Debio 0123, a highly selective WEE1 inhibitor, combined with carboplatin (CP) and etoposide (ETOP) in patients (pts) with small cell lung cancer (SCLC) that progressed after platinum-based therapy: A phase I dose escalation and expansion study

BackgroundDebio 0123 is an oral, brain-penetrant, highly selective WEE1 inhibitor. WEE1 inhibition leads to S phase and G2/M cell cycle abrogation, allowing mitosis without DNA repair, leading to mitotic catastrophe and cell death. Debio 0123 is in clinical development, as monotherapy or in combination, in solid tumors, and has shown manageable safety profile with early signals of antitumor activity. SCLC is an aggressive disease with poor prognosis carrying a high mutational burden and genomic instability. Preclinically, Debio 0123 has shown to significantly improve antitumor activity of CP and ETOP, in SCLC models. These data support clinical investigation of Debio 0123 combined with CP and ETOP in SCLC.Trial designA phase I study (NCT05765812) evaluating Debio 0123 combined with CP and ETOP in pts with recurrent SCLC after 1st line of platinum-based chemotherapy. During dose escalation (part 1), pts who had a platinum chemotherapy-free interval (CFI)>45 days receive escalating doses of Debio 0123 combined with CP (AUC5) and ETOP (100 mg/m2) in 21-day cycles. Dose escalation is supported by a Bayesian logistic regression model with overdosing control (BLRM-EWOC). After dose escalation, expansion cohort(s) (Part 2) in pts with recurrent SCLC who had CFI>90 days, may be opened at different dose levels to define the optimal recommended dose (RD) for further development. The primary objectives of the study are to identify the RD, and to characterize the safety and tolerability of Debio 0123 combined with CP and ETOP. Secondary objectives include preliminary antitumor activity and pharmacokinetics. Brain penetration is assessed with CSF/plasma Debio 0123 concentration ratios. Key inclusion/exclusion criteria: recurrence or progression after 1st line with platinum-based chemotherapy CFI>45 (part 1) and CFI>90 (part 2), ECOG Performance Status 0-1, and measurable disease per RECIST 1.1. Prior 2nd line with lurbinectedin, and treated, stable brain metastasis are allowed. Enrolment started in May 2023 and as of May 2024, the fifth cohort is ongoing in Spain and the US.Clinical trial identificationEudraCT Number: 2022-001976-32; IND Number(s): 162 871; NCT05815160.Legal entity responsible for the studyDebiopharm International.FundingDebiopharm International.DisclosureV. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer Ingelheim Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. A.F. Navarro Mendivil: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Oryzon Genomics, Amgen, Hengenix Biotech, MedSIR, BMS; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Pfizer, Takeda, Tecnofarma; Non-Financial Interests, Principal Investigator: BMS, PharmaMar, MSD, Amgen, Novartis, Debiopharm, Daiichi Sankyo, Roche, AstraZeneca. P. Jain: Financial Interests, Institutional, Other, Institutional Principal investigator: Harpoon Therapeutics; Financial Interests, Institutional, Other, Principal Investigator: Debiopharm; Financial Interests, Institutional, Other, Site Principal Investigator: Iovance Biotherapeutics, AADi Bioscience, SOPHiA Genetics, Sanofi; Financial Interests, Institutional, Other, Site Principal investigator: Johnson & Johnson; Financial Interests, Institutional, Local PI: Harpoon Therapeutics, Iovance Biotherapeutics, AADi Bioscience, SOPHiA Genetics, Sanofi, Johnson & Johnson; Financial Interests, Institutional, Coordinating PI: Debiopharm; Non-Financial Interests, Advisory Role: G1 Therapeutics; Non-Financial Interests, Other, Invited speaker: American Lung Association. G. Fernandez-Hinojal: Financial Interests, Personal, Invited Speaker, Talk on NSCLC management: GSK; Financial Interests, Personal, Advisory Board: MSD. M. De Miguel: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. J. Zugazagoitia: Financial Interests, Personal, Invited Speaker: Takeda, BMS, AstraZeneca, NanoString, Guardant Health; Financial Interests, Personal, Advisory Board: Roche, Sanofi, BMS, Pfizer, Novartis; Financial Interests, Personal and Institutional, Funding, Research Grant: AstraZeneca, Roche, BMS. S. Gadgeel: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Genentech/Roche, Bristol Myers Squibb, Pfizer, Daiichi, Mirati, Lilly, Merck, Eisai, Gilead, Regeneron, Takeda, Bayer; Financial Interests, Personal, Other, Data Safety Monitoring Board: AstraZeneca; Financial Interests, Personal, Other, Travel support to attend WCLC 2023 for oral presentation: Mirati, Merck; Financial Interests, Institutional, Local PI: AstraZeneca, Nuvalent, Tango Pharmaceuticals, Genentech/Roche, Genmab, Nimbus, Daiichi, Janssen, Amgen, Bayer, Mirati, BioAtla, Pfizer, D3 Bio, Debio Pharma, Arrivent, Grail, Iovance, Jacobio, Kymera, Keza Pharmaceuticals, AbbVie, Amgen, Novita, Regeneron, Turning Point, Verastem; Financial Interests, Institutional, Steering Committee Member: Genmab; Financial Interests, Personal, Local PI: Arcus, Effector. A. Vilalta: Financial Interests, Personal, Invited Speaker: AstraZeneca, Health in code. E. Castanon Alvarez: Financial Interests, Personal, Advisory Board: MSD, Roche, BMS, Pfizer; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Principal Investigator: AZ, BMS, Roche, MSD, GSK, ARC, Ascendis, Sanofi. P.F. Simoes da Rocha: Other, Congress and travel: MSD, BMS, AstraZeneca, Kyowa Kirin. S. Micallef, L. Piggott: Financial Interests, Personal, Full or part-time Employment: Debiopharm International. R. Frederiksen Franzen: Financial Interests, Personal, Full or part-time Employment: Debiopharm International SA. A. Bellon: Financial Interests, Institutional, Full or part-time Employment: Debiopharm International S.A. E. Rodrigo Imedio: Financial Interests, Personal, Full or part-time Employment: Debiopharm International; Non-Financial Interests, Other, Full time employee: Debiopharm International; Non-Financial Interests, Member: SEOM, ASCO. L.G. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, Beigene, Daiichi, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati, Boehringer; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Personal, Other, lectures: AICME; Financial Interests, Personal, Other, Lectures: CCO; Financial Interests, Personal, Member of Board of Directors, Board member: Stab Therapeutics; Financial Interests, Personal, Other, spinn off (I have arounfd 8% of stocks): Altum sequencing; Financial Interests, Personal, Ownership Interest, spin-off (10%): Stab Therapeutics; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, NOvartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President.ASEICA( Spanish Association of CancerResearch ): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group; Non-Financial Interests, Other, Board member of this anti-cancer Charity: AECC; Non-Financial Interests, Member, Past-President: ASEICA (Spanish Cancer Research Association); Non-Financial Interests, Leadership Role, President: Oncosur Foundation. All other authors have declared no conflicts of interest.