Document Type
Article
Publication Date
11-1-2024
Abstract
BACKGROUND: The Wnt pathway is involved in proliferation and tissue homeostasis. Aberrant activation promotes cancer cell proliferation and survival. Inhibition of the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) coreceptors that regulate Wnt signaling could prevent cancer cell proliferation. BI 905681 is a novel LRP5 antagonist that has demonstrated potent in vivo antitumor activity.
PATIENTS AND METHODS: This was a phase I, dose escalation study (NCT04147247) evaluating BI 905681 in patients with advanced solid tumors over two dosing schedules (schedule A: every 3 weeks, 3-week cycles and schedule B: every 2 weeks, 4-week cycles). The primary endpoint was the maximum tolerated dose (MTD) of BI 905681 and the number of patients experiencing adverse events (AEs). Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy.
RESULTS: As a result of difficulties enrolling patients, the trial was terminated early and the MTD for schedule A could not be determined. Twenty-one patients received BI 905681 over five dose cohorts (schedule A: 1.0, 2.5, 5.0, 7.0, and 8.5 mg/kg). No patients received schedule B. No dose-limiting toxicities (DLTs) were reported during the MTD evaluation period. However, during the entire treatment period, two patients (9.5%) experienced a DLT of grade 1 C-telopeptide increase in the 5.0 and 8.5 mg/kg dose cohorts. The most frequent treatment-related AEs were diarrhea (23.8%), vomiting (23.8%), nausea (19.0%), and infusion-related reactions (IRRs; 14.3%). Despite premedication to mitigate IRRs, one patient experienced a grade 2 IRR. The pharmacokinetic profiles of BI 905681 were biphasic, with a rapid distribution phase in the beginning followed by a slower elimination phase. The objective response rate was 0%; 5 (23.8%) and 14 patients (66.7%) had a best overall response of stable disease and progressive disease, respectively.
CONCLUSION: BI 905681 has minimal efficacy in an unselected patient population and was generally well tolerated.
Recommended Citation
Spigel, D. R.; Wang, J. S.; Pronk, L.; Muskens, B.; Teufel, M.; Bashir, Babar; and Burris, H., "A Phase I Dose Escalation Study of the LRP5 Antagonist BI 905681 in Patients with Advanced and Metastatic Solid Tumors" (2024). Department of Medical Oncology Faculty Papers. Paper 280.
https://jdc.jefferson.edu/medoncfp/280
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
39617535
Language
English
Comments
This article is the author's final published version in ESMO Open, Volume 9, Issue 11, November 2024, Article number 103730.
The published version is available at https://doi.org/10.1016/j.esmoop.2024.103730.
Copyright © 2024 The Authors.