Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).

Abstract

TPS191 Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.