A Phase 1 Study Of ARRY-520 With Bortezomib (BTZ) and Dexamethasone (dex) In Relapsed Or Refractory Multiple Myeloma (RRMM)
Authors: Chari Ajai , Htut Myo , Zonder Jeffrey , Fay Joseph W. , Jakubowiak Andrzej J , Harrison Beverly , Lau Kenneth , Hilder Brandi , Ptaszynski Ann , Rush Selena A , Kaufman Jonathan L. , Burt Steven Michael 
Published: October 2019

Abstract

Background
ARRY-520 is a novel KSP inhibitor with encouraging activity in patients (pts) with RRMM. In preclinical models, the activity of ARRY-520 is synergistic with BTZ, providing a rationale to combine these drugs in the clinic.

Methods
ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated dose of ARRY-520, BTZ and dex. Eligible pts have RRMM with ≥ 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent. ARRY-520 is administered intravenously (IV) on Days 1, 2, 15 and 16 (Schedule 1) or on Days 1 and 15 (Schedule 2); BTZ is administered IV or subcutaneously (SC) on Days 1, 8 and 15; and 40 mg oral dex, if applicable, is taken on Days 1, 8 and 15 in a 28-day cycle.

Results
A total of 41 pts have been treated to date at various dose levels of ARRY-520 and BTZ. Patients had a median of 5 prior regimens (range 2-10). All pts received a prior PI, 39 pts received prior BTZ, and 25 pts received at least 2 prior PI- including regimens (range 1-6).
In Schedule 1, the initial dose level of ARRY-520 (1.0 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was not tolerated, with dose-limiting toxicities (DLT) in 2/3 pts (pneumonia and pseudomonal sepsis). After a protocol amendment, dose escalation resumed at reduced doses of ARRY-520 (0.5 mg/m2/day) and BTZ (1.0 mg/m2/day) without dex. The addition of prophylactic filgrastim (G-CSF) enabled escalation to full dose ARRY-520 and BTZ (1.5 and 1.3 mg/m2/day, respectively). Only 1 DLT of pneumonia was observed during the further dose escalation, at 1.0 mg/m2/day ARRY-520 and 1.0 mg/m2/day BTZ. Dex has been added to the combination at 1.25 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ and this dose level has been well tolerated. Enrollment is ongoing in the final planned dose level.
In Schedule 2, the initial dose level of ARRY-520 (2.25 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was well tolerated and enrollment is ongoing at 3.0 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ + dex, the maximum planned dose of both drugs.
The most commonly reported adverse events (AEs) (in ≥ 15% of pts) include anemia, diarrhea, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, neutropenia, constipation, headache, fatigue, hyperuricemia, nausea, vomiting, and dizziness. All Grade 3 – 4 non-hematologic AEs have an incidence of < 10%. Based on the laboratory data, Grade 4 neutropenia was observed in 15% of patients, Grade 4 thrombocytopenia was observed in 10%. Apart from the one pt described above with the DLT of pseudomonal sepsis, no other febrile neutropenic events were reported. Neuropathy (Grade 2) was observed in 1 pt.
Monopolar spindles have been observed in a post-dose biopsy for a pt treated at 1.0 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, indicating that pharmacodynamic activity of ARRY-520 is maintained in the presence of full dose BTZ.
Preliminary signs of efficacy have been observed in this ongoing dose-escalation study. To date, among the subset of 13 evaluable pts who received doses at ≥ 1.25 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, 4 (31%) partial responses (PR) and 1 minimal response (MR) have been observed. By contrast, in the 27 patients receiving lower doses of ARRY-520 and BTZ, only 1 MR has been reported. An additional 29 pts experienced stable disease (SD) on ARRY-520 + weekly BTZ without the use of steroids (dex), including 17 pts with disease refractory to BTZ.

Conclusions
ARRY-520 + BTZ with prophylactic G-CSF appears well tolerated with manageable non-hematologic AEs in this heavily pretreated pt population and has demonstrated preliminary evidence of activity, including PRs and SD in pts with disease refractory to BTZ. These data support further exploration of this novel KSP inhibitor in combination with BTZ in expansion cohorts.
The authors would like to acknowledge the dedicated research staff and physicians at the participating centers of the Multiple Myeloma Research Consortium for their contribution to this study.

Disclosures:
Chari: Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: ARRY-520 is an investigational drug being combined with bortezomib in multiple myeloma. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Jakubowiak:Millenuim: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Kaufman:Millenium: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy; Janssen: Consultancy.