipuleucel-T or PROSTVAC) are allowable as a prior line of therapy. Radium-223 is allowable as a prior line of therapy, provided laboratory complete blood counts meet all inclusion criteria as above, without transfusion support in the preceding 4 weeks.
2. History of an active non-curative non-prostate primary malignancy within the prior 3 years
3. Subjects with a rising PSA, but who have never had radiologic evidence of metastatic disease (i.e. 'biochemical recurrence') RETIRED WITH PROTOCOL VERSION 6
4. Subjects who require the chronic use of systemic corticosteroid therapy. Patients may be on a low dose of steroids (≤10mg equivalent of prednisone).
5. Subjects who have received > 4 prior therapies for the treatment of castrate resistant prostate cancer (excluding luteinizing hormone-releasing hormone agonists or antagonists, or first generation anti-androgen therapies). Note: Docetaxel or abiraterone/prednisone administered in the castration-sensitive setting will count as a prior line of therapy. RETIRED WITH PROTOCOL V13
6. Subjects with Class III/IV cardiovascular disability according to the New York Heart Association Classification
7. Subjects with symptomatic vertebral metastases affecting spinal cord function (as determined by clinical history, physical exam, or MRI imaging)
8. Active autoimmune disease, including connective tissue disease, uveitis, inflammatory bowel disease, or multiple sclerosis; or a history of severe (as judged by the physician-investigator) autoimmune disease requiring prolonged immunosuppressive therapy
9. Patients with ongoing or active infection.
10. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40)
11. Active hepatitis B, hepatitis C or HIV infection.
12. Active medical condition that, in the opinion of the physician-investigator, would substantially increase the risk of uncontrollable CRS or CAR Neurotoxicity.

Sex/Gender

• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03089203
• Other Study ID Numbers: UPCC 32816, 826250
• 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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: University of Pennsylvania
• Study Sponsor: University of Pennsylvania
• Collaborators: Not Provided

Investigators

• Principal Investigator: Naomi Haas, MD; Universtiy of Pennsylvania

• PRS Account: University of Pennsylvania
• Verification Date: March 2022