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

Jorge Cortes, Moshe Talpaz, Hedy P. Smith, David S. Snyder, Jean Khoury, Kapil N. Bhalla, Javier Pinilla-Ibarz, Richard Larson, David Mitchell, Scott C. Wise, Thomas J. Rutkoski, Bryan D. Smith, Daniel L. Flynn, Hagop M. Kantarjian, Oliver Rosen, Richard A. Van Etten

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Available 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.

Original languageEnglish (US)
Pages (from-to)519-528
Number of pages10
JournalHaematologica
Volume102
Issue number3
DOIs
StatePublished - Feb 28 2017

ASJC Scopus subject areas

  • Hematology

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    Cortes, J., Talpaz, M., Smith, H. P., Snyder, D. S., Khoury, J., Bhalla, K. N., Pinilla-Ibarz, J., Larson, R., Mitchell, D., Wise, S. C., Rutkoski, T. J., Smith, B. D., Flynn, D. L., Kantarjian, H. M., Rosen, O., & Van Etten, R. A. (2017). Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia. Haematologica, 102(3), 519-528. https://doi.org/10.3324/haematol.2016.152710