In patients with metastatic EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), resistance to EGFR tyrosine kinase inhibitors (TKIs) arises from the T790M EGFR mutation in over half of cases; up-regulation of “bypass track” activity in non-EGFR signaling pathways is observed in other cases. Up-regulation of expression of the AXL tyrosine kinase has been observed in EGFRm NSCLC patients experiencing disease progression on erlotinib, and xenograft studies have supported the role of AXL inhibition in combination with EGFR TKI treatment in overcoming such resistance. DS-1205c is a novel, orally administered, specific small molecule inhibitor of AXL.
This is a multicenter, open-label, Phase 1, dose escalation and dose expansion study of DS-1205c in combination with osimertinib in metastatic or unresectable EGFR-mutant NSCLC subjects experiencing disease progression during treatment with erlotinib, gefitinib, or afatinib, and without T790M resistance mutation; or during treatment with osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression on erlotinib, gefitinib, afatinib, or osimertinib, and have at least one measurable lesion. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive DS-1205c during a run-in period, followed by combination treatment with DS-1205c and 80 mg daily of osimertinib. Escalation of DS-1205c dosing is guided by the modified Continuous Reassessment Method using a Bayesian logistic regression model following the escalation with overdose control principle. In Dose Expansion, subjects receive DS-1205c at the recommended dose for expansion (RDE) determined in Dose Escalation, in combination with 80 mg daily of osimertinib. Primary objectives are to determine safety, tolerability, and RDE of DS-1205c in combination with osimertinib. Secondary objectives are to assess pharmacokinetic parameters of DS-1205a (free form of DS-1205c), osimertinib, and osimertinib active metabolites, and to assess antitumor activity (RECIST v1.1). Retrospective analysis of AXL expression will be conducted using tumor tissue collected prior to study treatment. Enrollment opened in December 2017.
Clinical trial identification
Legal entity responsible for the study
Daiichi Sankyo, Inc.
Daiichi Sankyo, Inc.
D. Planchard: Advisory boards: AstraZeneca, Boehringer, BMS, Celgene, MSD, Novartis, Pfizer, Roche. P.A. Janne: Consultant: AstraZeneca, Boehringer Ingelheim, Pfizer, Merrimack Pharmaceuticals, Roche/Genentech, Chugai Pharmaceuticals, Acea Biosciences, Ignyta, Loxo Oncology, Ariad Pharmaceuticals, Eli Lilly Pharmaceuticals, Araxes Pharmaceuticals, Gatekeeper Pharmaceuticals; Research Funding: Astellas Pharmaceuticals, AstraZenenca, Daiichi Sankyo, Puma, Eli Lilly Pharmaceuticals, Boehringer Ingelheim. Patents, Royalties, Other intellectual property: LabCorp. H.A. Yu: Research funding to institution: AstraZeneca, Novartis, Daiichi, Pfizer; Consulting: AstraZeneca. D. Moro-Sibilot: Roche, Abbvie, Eli Lilly, Boehringer, BMS, MSD, Takeda, AstraZeneca. T. Goldberg, J. Li, J. McGill, C. Yu: Employee: Daiichi Sankyo, Inc. X. Gu, E. Slosberg: Employee and stockholder: Daiichi Sankyo.