A Study of CART-PSMA-TGFβRDN in Patients With Metastatic Castration Resistant Prostate Cancer

Metastatic Castration-resistant Prostate Cancer Clinical Trial

Official title:

A Phase 1 Open-Label, Multi-Center Study of PSMA Targeted Genetically Modified Chimeric Antigen Receptor T Cells in Patients With Metastatic Castration Resistant Prostate Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04227275
• Other study ID #: CART-PSMA-TGFßRDN-02
• Status: Terminated
• Phase: Phase 1
• Start date: November 22, 2019
• Est. completion date: November 7, 2022

Study information

• Verified date: August 2023
• Source: Tceleron Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Multi-center, open-label, Phase 1 study of the safety, tolerability and feasibility of dosing patients harboring metastatic castration resistant prostate cancer (mCRPC) with genetically modified autologous T cells (CART-PSMA-TGFβRDN cells) engineered to express a chimeric antigen receptor (CAR) capable of recognizing the tumor antigen prostate-specific membrane antigen (PSMA) and activating the T cell.

Description:

This is a Phase 1 single-arm study designed to identify the dose and regimen of CART-PSMA- TGFβRDN cells that can be safely administered intravenously following the lymphodepletion (LD) regimen to patients with metastatic castration resistant prostate cancer (mCRPC). Following Dose Escalation, a Cohort Expansion will enroll patients to further explore the safety and tolerability of the selected dose and schedule. It is anticipated that up to 50 patients will enroll in this study in both dose escalation and cohort expansion.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: November 7, 2022
• Est. primary completion date: November 7, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Confirmed histologic diagnosis of prostate cancer and have mCRPC, with castrate levels of testosterone (<50 ng/mL)
• PSA measurable disease per Prostate Working Group 3 (PCWG3) criteria
• Prior therapies defined as at least 2 prior lines of systemic therapy for prostate cancer, including at least one second generation androgen receptor inhibitor and/or CYP17a inhibitor. At least one line of prior therapy must be in the mCRPC setting
• Estimated estimated glomerular filtration rate = 60 mL/min by Modification of Diet in Renal Disease criteria
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5x the upper limit of normal (ULN); patients with hepatic metastases ALT and AST = 3.0 x ULN
• Serum total bilirubin < 1.5 mg/dL unless patient has known Gilbert's Syndrome, then serum bilirubin =3 mg/dL
• Serum albumin = 3.0 g/dL
• Left ventricular ejection fraction (LVEF) = 50%. LVEF assessment must have been performed within 8 weeks of enrollment
• Hemoglobin = 8 g/dL
• Absolute neutrophil count = 1000/µL
• Platelet count = 75,000/µL
• Patients who have not undergone bilateral orchiectomy must be able to continue gonadotropin-releasing hormone (GnRH) therapy during the study
• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
• Toxicities from any previous therapy must have recovered to Grade 1 or baseline
• Patients of reproductive potential agree to use of approved highly effective contraceptive methods

Exclusion Criteria:

• Active invasive cancer, other than the proposed cancer included in the study, within 2 years prior to screening, unless treated with curative intent
• Current treatment with systemic corticosteroids (defined as a dose greater than the equivalent of prednisone 10 mg/day)
• Active autoimmune disease (including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease or multiple sclerosis) or a history of severe autoimmune disease requiring prolonged immunosuppressive therapy (any immunosuppressive therapy within 6 weeks prior to screening visit)
• Current human immunodeficiency virus (HIV), hepatitis C virus, hepatitis B virus infections; Patients who are hepatitis B core antigen positive, hepatitis B surface antigen negative, should have a quantitative viral load measured; If viral load is undetectable, the patient will not be excluded if hey are able to be treated with anti-viral medication for at least 7 days prior to lymphodepletion until at least 6 months after infusion with viral load and ALT monitoring
• Active or uncontrolled medical or psychological condition that would preclude participation
• History of seizure disorder
• Prior allogeneic stem cell transplant
• Central nervous system malignancy
• History of severe infusion reaction to monoclonal antibodies or biological therapies, or to study product excipients that would preclude the patient safely receiving CART-PSMA-TGFßRDN cells
• History of being previously treated with a J591 antibody-based therapy
• Ferritin levels = 4x the upper limit of normal prior to apheresis or prior to the start of lymphodepleting chemotherapy
• Active or recent (within the past 6 months prior to apheresis or lymphodepletion) cardiovascular disease, defined as (1) New York Heart Association Class III or IV heart failure, (2) unstable angina, (3) a history of recent (within 6 months) myocardial infarction or sustained (> 30 second) ventricular tachyarrhythmias, or (4) cerebrovascular accident
• Any active infection currently being treated or any infection within the last 6 weeks that required 7 days or more of IV antibiotics or any active infection within the last 4 weeks that requires use of oral antibiotics. Patients may be eligible once these timeframes elapse and with evidence that the infection has completely resolved
• Have inadequate venous access for or contraindications for the apheresis procedure
• Must agree not to participate in a conception process or must agree to a highly effective method of contraception

Related Conditions & MeSH terms

• Metastatic Castration-resistant Prostate Cancer
• Prostatic Neoplasms

Intervention

Biological:
• CART-PSMA-TGFßRDN
Intravenous administration of genetically modified autologous T cells engineered to express a protein capable of recognizing the tumor antigen prostate-specific membrane antigen (PSMA), as well as a dominant negative TGFß receptor

Drug:
• Cyclophosphamide
Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-PSMA-TGFßRDN genetically modified T cells
• Fludarabine
Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-PSMA-TGFßRDN genetically modified T cells
• Anakinra
In applicable cohorts, patients will receive anakinra prophylactically starting on the day of administration of investigational product, CART-PSMA-TGFßRDN genetically modified T cells

Locations

Country	Name	City	State
United States	The University of Kansas Hospital	Kansas City	Kansas
United States	Sarah Cannon Research Insitute	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Washington Medical Center	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Tceleron Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation: Dose Identification of CART-PSMA-TGFßRDN	Incidence of Dose Limiting Toxicity (DLT)	Up to 2 years
Primary	Cohort Expansion: Safety of CART-PSMA-TGFßRDN	Percentage of patients experiencing adverse events (AEs), including serious and severe AEs overall, by dose level, and severity grade	Up to 2 years
Secondary	Preliminary efficacy of CART-PSMA-TGFßRDN as assessed by biochemical Objective Response Rate (ORR)	ORR defined as the proportion of patients with maximal prostate-specific antigen (PSA) decline of greater than or equal to 50% at 12 weeks post infusion	Up to 2 years
Secondary	Feasibility of CART-PSMA-TGFßRDN	Proportion of patients who did not receive CART-PSMA-TGFßRDN cells	Up to 2 years
Secondary	Peripheral expansion and persistence of CART-PSMA-TGFßRDN	Quantitative polymerase chain reaction (qPCR)	Up to 15 years