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1860 ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study 

Program: Oral and Poster Abstracts
Session: 653. Myeloma - Therapy, excluding Transplantation: Poster I
Saturday, December 10, 2011, 5:30 PM-7:30 PM
Hall GH (San Diego Convention Center)

Jatin J Shah, MD1, Jeffrey Zonder, MD2, Adam Cohen3*, Robert Z. Orlowski, MD, PhD4, Raymond Alexanian, M.D.5, Sheeba K Thomas, M.D.5, Donna Weber, MD6, Jonathan L. Kaufman, MD7, R. Donald Harvey, PharmD8, Duncan Walker, PhD9*, Kevin Litwiler, PhD10*, Sharon Karan10*, Brandi Hilder9*, Ann Marie Ptaszynski, MD9* and Sagar Lonial, MD11

1Lymphoma/Myeloma, UT MD Anderson Cancer Center, Houston, TX
2Karmanos Cancer Institute Wayne State University , Detroit, MI
3Fox Chase Cancer Center, Philadelphia, PA
4University of Texas M. D. Anderson Cancer Center, Houston, TX
5Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX
6M.D. Anderson Cancer Center, University of Texas, Houston, TX
7Winship Cancer Institute of Emory University, Atlanta, GA
8Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
9Array BioPharma, Boulder, CO
10Clinical Pharmacology, Array BioPharma, Boulder, CO
11Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA

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 induction of apoptosis due to degradation of survival signals during mitotic arrest. Cancers, such as multiple myeloma (MM), that depend on the short-lived survival protein Myeloid cell leukemia (MCL)-1 are highly sensitive to treatment with ARRY‑520 in preclinical MM models, providing a strong rationale for its clinical investigation in this disease


Methods: This Phase 1 study was designed to evaluate the safety, pharmacokinetics (PK), preliminary efficacy and biological activity of ARRY‑520 administered intravenously on Days 1 and 2 every 2 weeks without/with granulocyte colony-stimulating factor (G‑CSF) support. Eligible patients (pts) had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both bortezomib [BTZ] and an immunomodulatory [IMiD] agent), unless refusing or ineligible for this therapy. Cohorts were enrolled in a classical 3+3 dose escalation design.


Results: Enrollment in this Phase 1 study is complete. Thirty-one pts have been treated, with a median age of 60 years (range 43-79) and a median of 6 prior regimens (range 2‑16). All pts received a prior proteasome inhibitor (30 pts BTZ, 4 pts carfilzomib) and an IMiD-based agent (28 pts lenalidomide, 23 pts thalidomide). Twenty-four pts had an autologous stem cell transplant.

The maximum tolerated dose (MTD) was determined to be 1.25 mg/m2/day without G‑CSF. As neutropenia was the dose-limiting toxicity (DLT), dose escalation with G‑CSF support was conducted and the MTD for ARRY‑520 with G‑CSF was determined to be 1.5 mg/m2/day. At the MTD, 1 of 7 pts had a DLT of febrile neutropenia. At doses above the MTD, additional DLTs of Grade 3 mucositis and Grade 3 corneal disorder were observed.

ARRY-520 demonstrated an acceptable safety profile. The most commonly reported treatment-related adverse events (AEs) included hematologic events (anemia, leukopenia, neutropenia, thrombocytopenia), as well as anorexia, blurred vision, diarrhea, dizziness, fatigue, febrile neutropenia, mucositis, nausea and rash. No treatment-related AEs of neuropathy or alopecia were reported at the MTD. ARRY‑520 has been dosed over extended periods of time (to date, median 7 cycles [range 1‑44]), with no evidence of cumulative toxicity.

The plasma concentrations of ARRY-520 were determined over a 7‑day period during Cycle 1 following the Day 1 and 2 infusions of ARRY‑520. The preliminary noncompartmental PK parameter estimates in this population were similar to those observed in prior oncology studies. The PK was characterized by low clearance (CL = 2.2 L/hr/m2) and a large volume of distribution (Vss = 232 L/m2). The t1/2 of elimination was very long (67 hrs). Concentrations were typically maintained above the in vitro IC50 for KSP inhibition for ≥ 7 days suggesting therapeutically active concentrations of drug were maintained in pts for sustained periods. Further analyses of PK relative to safety and activity are on-going.

ARRY-520 showed activity as a single agent across a range of doses in this heavily pretreated population (31 evaluable pts) with 3 confirmed partial responses (PR) and 1 confirmed minimal response (MR) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 7 prior therapies (range 2‑8). Responses were durable; to date, the durations of responses for PRs were 3.4+ months (mos), 11.9+ mos and 12.0 mos, respectively. Of interest, the time to response with ARRY‑520 was prolonged, with a median time to PR of 3.7 mos (range 3.7-8.1). Notably, responses were observed in pts refractory to multiple standard-of-care agents. In addition, 4 pts experienced a best response of stable disease (SD) lasting ≥ 10 mos. To date, 5 pts remain on study, including 2 of 3 PRs.


Conclusions: In this Phase 1 study, ARRY-520 shows promising evidence of clinical activity, with a long duration of response and an acceptable safety profile in heavily pretreated MM Patients. A Phase 2 portion of the study is ongoing to obtain additional information on the efficacy, safety and biological effects of ARRY‑520 at 1.5 mg/m2/day with G-CSF support.

Disclosures: Shah: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding. Off Label Use: ARRY-520. Zonder: Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Cohen: Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. 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. Kaufman: Keryx: Consultancy; Celgene: Research Funding; Merck: Research Funding. Walker: Array BioPharma: Employment, Equity Ownership. Litwiler: Array BioPharma: Employment. Karan: Array BioPharma: Employment. Hilder: a: Employment. Ptaszynski: Array BioPharma Inc.: Consultancy. Lonial: Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

*signifies non-member of ASH