Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
Chimeric Antigen Receptor (CAR), T-cells, Prostate-Specific Membrane Antigen (PSMA), Prostate Cancer
Brief 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.
Detailed 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.
Interventions
BIOLOGICALCART-PSMA-TGFβRDN
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 TGFβ receptor
DRUGCyclophosphamide
Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-PSMA-TGFβRDN genetically modified T cells
DRUGFludarabine
Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-PSMA-TGFβRDN genetically modified T cells
DRUGAnakinra
In applicable cohorts, patients will receive anakinra prophylactically starting on the day of administration of investigational product, CART-PSMA-TGFβRDN genetically modified T cells
Sponsors
Tceleron Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Sequential dose escalation
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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 CYP17α 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-TGFβRDN 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation: Dose Identification of CART-PSMA-TGFβRDN | Up to 2 years | Incidence of Dose Limiting Toxicity (DLT) |
| Cohort Expansion: Safety of CART-PSMA-TGFβRDN | Up to 2 years | Percentage of patients experiencing adverse events (AEs), including serious and severe AEs overall, by dose level, and severity grade |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary efficacy of CART-PSMA-TGFβRDN as assessed by biochemical Objective Response Rate (ORR) | Up to 2 years | 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 |
| Feasibility of CART-PSMA-TGFβRDN | Up to 2 years | Proportion of patients who did not receive CART-PSMA-TGFβRDN cells |
| Peripheral expansion and persistence of CART-PSMA-TGFβRDN | Up to 15 years | Quantitative polymerase chain reaction (qPCR) |
Countries
United States
Outcome results
None listed