Phase 1 study of RX-5902, a novel orally bioavailable inhibitor of phosphorylated P68, which prevents β-catenin translocation in advanced solid tumors

Abstract

Background: RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression through inhibition of beta-catenin translocation. We report preliminary results of the Phase 1 study of RX-5902 as a single agent to treat advanced solid tumors. Method(s): The dose finding portion of the Phase 1 study (NCT02003092) was designed to evaluate safety, tolerability and dose limiting toxicities, to identify the maximum tolerated dose and a recommended phase 2 dose and schedule (RP2D). Secondary objectives were pharmacokinetics (PK) and antitumor activity (RECIST v1.1). Eligible subjects (aged >=18 years), with relapsed/refractory solid tumors that had been heavily pretreated, received oral RX-5902 ranging from 25 mg to 350 mg and administered at 1, 3, 5 or 7 times per week for 3 weeks followed by 1 week of rest or for 4 weeks without rest. Result(s): As of May 2017, 35 subjects (23 Females, 12 males) were treated with oral RX- 5902. The dose limiting toxicities were G4 hyponatremia (n=1) and G3 fatigue (n=1) at 300 mg administered daily for 4 weeks. The maximum tolerated dose of 250 mg, will be studied further in the Phase 2a portion. Of the 35 subjects treated, 15 subjects (breast ER+/PR+/Her2-, triple negative breast (n=2), cervical (n=2), neuroendocrine (n=3), paraganglioma, colorectal (N=3), pancreatic, ovarian, head and neck cancers) experienced stable disease; 2 subjects have received treatment for > 2.5 years. The most common related adverse events were G1/G2 anorexia, G1/G2 nausea, G1/G2 vomiting, G1/G2 diarrhea, G1 weight loss and G1/G2 fatigue. Oral RX-5902 was bioavailable with median Tmax of 2 hours and median elimination half-life of 12 hours. Conclusion(s): Data from this study support that RX-5902 is safe and well-tolerated at the doses and schedules tested. The RP2D of 250 mg of RX-5902 administered daily for 5 consecutive days for 4 weeks is being studied further in metastatic triple negative breast cancer in the Phase 2 portion of this study.