A phase I dose-escalation study of LRP5/6 antagonist BI 905677 in patients with advanced solid tumors Journal Article
| Authors: | Lenz, H. J.; Argilés, G.; de Jonge, M. J. A.; Yaeger, R.; Doi, T.; El-Khoueiry, A.; Eskens, F.; Kuboki, Y.; Bertulis, J.; Nazabadioko, S.; Pronk, L.; Tabernero, J. |
| Article Title: | A phase I dose-escalation study of LRP5/6 antagonist BI 905677 in patients with advanced solid tumors |
| Abstract: | 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. © 2024 The Authors |
| Keywords: | signal transduction; adult; cancer chemotherapy; aged; middle aged; unclassified drug; major clinical study; clinical trial; advanced cancer; diarrhea; dose response; solid tumor; treatment duration; antineoplastic agents; antineoplastic agent; neoplasm; neoplasms; metabolism; cancer immunotherapy; reverse transcription polymerase chain reaction; skin biopsy; vomiting; local therapy; cohort analysis; antineoplastic activity; dose-response relationship, drug; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; hyponatremia; multicenter study; immunogenicity; hyperbilirubinemia; bone mass; maximum tolerated dose; phase 1 clinical trial; drug therapy; gamma glutamyltransferase; carboxy terminal telopeptide; pharmacokinetics; canonical wnt signaling; wnt; phase i; molecularly targeted therapy; low density lipoprotein receptor related protein 5; low density lipoprotein receptor related protein 6; humans; human; male; female; article; ecog performance status; lrp5/6; low density lipoprotein receptor-related protein-5; low density lipoprotein receptor-related protein-6; bi 905677; lrp5 protein, human; lrp6 protein, human |
| Journal Title: | ESMO Open |
| Volume: | 9 |
| Issue: | 11 |
| ISSN: | 2059-7029 |
| Publisher: | European Society for Medical Oncology |
| Date Published: | 2024-11-01 |
| Start Page: | 103729 |
| Language: | English |
| DOI: | 10.1016/j.esmoop.2024.103729 |
| PUBMED: | 39617530 |
| PROVIDER: | scopus |
| PMCID: | PMC11670700 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
