ABSTRACT
Background: The Wee1 tyrosine kinase is activated upon DNA damage and regulates the G2-M cell cycle checkpoint. Inhibition of Wee1, in conjunction with additional genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, being an attractive approach for treating cancer. Debio 0123 is a potent and highly specific WEE1 inhibitor with an IC50 in the low nanomolar range. Debio 0123 was demonstrated to inhibit phospho-CDC2 which translated into an increase in DNA damage and premature entry into mitosis (AACR 2019, abstract 4423). Debio 0123 combination with carboplatin (CbPt) was synergic in vitro. In vivo, Debio 0123 was demonstrated to increase antitumoral activity of cbPt in models where neither agent was active alone. Trial design: Methods This is a phase I, multi-center, open-label, dose escalation study of Debio 0123 as monotherapy (first cycle only) and in combination with CbPt, from cycle 2 in subjects with advanced solid tumors that recurred or progressed following prior platinum therapy. Primary objective: determination of the recommended phase II dose (RP2D) of Debio 0123 when administered in combination with CbPt using a modified Continual Reassessment Method (mCRM). Patients receive Debio 0123 orally once daily for the first 3 days of a 21 day-cycle as monotherapy during first cycle and in combination with CbPt in following cycles. Secondary objectives: includes determination of occurrence of dose-limiting toxicities (DLT) and characterization of the pharmacokinetics of Debio 0123 and its active metabolite, which are evaluated after single and repeated administration when administered alone or in combination with CbPt. Potential risk of QTc prolongation is evaluated by exposure-response modeling. Pharmacodynamics biomarkers including phospho-CDC2 are explored in pre- and post-treatment tumors and skin biopsies. Recruitment started in July 2019. Cohort 2 has been completed. Start of enrollment into cohort 3 is currently unknow due to COVID-19 but will begin as soon as possible. Clinical trial identification: NCT03968653. Legal entity responsible for the study: Debiopharm Interbational S.A. Funding: Debiopharm International S.A. Disclosure: V. Nicolas: Full/Part-time employment: Debiopharm AS. A. Vaslin: Full/Part-time employment: Debiopharm AS. K. Tobal: Full/Part-time employment: Debiopharm AS. D. Purcea: Full/Part-time employment: Debiopharm AS. S.F. van Haren: Full/Part-time employment: Debiopharm AS. L. Damstrup: Full/Part-time employment: Debiopharm International S.A. All other authors have declared no conflicts of interest.