Phase I trial of Debio 1143, an antagonist of inhibitor of apoptosis proteins, combined with cisplatin-chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head & neck

Purpose: Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins which enhances tumour response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally-advanced (LA)-SCCHN was evaluated in a phase I/II study to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Phase I results are reported. Experimental design: Treatment-naive LA-SCCHN patients (stages III/IVA/IVB) received Debio 1143 (100/200/300mg/day), for 14 days every-three-weeks (q3w), with cisplatin (100mg/m², q3w), three cycles, and concomitant conventional-fractionation radiotherapy (70Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment. Results: Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, all patients were current/former smokers. Primary tumours were hypopharynx, oropharynx (all HPV/p16-negative), larynx and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 AST/ALT increase, grade 4 febrile neutropenia; grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3-4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anaemia, WBC decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18-months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24-months was 74%. Conclusions: The RP2D of Debio 1143 is 200 mg/day for 14 days, q3w when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.