Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia

• Type of Material: Article
• Authors: Jorge Cortes, University of Texas MD Anderson Cancer Center; Moshe Talpaz, University of Michigan; Hedy P. Smith, Tufts University; David S. Snyder, City of Hope Cancer Center; H Jean Khoury, Emory University; Kapil N. Bhalla, University of Texas MD Anderson Cancer Center; Javier Pinilla-Ibarz, Moffitt Cancer Center and Research Institute; Richard Larson, University of Chicago; David Mitchell, Mitchell Pharmaceutical Consulting; Scott C. Wise, Deciphera Pharmaceuticals LLC; Thomas J. Rutkoski, Deciphera Pharmaceuticals LLC; Bryan D. Smith, Deciphera Pharmaceuticals LLC; Daniel L. Flynn, Deciphera Pharmaceuticals LLC; Hagop M. Kantarjian, University of Texas MD Anderson Cancer Center; Olivier Rosen, Deciphera Pharmaceuticals LLC; Richard A. Van Etten, UC Irvine Chao Family Comprehensive Cancer Center
• Language: English
• Date: 2017-03
• Publisher: Ferrata Storti Foundation
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2017 Ferrata Storti Foundation
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3324/haematol.2016.152710
• Title of Journal or Parent Work: Haematologica
• Volume: 102
• Issue: 3
• Start Page: 519
• End Page: 528
• Grant/Funding Information: The conduct of the study at MD Anderson Cancer Center was supported in part by MD Anderson Cancer Center Support Grant P30 CA016672 (PI: Dr. Ronald DePinho) and P01 CA049639 (PI: Dr. Richard Champlin); Studies at Tufts Medical Center were supported in part by R01 CA090576 (PI: Dr. Richard Van Etten).
• Keywords: rebastinib; chronic myeloid leukemia; acute myeloid leukemia; medication
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).