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Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer-Lack of
Andreas Schneeweiss1, Dagmar Hess2, Markus Joerger2
1National Center for Tumor Diseases, University Hospital Heidelberg and German Cancer Research Center, 69120 Heidelberg, Germany.
Abstract:
This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the AKT1 mutation, was performed at the recommended phase 2 dose (R2D) of 60 mg BID. Dose-limiting toxicities (Grades 3-4) were increased in transaminases, γ-glutamyltransferase (γ-GT), and alkaline phosphatase in four patients in both schedules and stomach pain in one patient. Of the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. AKT1 mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity.
Insights
BAY 1125976, an AKT1/2 inhibitor, was evaluated for safety and efficacy in advanced solid tumors. While well-tolerated, it showed limited clinical benefit, highlighting the need for better biomarkers for AKT inhibitor therapy.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- AKT signaling pathway is crucial in cancer cell growth.
- AKT inhibitors are a potential therapeutic strategy for various cancers.
Purpose of the Study:
- Evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976.
- Assess the efficacy of BAY 1125976 in patients with advanced solid tumors, including breast cancer.
- Investigate the role of AKT1 mutations in treatment response.
Main Methods:
- Open-label, Phase I first-in-human study.
- Oral dose escalation (QD and BID schedules).
- Dose expansion cohort in hormone receptor-positive metastatic breast cancer patients.
Main Results:
- BAY 1125976 was generally well-tolerated.
- Dose-limiting toxicities included elevated transaminases and gastrointestinal issues.
- Limited tumor response observed; clinical benefit rate of 27.9% at the recommended phase 2 dose.
- AKT1 mutation status did not correlate with tumor response.
Conclusions:
- BAY 1125976 inhibits AKT1/2 signaling but did not demonstrate significant clinical activity as monotherapy.
- Further research is needed to identify predictive biomarkers for AKT inhibitor efficacy.
- Biomarker refinement is essential to improve patient selection and therapeutic outcomes for AKT inhibitors.
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