a study of tmpsma-02 chimeric antigen receptor (car) t-cells in patients with metastatic castration resistant prostate cancer (mcrpc)

Conditions: Metastatic Castration-resistant Prostate Cancer

Summary: an open-label, multi-center, phase 1/2 study to determine the safety, tolerability, and feasibility of dosing adult patients with mcrpc with genetically modified autologous t-cells (tmpsma-02) engineered to express a car capable of recognizing the tumor antigen prostate-specific membrane antigen (psma) and activating the t-cell.

this is a phase 1/2 single-arm study designed to identify the dose and regimen of tmpsma-02 that can be safely administered intravenously following the lymphodepletion (ld) regimen to patients with mcrpc. the phase 1 dose escalation portion of the study will employ a bayesian optimal interval (boin) design to define the maximum tolerated dose (mtd) and determine the recommended phase 2 dose (rp2d). dose-limiting toxicities (dlts) will be assessed from the start of ld regimen through 28-days post infusion of tmpsma-02. the phase 2 portion will employ a simon's 2-stage design and include a single-arm of adult patients with mcrpc treated with the tmpsma-02 at the rp2d. it is anticipated that up to 30 patients will enroll in the phase 1 portion of the study and up to 84 patients will enroll in the phase 2 portion of the study.

Eligibility criteria:
inclusion criteria: * adults at least 18 years of age. * a confirmed histologic diagnosis of prostate cancer. * castrate levels of testosterone (\< 50 ng/dl). * measurable disease (radiographic or prostate specific antigen \[psa\]) per pcwg3 criteria (see appendix 3) * received at least 2 prior lines of systemic therapy for prostate cancer, including at least one second generation androgen receptor inhibitor (e.g., enzalutamide or apalutamide) or cyp17α inhibitor (e.g., abiraterone/ prednisone) and a taxane based regimen (e.g., docetaxel, cabazitaxel, etc). at least one line of prior therapy must be in the mcrpc setting. note: androgen deprivation therapy (adt) with gonadotropin- releasing hormone (gnrh) agonist/antagonist does not count as a line of therapy nor does a first-generation nonsteroidal antiandrogen (e.g., bicalutamide, flutamide, etc.). * adequate vital organ function as defined by: (a) estimated glomerular filtration rate (egfr) egfr ≥ 50 ml/min by modification of diet in renal disease criteria, (b) alanine aminotransferase (alt) and aspartate aminotransferase (ast) ≤ 2.5 x the upper limit of normal (uln); patients with hepatic metastases alt and ast ≤ 3.0 uln. (c) serum total bilirubin \< 1.5 × uln unless patient has known gilbert's; if so, then serum bilirubin ≤ 3 mg/dl, or (d) left ventricular ejection fraction ≥ 45%. * patients must have adequate hematologic reserve and must not be dependent on transfusions to maintain these hematologic parameters. adequate hematologic reserve is defined as: (a) hemoglobin ≥ 8 g/dl, (b) absolute neutrophil count ≥ 1000/ μl, or (c) platelet count ≥ 75,000/μl. * patients who have not undergone bilateral orchiectomy must be able to continue 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 to the baseline. exceptions include non-clinically significant toxicities as a result of previous therapy (e.g., alopecia, hormonal changes, weight loss, etc). * patients of reproductive potential agree to use protocol-specified highly effective contraceptive methods exclusion criteria: * active invasive cancer, other than the proposed cancer included in the study, within 2 years prior to screening. \[note: non-invasive cancers treated with curative intent (e.g., non-melanoma skin cancer may still be eligible\], unless treated with curative intent, i.e., non-melanoma skin cancer. * prior treatment with autologous t-cell therapy. note: prior treatment with sipuleucel-t is allowed. * patients who require chronic treatment with systemic corticosteroids (defined as a dose greater than the equivalent of prednisone 10 mg/day). low-dose physiologic replacement therapy with corticosteroids equivalent to prednisone 10 mg/day or lower, topical steroids and inhaled steroids are acceptable. * prior allogeneic stem cell transplant. * active autoimmune disease (including, but not limited to, connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease or multiple sclerosis) or a history of severe autoimmune disease requiring prolonged immunosuppressive therapy. patients should have stopped any immunosuppressive therapy within 6 weeks prior to screening. * current infection with human immunodeficiency virus (hiv), hepatitis c virus (hcv), or hepatitis b virus (hbv). viral testing at screening is required in all patients to rule out subclinical infections. patients who are hepatitis b core antibody positive and hepatitis b surface antigen negative should have quantitative viral load measured. if viral load is undetectable, the patient may enroll and be monitored as per asco guidelines. * seizure disorder requiring anti-epileptic medications. * history of severe infusion reaction to monoclonal antibodies or biological therapies, or to study product excipients (e.g., human serum albumin, dimethyl sulfoxide \[dmso\], dextran 40) that would preclude the patient safely receiving tmpsma-02. * history of or known predisposition to hemophagocytosis lymphohistiocytosis (hlh) or macrophage activation syndrome (mas) * any active infection currently being treated with antibiotics, anti-virals or anti-fungal. prophylactic anti-microbials are not exclusionary. * active or recent (within the past 6 months prior to leukapheresis) cardiovascular disease, defined as (1) new york heart association class iii or iv heart failure, (2) unstable angina or (3) a history of recent (within 6 months) myocardial infarction or sustained (\> 30 second) ventricular tachyarrhythmias, (4) cerebrovascular accident. * active or uncontrolled medical or psychiatric condition that would preclude participation in the opinion of the sponsor, principal investigator (pi) and/or their designee. * have inadequate venous access for or contraindications for the leukapheresis procedure. central venous access is acceptable.

Keywords: chimeric antigen receptor (car) t-cells prostate-specific membrane antigen (psma) prostate cancer