A Phase 1 Dose-Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients With Recurrent/ Refractory Multiple Myeloma

• Type of Material: Article
• Authors: Ajai Chari, Icahn School of Medicine at Mount Sinai; Myo Htut, City Hope National Medical Center; Jeffrey A. Zonder, Wayne State University; Joseph W. Fay, Baylor Research Institute; Andrzej Jakubowiak, University of Chicago; Joan B. Levy, Multiple Myeloma Research Consortium; Kenneth Lau, Icahn School of Medicine at Mount Sinai; Steven M. Burt, Wayne State University; Brian J. Tunquist, Array BioPharma Inc; Brandi W. Hilder, Array BioPharma Inc; Selena A. Rush, Array BioPharma Inc; Duncan H. Walker, Array BioPharma Inc; Mieke Ptaszynski, Array BioPharma Inc; Jonathan Kaufman, Emory University
• Language: English
• Date: 2016-11-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Cancer Society
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.30174
• Title of Journal or Parent Work: Cancer
• Volume: 122
• Issue: 21
• Start Page: 3327
• End Page: 3335
• Grant/Funding Information: Funded by Array BioPharma Inc. Biostatistics support was provided by Roger Aitchison (Array BioPharma Inc).; Lindsey Lozano, a medical writer supported by funding from Array BioPharma Inc, provided drafts and editorial assistance to the authors during the preparation of this article.; Statistical programming was performed by Jennifer Regensburger (Array BioPharma Inc)
• Keywords: proteasome inhibitors; MCL-1; dexamethasone; bortezomib; Life Sciences & Biomedicine; recurrent/refractory; CELLS; neoplasm recurrence; filanesib; Oncology; multiple myeloma; SURVIVAL; RISK; Science & Technology; PROTEIN
• Research Categories: Health Sciences, Oncology

Abstract

BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2/day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2/day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2/day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;122:3327–3335.