Open-Label, Multicenter, Phase I Study to Assess Safety and Tolerability of Adavosertib Plus Durvalumab in Patients with Advanced Solid Tumors.

Abstract

Adavosertib (AZD1775) is a small-molecule Wee1 inhibitor. Durvalumab is a PD-L1 inhibitor. The safety, tolerability, pharmacokinetics, and preliminary antitumor activity of adavosertib plus durvalumab were evaluated in patients with refractory solid tumors to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). This phase 1, non-randomized, open-label study determined MTD/RP2D using dose-escalation cohorts. Eligible patients had histologically confirmed tumors refractory to standard therapy or for which no standard of care existed. A total of 55 patients received adavosertib with durvalumab. Overall, 3/52 evaluable patients experienced dose-limiting toxicities (DLTs; two grade 3 nausea, one grade 3 diarrhea that did not respond to care within 48 h). The most frequent (in > 5% of patients) treatment-emergent grade ≥ 3 toxicities were fatigue, diarrhea, nausea, anemia, and abdominal pain. MTD for twice-daily (bid) adavosertib dosing was oral adavosertib 150 mg bid (3 days on/4 days off; treatment days 15-17 and 22-24 of a 28-day cycle) with intravenous durvalumab 1500 mg four times a week (Q4W), which was also the RP2D. MTD for once-daily (qd) adavosertib dosing was oral adavosertib 300 mg qd (5 days on/2 days off; treatment days 15-19 and 22-26 of a 28-day cycle) with intravenous durvalumab 1500 mg Q4W. This study defined the MTD/RP2D of adavosertib plus durvalumab in patients with advanced solid tumors. The safety profile of adavosertib with durvalumab was consistent with the known safety data of each agent. Findings provide preliminary evidence of limited antitumor activity of adavosertib plus durvalumab. ClinicalTrials.gov, NCT02617277 (registration: 30 November 2015).