630P - Debio 0123 + carboplatin (CP) for patients (pts) with advanced solid tumors: Safety, preliminary efficacy and determination of recommended phase II dose (RP2D)

Background

Cell cycle defects are common in cancer and cells rely on checkpoint proteins, such as WEE1, to avoid excess DNA damage. WEE1 inhibition abrogates S phase and G2-M checkpoints, leading to mitotic catastrophe and apoptosis. Debio 0123 is an oral, highly selective, brain-penetrant WEE1 inhibitor that has shown synergy with CP preclinically. Debio 0123-101 (NCT03968653) is a Phase 1 study evaluating Debio 0123 + CP. Arm A dose escalation (DE) data were reported at ASCO 2023; here, complete Debio 0123 DE and RP2D data are described.

Methods

Pts with advanced solid tumors recurring or progressing after platinum-based therapy were included. In Arm A, Debio 0123 was given as monotherapy in cycle (C) 1 (single dose on day [D] -3; qd over D1–3) and with CP from C2 (D1–3 q21d) until end of treatment (EOT). In Arm B, Debio 0123 was given with CP on D1–3 and D8–10, from C1 to EOT. CP AUC5 was given on D1 of each 21-day cycle in both arms.

Results

Data from both arms are reported. Overall, 55 pts (Arm A: 38; Arm B: 17) were treated (3 ongoing). Median pt age was 62 years, 82% were female, and median number of prior lines of systemic therapy was 3. The most common cancer was ovarian cancer (OC) (40%). Using a Bayesian logistic regression model-guided DE, Debio 0123 doses of 30–720 mg were tested. The maximum tolerated dose was declared at 520 mg (both arms). Based on overall safety, efficacy and PK/PD data, the RP2D was selected as 520 mg, with Arm B schedule. Overall, Debio 0123 was well-tolerated with manageable toxicity, in line with that expected for CP monotherapy. The most common related adverse events were thrombocytopenia, anaemia, fatigue, nausea, vomiting and QTc prolongation, mainly low grade. Of 48 evaluable pts, 7 had confirmed partial response (cPR) and 24 had stable disease (SD). Of 20 pts with OC, 6 had cPR and 11 had SD (one with 29% tumor shrinkage). Overall, median duration of response and progression-free survival were 8.5 (4.4–NR) and 5.5 months (3.4–6.6), respectively.

Conclusions

Debio 0123 + CP showed encouraging antitumor activity in heavily pretreated pts with solid tumors, with a manageable safety profile. An expansion cohort in platinum-resistant OC is ongoing.

Clinical trial identification

NCT03968653.

Editorial acknowledgement

Editorial assistance was provided by Dr Georgia Greaves of Cancer Communications and Consultancy Ltd (part of Bioscript Group).

Legal entity responsible for the study

Debiopharm International SA.

Funding

Debiopharm International SA.

Disclosure

H. Gelderblom: Financial Interests, Institutional, Local PI: Daiichi, Deciphera, Novartis, Cytovation; Financial Interests, Institutional, Coordinating PI: Boehringer Ingelheim, AmMax Bio, Debiopharm, Abbisko. M. Jalving: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Merck, Pierre Fabre. J.A. Gietema: Financial Interests, Institutional, Research grant paid to the institution UMCG: Roche, Siemens, AbbVie. R. Frederiksen Franzen: Financial Interests, Personal, Full or part-time Employment: Debiopharm International SA. S. Micallef, V. Dozio, A. Bellon, N. Luong: Financial Interests, Institutional, Full or part-time Employment: Debiopharm International S.A. T. Tat: Financial Interests, Institutional, Full or part-time Employment, Employed as statistician: Debiopharm. 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. All other authors have declared no conflicts of interest.