Safety, tolerability, pharmacokinetics, and antitumor activity of adavosertib in Japanese patients with advanced solid tumors: A phase I, open-label study

Introduction We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors. Materials and Methods This was a single-center, open-label, phase I study with two consecutive cohorts (250-mg and 200-mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle. Results Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250-mg cohort. None of the three patients in the 200-mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250-mg: 83.3%; 200-mg: 100.0%). Median time to peak drug concentration was 4.03 and 2.08 hours after the first dose and 2.82 and 1.90 hours after multiple dosing in the 250- and 200-mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 hours (first dose) and 10.55 and 8.88 hours (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0% and 33.3% in the 250- and 200-mg cohorts, respectively. One patient (33.3%) in the 200-mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease. Conclusions Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown. Trial registration ClinicalTrials.gov, NCT04462952