A Phase 1 and 2 Study of Filanesib Alone and in Combination With Low-Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma

• Type of Material: Article
• Authors: Jatin J. Shah, University of Texas MD Anderson Cancer Center; Jonathan Kaufman, Emory University; Jeffrey A. Zonder, Wayne State University; Adam D. Cohen, Fox Chase Cancer Center; William I. Bensinger, Fred Hutchinson Cancer Research Center; Brandi Hilder, Array BioPharma Inc; Selena Rush, Array BioPharma Inc; Duncan Walker, Array BioPharma Inc; Brian Tunquist, Array BioPharma Inc; Kevin Litwiler, Array BioPharma Inc; Mieke Ptaszynski, Array BioPharma Inc; Robert Z. Orlowski, University of Texas MD Anderson Cancer Center; Sagar Lonial, Emory University
• Language: English
• Date: 2017-12-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 American Cancer Society
• Final Published Version (URL): http://dx.doi.org/10.1002/cncr.30892
• Title of Journal or Parent Work: Cancer
• ISSN: 0008-543X
• Volume: 123
• Issue: 23
• Start Page: 4617
• End Page: 4630
• Grant/Funding Information: Statistical programming was performed by Jennifer Regensburger (Array BioPharma Inc.).; This study was funded by Array BioPharma Inc. Biostatistics support was provided by Roger Aitchison (Array BioPharma Inc.).; Grant : NIH/NCI P30 CA16672.; Catriona Byrne, Christopher Tennant and Anthony Maine, medical writers supported by funding from Array BioPharma Inc., provided drafts and editorial assistance to the authors during the preparation of this manuscript.
• Keywords: spindle poles; ALPHA-1-ACID GLYCOPROTEIN; MCL-1; kinesin; filanesib; BORTEZOMIB; multiple myeloma; dexamethasone; SPINDLE PROTEIN INHIBITOR; Science & Technology; CELLS; TRIAL; Life Sciences & Biomedicine; Oncology; maximum tolerated dose; pharmacokinetics; PHOSPHORYLATION; SURVIVAL; ARRY-520
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide. Patients in the Phase 2 Filanesib plus dexamethasone cohort (N = 55) had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout Phase 2. RESULTS: Patients in each cohort had received a median of ≥6 prior therapies. The most common dose-limiting toxicities were febrile neutropenia and mucosal inflammation. In Phase 2, Grade 3 and 4 cytopenias were reported in approximately 50% of patients. Nonhematologic toxicities were infrequent. Phase 2 response rates (partial responses or better) were 16% (single agent) and 15% (Filanesib plus dexamethasone). All responding patients had low baseline levels of α1-acid glycoprotein, a potential selective biomarker. CONCLUSIONS: Filanesib 1.50 mg/m2/day administered with prophylactic filgrastim has a manageable safety profile and encouraging activity in heavily pretreated patients This study is registered at www.clinicaltrials.gov as NCT00821249. Cancer 2017;123:4617-4630. © 2017 American Cancer Society.