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

Phase I Study of CART-PSMA-TGFβRDN Cells in Patients With Advanced Castrate Resistant Prostate Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Biological: CART-PSMA-TGFβRDN cells; Drug: Cyclophosphamide; Drug: Fludarabine

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
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Metastatic castrate resistant prostate cancer
2. 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. RETIRED WITH PROTOCOL V16
2. History of an active non-curative non-prostate primary malignancy within the prior 3 years
3. 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. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0	Biological: CART-PSMA-TGFβRDN cells; autologous CAR T cells
Experimental: Cohort 2; CART-PSMA-TGFβRDN cells 1-3x10^8 Day 0	Biological: CART-PSMA-TGFβRDN cells; autologous CAR T cells
Experimental: Cohort -3; CART-PSMA-TGFβRDN cells 1-3x10^7 Day 0	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
Experimental: Cohort 4; CART-PSMA-TGFβRDN cells 0.70-1.00 x 10^8 Day 0	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
Experimental: Cohort 3; CART-PSMA-TGFβRDN cells at the MTD (established by Cohorts 1-2) on day 0	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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Naomi Haas, MD, Universtiy of Pennsylvania

Publications and helpful links

General Publications

• Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, Maus MV, Fraietta JA, Zhao Y, June CH. Dominant-Negative TGF-beta 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.
• Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, Hwang WT, Lal P, Carpenter EL, Maude SL, Plesa G, Vapiwala N, Chew A, Moniak M, Sebro RA, Farwell MD, Marshall A, Gilmore J, Lledo L, Dengel K, Church SE, Hether TD, Xu J, Gohil M, Buckingham TH, Yee SS, Gonzalez VE, Kulikovskaya I, Chen F, Tian L, Tien K, Gladney W, Nobles CL, Raymond HE; Prostate Cancer Cellular Therapy Program Investigators; Hexner EO, Siegel DL, Bushman FD, June CH, Fraietta JA, Haas NB. PSMA-targeting TGFbeta-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022 Apr;28(4):724-734. doi: 10.1038/s41591-022-01726-1. Epub 2022 Mar 21.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2017
• Primary Completion (Estimated): September 8, 2038
• Study Completion (Estimated): December 8, 2038

Study Registration Dates

• First Submitted: March 20, 2017
• First Submitted That Met QC Criteria: March 20, 2017
• First Posted (Actual): March 24, 2017

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; fludarabine
• Other Study ID Numbers: UPCC 32816, 826250

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No