A phase I dose escalation study of the LRP5 antagonist BI 905681 in patients with advanced and metastatic solid
D R Spigel1, J S Wang2, L Pronk3
1Sarah Cannon Research Institute, Nashville.
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.
Insights
BI 905681, an LRP5 antagonist, showed minimal efficacy in advanced solid tumors. The drug was generally well tolerated, but the trial terminated early, preventing MTD determination.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- The Wnt pathway regulates cell proliferation and tissue homeostasis.
- Aberrant Wnt signaling drives cancer progression.
- Inhibiting LRP5/6 coreceptors is a potential anti-cancer strategy.
Purpose of the Study:
- To evaluate the safety and tolerability of BI 905681, a novel LRP5 antagonist.
- To determine the maximum tolerated dose (MTD) of BI 905681 in patients with advanced solid tumors.
- To assess the pharmacokinetics, pharmacodynamics, and efficacy of BI 905681.
Main Methods:
- Phase I, dose escalation study (NCT04147247) with two dosing schedules.
- 21 patients received BI 905681 across five dose cohorts on schedule A.
- Primary endpoints: MTD and adverse events; secondary endpoints: PK, PD, and efficacy.
Main Results:
- Trial terminated early due to enrollment difficulties; MTD not determined.
- Two patients (9.5%) experienced dose-limiting toxicities (C-telopeptide increase).
- Most frequent AEs: diarrhea, vomiting, nausea, and infusion-related reactions. Objective response rate was 0%.
Conclusions:
- BI 905681 demonstrated minimal efficacy in an unselected patient population.
- The drug was generally well tolerated.
- Further investigation may be needed in specific patient populations or combinations.
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