title: Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.
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).
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, TX, USA jcortes@mdanderson.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.affiliation: University of Michigan, Ann Arbor, MI, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Tufts Medical Center, Boston, MA, USA.
authors.forename: Hedy P
authors.initials: HP
authors.lastname: Smith
authors.affiliation: City of Hope Cancer Center, Duarte, CA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Snyder
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Khoury
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Pinilla-Ibarz
authors.affiliation: University of Chicago, IL, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Larson
authors.affiliation: Mitchell Pharmaceutical Consulting, Lafayette, CO, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mitchell
authors.affiliation: Deciphera Pharmaceuticals LLC, Waltham, MA, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wise
authors.affiliation: Deciphera Pharmaceuticals LLC, Waltham, MA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rutkoski
authors.affiliation: Deciphera Pharmaceuticals LLC, Waltham, MA, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Deciphera Pharmaceuticals LLC, Waltham, MA, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Flynn
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Deciphera Pharmaceuticals LLC, Waltham, MA, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rosen
authors.affiliation: UC Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C560099:DCC-2036; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D016044:Fusion Proteins, bcr-abl