A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma

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.

Keywords: dexamethasone; filanesib. kinesin; maximum tolerated dose; multiple myeloma; pharmacokinetics; spindle poles.

Figure 1

Neutrophil and platelet values over time for Phase 2 patients with post-baseline abnormalities ≥ Grade 3. (A and B) Absolute neutrophil values in Phase 2-Filanesib and Phase 2 Filanesib/Dex, respectively. (C and D) Platelet values in Phase 2-Filanesib and Phase 2 Filanesib/Dex, respectively. Black stars indicate Day 1 dosing of each cycle. Gray lines represent thresholds for Grade 3 and Grade 4 values.

Figure 2

Geometric mean plasma concentrations for filanesib as a function of time following filanesib administration as a 1-hour infusion on Day 1 and Day 2 (vertical gray lines) of Cycle 1 (closed circles) and Cycle 2 (open boxes). Plots are shown for doses of 1, 1.25, 1.5, 1.75, 2, or 2.25 mg/m2/day. Error bars represent ± one geometric standard deviation.

Figure 3

(A) AAG vs Baseline ISS or Cytogenetics Status Box plots display median (Med) AAG levels. ANOVA was performed to test the differences in mean AAG in the 3 levels of ISS (p=0.062) or high/low risk cytogenetics (p=0.20). (B) Baseline LDH or beta-2 microglobulin (b2M) vs AAG Status. Box plots display median LDH or b2M levels. ANOVA was performed to test the differences in mean LDH (p=0.066) or mean b2M (p=0.15) by high/low risk patient AAG status.

Figure 4

(A) PFS and (B) OS in Phase 2. PFS is based on investigator assessment.