Abstract 84P
Background
Debio 0123 is an investigational, orally bioavailable, highly selective, adenosine triphosphate (ATP)-competitive inhibitor of the WEE1 tyrosine kinase. WEE1 is a key regulator of cell cycle progression that influences entry into mitosis by modulating activity of cyclin-dependent kinase 1 (CDK1, also referred to as cell division cycle 2 [CDC2]). Inhibition of WEE1 presents an opportunity as a therapeutic strategy in cancer, either as monotherapy or in combination with other therapies1, by inducing a reduction of phosphorylated CDC2 (pCDC2) and driving cancer cells into mitotic catastrophe and apoptosis.
Methods
Debio 0123 is currently being tested in a phase I clinical trial, in combination with carboplatin. Debio 0123 is administered as monotherapy in the first cycle, and from cycle 2 onwards is given with the same schedule combined with carboplatin on D1 q21d. Pharmacokinetic (PK) samples and pharmacodynamic (PDy) markers are collected during the study to monitor the effect of increasing doses of Debio 0123 and to support the determination of the optimal recommended phase II dose. Baseline and on treatment biopsies were taken during cycle 1, prepared as formalin-fixed paraffin-embedded (FFPE) blocks, and pCDC2 was analyzed by immunohistochemistry.
Results
Here we present data on modulation of pCDC2 upon treatment with Debio 0123 and relationship with exposure to Debio 0123. Biopsies from patients across all dose levels were analyzed. Changes in pCDC2 are represented as a percentage due to variability of baseline measurements. A consistent signal reduction was seen from the 150 mg dose level, becoming more pronounced with increasing doses. A positive correlation could be made between Debio 0123 plasma exposure and pCDC2 reduction.
Conclusions
Overall, these data suggest target engagement by Debio 0123 from a dose of 150mg onwards when administered within 1st week of a 21d cycle, getting more pronounced at higher doses. Reference 1: Do K. et al., Cell Cycle. 2013 Oct 1;12(19):3159-64.
Clinical trial identification
NCT03968653.
Editorial acknowledgement
Legal entity responsible for the study
Debiopharm International SA.
Funding
Debiopharm International SA.
Disclosure
H. Gelderblom: Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Deciphera, Novartis, Boehringer Ingelheim, AmMax Bio, Debiopharm, Cytovation. N. Luong: Financial Interests, Institutional, Full or part-time Employment: Debiopharm. J.A. Gietema: Financial Interests, Institutional, Research Grant, Research grant paid to the institution UMCG: Roche, Siemens, AbbVie. M. Jalving: Financial Interests, Institutional, Advisory Board, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board, Advisory board: Merck. A. Bellon: Financial Interests, Institutional, Full or part-time Employment: Debiopharm. J. Nowakowska: Financial Interests, Institutional, Full or part-time Employment: Debiopharm. M. Jonnaert: Financial Interests, Institutional, Full or part-time Employment: Debiopharm. E. Rodrigo Imedio: Financial Interests, Institutional, Full or part-time Employment: Debiopharm. All other authors have declared no conflicts of interest.