Debio 0123, a WEE1 kinase inhibitor: Phase 1 results from dose escalation in patients with advanced solid tumors.

PURPOSE: The DNA damage-activated G2/M and S phase cell cycle checkpoint regulator WEE1 kinase is an attractive therapeutic target for solid tumors. We report the results of the dose escalation part of a phase 1 trial assessing the WEE1 inhibitor Debio 0123.

PATIENTS AND

METHODS

The study enrolled patients with relapsed/refractory advanced solid tumors. Debio 0123 was given orally, once daily. Safety, preliminary antitumor activity, pharmacokinetics, and pharmacodynamics were assessed.

RESULTS

Twenty-seven patients were treated with Debio 0123 at doses ranging from 30 to 350 mg. Any grade treatment-related adverse events (TRAEs) were experienced by 92.6% of patients. The most frequent events were increased blood creatinine and QT interval corrected using Fridericia's formula (QTcF) prolongation (37% each). Grade 3 TRAEs were experienced by 33.3% of patients; QTcF prolongation (11%, only observed at 350 mg) and fatigue (7%) were the most common. The maximum tolerated dose and recommended phase 2 dose of Debio 0123 was 260 mg once daily. Proportional pharmacokinetics were seen up to 350 mg, the highest dose level tested. In paired skin biopsies, decreased phosphorylation of the WEE1 target CDC2 was consistently observed at doses ≥200 mg. Exploratory analysis of efficacy showed eight patients (32%) with stable disease as best response, including 5 tumor regressions (up to 20%).

CONCLUSIONS

Debio 0123 demonstrated a manageable toxicity profile, exhibited linear pharmacokinetics and showed target engagement at doses ≥200 mg. Given the response observed in a subset of this heavily pre-treated population, results support further investigation of Debio 0123 in selected indications.