A first-in-human phase 1 study of proxalutamide (GT0918), a dual MOA androgen receptor blocker in patients with advanced CRPC.

Abstract

e16511 Background: Proxaluatmide is a novel dual MOA androgen receptor (AR) blocker with potent AR antagonist activity and capability to down-regulate AR level. We conducted a first-in-human phase 1 study to investigate safety, tolerability, and pharmacokinetics of GT0918 in patients with advanced CRPC. Methods: All participating patients must be confirmed with advanced CRPC progressed on SoC, PS 0-1, went through 2 periods of time of both single-dose and repeated-dose PK. Patients received GT0918 once orally followed by PK in first 7 days, and then once daily continuously for 28 days for DLT evaluation and repeated-dose PK. PK of drug elimination was done at the end of first cycle (7 days off-treatment). By the end of first 28-day cycle, DLT was evaluated and dose escalation was determined by modified Fibonacci's rule of 3+3 design. If patient tolerated GT0918 well and had no sign of tumor progression, he continued on the study medication thereafter. Results: Ninteen patients were enrolled and 16 patients were treated with GT0918 at five dose levels: 50 mg (n = 2), 100 mg (n = 4), 200 mg (n = 3), 300 mg (n = 3) and 400 mg (n = 4). No DLT was observed. MTD was not reached. GT0918-related adverse events were relatively mild (CTCAE grade 1 or 2), including hypercholesterolemia, peripheral edma, fatigue, flush, constipation and anorexia. PK study showed plasma drug concentrations increased as dose increased from 50mg to 300mg and saturation observed between 300mg and 400mg. Compared single dose (D1) with repeated dose (D35), the elimination half-life (T1/2) were shown 14-35h and 28-51h, respectively. With consideration of overly drug exposure and saturation of oral absorption, 100-400mg were recommended to be the dose range for Phase 2 for further clinical evaluations and dose selection. Clinical activities have been observed in numbers of patients in 100/200/300/400mg dose cohorts. Conclusions: Proxalutamide (GT0918) dosed orally once a day continuously for 12 weeks was generally well tolerated. GT0918 showed promising preliminary anti-tumor activity. Dose range of 100-400mg was recommended for Phase 2 trial and for 24 weeks of treatment.