A phase-1 trial of linsitinib (OSI-906) in combination with bortezomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

Abstract

We report results of a phase-1 study evaluating the safety and anti-cancer activity of the small molecule insulin-like growth factor-1 receptor (IGF-1R) inhibitor, linsitinib combined with bortezomib, and dexamethasone in relapsed/refractory multiple myeloma. Nineteen patients were enrolled across four dose-escalation cohorts (75–150 mg bid). The maximum tolerated dose of linsitinib was 125 mg. The most frequent Grade 3/4 AEs occurring in ≥10% of patients were thrombocytopenia (53%), bone pain (26%), neutropenia (21%), diarrhea (14%), anemia (14%), rash (10%), and lung infection (10%). Study discontinuation due to treatment-related AEs was low (16%). Across all cohorts the ORR was 61% (95% CI: 28.9–75.6%). Three partial response or greater and one stable disease were observed in proteasome inhibitor (PI) refractory patients (n = 5). Median PFS was 7.1 months (95% CI: 3.6–NA). Linsitinib plus bortezomib and dexamethasone demonstrate a manageable safety profile while the clinical benefit particularly in PI refractory patients warrants further exploration.

Keywords:

• Multiple myeloma
• linsitinib
• IGF-1R
• phase 1

Acknowledgements

EG is supported by the MMRC. This material was presented in part at the annual meetings of the American Society of Hematology 2015 and the International Myeloma Workshop 2015. We are grateful to the patients who participated in this study, the investigators and coordinators at the clinical sites, and the employees of Astellas Margaret Singh and MMRC including Daniel Auclair and Joan Levy.

Author contributions

SK contributed to data analysis and wrote the manuscript; DW, MG, RL, JK, AJ, EG HP, ZL data acquisition, data analysis and interpretation; LEL and AL contributed to the statistical design and analysis; ST designed the study, contributed to the acquisition of data, data analysis and interpretation; All authors were involved at each stage of manuscript preparation and approved the final version.

Disclosure statement

Honoria-BMS, Janssen, Takeda, Amgen, Sanofi, Karyopharm; Consultant-GlaxoSmithKine, BMS, Amgen Canada, Grants-Amgen, BMS, Pfizer, Genentech, GlaxoSmithKline, Janssen.

Additional information

Funding

This work was supported by Astellas and the Multiple Myeloma Research Consortium (MMRC).