The Novel KSP Inhibitor ARRY-520 Demonstrates Single-Agent Activity in Refractory Myeloma: Results From a Phase 2 Trial in Patients with Relapsed/Refractory Multiple Myeloma (MM)
Authors: Lonial Sagar , Cohen Adam , Zonder Jeffrey , Benzinger William I , Kaufman Jonathan L. , Orlowski Robert Z. , Harvey R. Donald , Alexanian Raymond , Thomas Sheeba K , Weber Donna , Walker Duncan , Hilder Brandi , Ptaszynski Ann , Shah Jatin J 
Published: October 2019

Abstract 2935

Background:

ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent onset of apoptosis due to degradation of survival signals during mitotic arrest. While immunomodulators [IMiDs] and proteasome inhibitors have improved outcomes in MM, patients with MM that is refractory to both bortezomib (BTZ) and thalidomide (THAL) or lenalidomide (LEN) have a poor prognosis with median survival of 9 months. Since ARRY-520 is a novel agent with a unique mechanism of action (MOA) relative to current standard-of-care (SOC) agents, it might be expected to show activity in patients refractory to other drugs. Preclinically, ARRY-520 showed activity in BTZ-refractory models, suggesting prior treatments may not predict patient response to ARRY-520.

Methods:

This Phase 2 study was designed to evaluate the efficacy, safety and biological effects of 1.5 mg/m2/day ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both BTZ and an IMiD), unless refusing or ineligible for this therapy.

Results:

Thirty-two patients have been treated, with a median age of 65 years (range 51–82) and a median of 5 prior regimens (n = 31; range 2–20). Twenty-eight patients received prior BTZ, 28 patients prior LEN, 17 patients prior THAL and 25 patients had an autologous stem cell transplant. One patient has been lost to follow-up.

ARRY-520 demonstrated an acceptable safety profile, confirming the safety profile observed in the Phase 1 study. The most commonly reported (≥ 10% of patients) treatment-related adverse events (AEs) included hematologic events such as anemia (11 patients [34%], 4 Grade 3/4 [12%]), neutropenia (11 patients [34%], 9 Grade 3/4 [28%]) and thrombocytopenia (20 patients [63%], 11 Grade 3/4 [34%]), as well as fatigue (4 patients [16%], 2 Grade 1/2 and 2 Grade 3) and mucositis (4 patients [13%], all Grade 1/2). No treatment-related events of alopecia or neuropathy were reported. One patient discontinued study due to a treatment-related AE of blisters.

ARRY-520 has shown preliminary activity as a single agent in this heavily pretreated population. To date, of 32 evaluable patients, 3 confirmed partial responses (PR) and 2 confirmed minimal responses (MR) have been observed, per International Myeloma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 5 prior therapies (range 2–8). As observed in the Phase 1 study, the time to response with ARRY-520 was prolonged. Notably, clinical responses have been observed in this study in patients refractory to both LEN and BTZ. To date, in this ongoing study 33% (5/15) of patients with disease refractory to both LEN and BTZ achieved clinical benefit (PR + MR + SD > 4 months). While this trial has been fully recruited, as of July 2011, 8 patients remain on study.

Conclusions:

ARRY-520 is a novel agent with a differentiated MOA relative to other myeloma drugs. ARRY-520 shows promising evidence of single-agent clinical activity and an acceptable safety profile in heavily pretreated patients with MM. Notably, ARRY-520 has demonstrated activity in patients refractory to both LEN and BTZ, a population with limited treatment options. An expansion cohort is planned in order to evaluate the safety and efficacy of ARRY-520 in combination with dexamethasone in patients who are refractory to their last myeloma treatment and refractory to prior LEN, BTZ and dexamethasone.

Disclosures:

Lonial: Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy. Off Label Use: ARRY-520. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Benzinger:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Shah:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding.