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Poster session 01

84P - Pharmacodynamic marker modulation of the selective WEE1 inhibitor Debio 0123 in patient biopsies from phase I clinical trial

Date

10 Sep 2022

Session

Poster session 01

Topics

Clinical Research

Tumour Site

Presenters

Hans Gelderblom

Citation

Annals of Oncology (2022) 33 (suppl_7): S27-S54. 10.1016/annonc/annonc1037

Authors

H. Gelderblom1, N. Luong2, J.A. Gietema3, I. Desar4, O. Saavedra5, M. Jalving3, J.R. Kroep6, A. Bellon2, J. Nowakowska2, M. Jonnaert7, E. Rodrigo Imedio7

Author affiliations

  • 1 Medical Oncology Dept, LUMC - Leids Universitair Medisch Centrum, 2300 RC - Leiden/NL
  • 2 Translational Medicine Department, Debiopharm International S.A., 1002 - Lausanne/CH
  • 3 Medical Oncology Department, UMCG - University Medical Center Groningen, 9700 RB - Groningen/NL
  • 4 Medical Oncology Dept., Radboud University Medical Center, Nijmegen, 6525 GA - Nijmegen/NL
  • 5 Medical Oncology Department, Vall d'Hebron University Hospital, 8035 - Barcelona/ES
  • 6 Medical Oncology Department, LUMC - Leids Universitair Medisch Centrum, 2300 RC - Leiden/NL
  • 7 Oncology Global Clinical Development Department, Debiopharm International S.A., 1002 - Lausanne/CH
More

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.

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