Background: Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity.
Patients and methods: This (NCT03604445) was a phase I, dose-escalation study evaluating BI 905677 for patients with advanced solid tumors over two dosing schedules (A: i.v. infusion every 3 weeks, 3-week cycles; B: i.v. infusion every 2 weeks, 4-week cycles). Adult patients were eligible if they had exhausted treatment options and had an Eastern Cooperative Oncology Group performance status of 0-1. The primary endpoints were the maximum tolerated dose (MTD) and safety. Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy.
Results: In total, 37 patients received BI 905677 over nine dose cohorts (0.05-3.6 mg/kg/every 3 weeks). Dose-limiting toxicities were only reported during cycle 1 in the 3.6 mg/kg cohort and the MTD was established at 2.8 mg/kg every 3 weeks. Enrollment for schedule B was not pursued. The most frequently reported adverse events were diarrhea (35.1%), vomiting (21.6%), and C-telopeptide increase (18.9%). All patients in the 3.6 mg/kg cohort experienced a dose-limiting toxicity, suggesting a narrow therapeutic index. Paired pre-treatment and on-treatment biopsies, where available, showed decreased Axin2 expression by reverse transcriptase polymerase chain reaction with treatment, suggesting target inhibition. Best response observed was stable disease in 14 (38%) patients.
Conclusion: The MTD of BI 905677 was set at 2.8 mg/kg every 3 weeks. BI 905677 was well tolerated but a narrow therapeutic range and minimal efficacy led to early termination of the trial.
Keywords: LRP5/6; Wnt; clinical trial; phase I; solid tumor.
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