ALBERT

Description: Abstract 1860 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.

Description: Abstract 4082 Background: ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim. Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway. Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial. In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations. An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions: The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 449 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that arrests cells in mitosis and induces apoptosis due to degradation of the BCL2 family survival protein MCL-1. As previously reported, ARRY-520 has demonstrated single-agent activity in relapsed and refractory multiple myeloma (RRMM). In preclinical myeloma models, the addition of dexamethasone (Dex) increases the activity of ARRY-520, supporting clinical investigation of ARRY-520 combined with low-dose Dex (LoDex). Here, the efficacy and safety of ARRY-520 is compared in 2 Phase 2 cohorts in RRMM: as a single agent (Cohort 1) and in combination with LoDex (Cohort 2). Methods Both cohorts were designed as 2-stage single-arm Phase 2 studies. Cohort 1 evaluated the efficacy and safety of 1.5 mg/m2/d ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with prophylactic granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had RRMM with 2 prior lines of therapy that included both bortezomib (BTZ) and an immunomodulatory agent (IMiD), unless refusing or ineligible for this therapy. Cohort 2 is evaluating the efficacy and safety of the same dose and schedule of ARRY-520 and G-CSF with LoDex (40 mg PO weekly). Eligible patients had RRMM with 2 prior lines of therapy, and had disease refractory to (progressed on or ≤ 60 days of treatment) their last line of therapy and that was refractory to BTZ, lenalidomide (Len) and dexamethasone. Data from Cohort 1 and the first stage of Cohort 2 are reported. Results At the time of data cutoff, a total of 32 patients were enrolled into Cohort 1 with a median age of 65 years (range 51–82) and a median of 6 prior regimens (range 2–19). All patients received prior IMiD, 90% received prior BTZ and 78% had prior autologous stem cell transplant (ASCT). The defined first stage of Cohort 2 has been enrolled with 18 evaluable patients. These patients had a median age of 67 years (range 53–78) and were more heavily pretreated, with a median of 10 prior therapies (range 5–13). Safety was similar for both cohorts. A possible trend for more infections in Cohort 2 was noted. The most commonly reported (20% of patients) treatment-related adverse events (AEs) in both cohorts included thrombocytopenia, anemia, neutropenia and fatigue. No treatment-related events of neuropathy were observed in either cohort. The most common Gr 3/4 AEs (in Cohort 1, Cohort 2) included neutropenia (38%, 33%), thrombocytopenia (44%, 44%) anemia (28%, 50%), pneumonia (3%, 17%) and fatigue (16%, 11%). Treatment discontinuations due to AEs were infrequent (9%, 11%). Of 32 patients in Cohort 1, confirmed responses (≥ Minor Response (MR)) were observed in 6 patients (19%) with 5 Partial responses (PR) (16%) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria. The median treatment time was 2.1 months. In the subset of patients with disease refractory to both BTZ and Len, a 15% overall response rate (ORR ≥ MR) was observed. Among the 18 evaluable patients in Cohort 2, the ORR (≥ MR) was 28% (5/18), with 4 patients ≥ PR (22%). At the time of data cutoff, the median treatment time was 3.9 months. Summary Patients with RRMM refractory to both IMiD and proteasome inhibitor therapy have a poor prognosis with median survival of as little as 6 months1. New drugs with clinically meaningful activity in this population are needed. ARRY-520 is a novel agent with a distinct mechanism of action relative to other myeloma drugs and shows promising clinical activity both alone and combined with Dex in RRMM. Notably, in patients with triple-refractory MM, ARRY-520 + LoDex has shown a preliminary 28% ORR (≥ MR), with a manageable safety profile. These data are comparable to those reported for pomalidomide or carfilzomib in less heavily pretreated patients. Both the median time on study and ORR in Cohort 2 were greater than the activity seen for Cohort 1, despite the more advanced stage of these patients and the fact that they were heavily pretreated with Dex, suggesting that LoDex may enhance ARRY-520 activity. Based on this evidence of activity, further development of ARRY-520 + LoDex is warranted in patients who have exhausted other therapeutic options. Disclosures: Shah: Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: ARRY-520. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kaufman:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walker:Array BioPharma: Employment. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: 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; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: 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.

Description: 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.

Description: Background The availability of multiple immunomodulators (IMiDs) and proteasome inhibitors (PIs) has resulted in improved outcomes for patients (pts) with multiple myeloma (MM). Pts refractory to these 2 classes of drugs have a poor prognosis and new drugs with novel mechanisms of action are needed. ARRY-520, a potent, selective inhibitor of the novel drug target KSP, has shown single-agent activity in MM. The acute-phase protein AAG can bind ARRY-520, reducing free drug, possibly resulting in reduced treatment effect in pts with high AAG. Methods ARRAY-520-212 is a Phase 1/2 study. The Phase 2 portion was designed to evaluate the efficacy and safety of 1.5 mg/m2/day ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with filgrastim support. 2 Cohorts have been enrolled: Cohort 1 investigated single-agent ARRY-520 in pts with relapsed or refractory MM with ≥ 2 prior lines of therapy, including both bortezomib (BTZ) and an IMiD. Cohort 2 (cohort2) investigated ARRY-520 with Low-dose dexamethasone (LoDex -40mg weekly) in pts with RRMM with ≥ 2 prior lines of therapy, refractory (progression on or within 60 days of last treatment) to last line of therapy, and refractory to BTZ, lenalidomide (Len) and dexamethasone (triple-refractory). Pts intolerant to Len or BTZ were not included in cohort2. Baseline plasma AAG levels were measured in both cohorts. Results Results are summarized in the attached table. In cohort 1, 32 pts have been treated, with a median age of 65 years and a median of 6 prior regimens. 41% of cohort 1 pts were refractory to BTZ and Len. 6/27 pts (22%) had high baseline AAG. In cohort 2, 50 pts have been treated to date, with a median age of 63 years and a median of 9 prior regimens. As described in the table, cohort 2 pts had more prior treatment regimens, were primarily triple refractory and had a short time to progression (TTP) on prior therapy. 13/44 (30%) of cohort 2 pts had high baseline AAG. ARRY-520 showed a similar safety profile in both Cohorts. The most commonly reported (≥ 10% of pts) treatment-emergent Grade 3/4 adverse events, regardless of attribution, were thrombocytopenia (44% cohort 1, 42% cohort 2), anemia (38% and 50%), neutropenia (38% and 38%), fatigue (16% and 8%), leukopenia (13 and 4%) and pneumonia (3% and 12%). The incidence of febrile neutropenia was low in both cohorts (3% and 6%). ARRY-520 has shown activity both alone and with LoDex (See table). To date, in both cohorts, pts with High AAG have had no objective responses as compared to pts with Low AAG. In the completed cohort 1, ARRY-520 showed a durable 16% overall response rate (ORR) with an 8.6 month (mo) duration of response. In pts with Low AAG a prolonged OS (median = 23 mo) was observed compared to pts with High AAG (OS = 4.5 mo). Follow-up in cohort 2 is ongoing and ARRY-520+LoDex has shown a 16% ORR to date in this very heavily pretreated population. Notably in cohort 2, 4 PR were observed in the 16 patients (25%) who were previously treated with either a novel PI (carfilzomib or MLN9708) and/or IMiD (pomalidomide). Conclusions ARRY-520 is a novel first-in class agent in MM. In this Phase 2 analysis, ARRY-520 showed a similar activity and safety profile both alone and in combination with LoDex. While transient non-cumulative neutropenia is observed, the incidence of febrile neutropenia was low. ARRY-520 showed clear activity both alone and in combination with LoDex. Activity in pts refractory to novel PI and IMiDs suggests a lack of cross-resistance with drugs with existing mechanisms of action. High levels of AAG are associated with a lack of tumor responses and shorter OS following treatment with ARRY-520, suggesting AAG may be a potential patient selection marker identifying pts unlikely to benefit from ARRY-520. Disclosures: Lonial: Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy; Celgene Corporation: Consultancy. Off Label Use: ARRY-520 (Investigational Drug). Shah:Array BioPharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Hilder:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Walker:Array BioPharma: Employment. Orlowski:Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Resverlogix: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity’s Board of Directors or advisory committees.

Description: Background: Re-admission to the hospital within 30 days is a measure for quality care and a point of emphasis for reducing health care costs in individuals with chronic disease. Potentially modifiable risk factors for 30 day re-admission in children with sickle cell disease (SCD) includes not being seen in the SCD clinic within 30-days of discharge (OR 7.7, 95% CI 2.4–24.4), 3 or more admissions in the previous 12 months (OR 7.3, 95% CI 2.8–18.9) and co-morbid asthma (OR 2.9, 95% CI 1.2–7.3) (Pediatr Blood Cancer. 2009 Apr;52(4):481-5). Limited data exists regarding potentially modifiable risk factors for 30-day re-admission in adults with SCD. The primary objective of this study was to define modifiable risk factors for 30-day re-admission in adults with SCD, leading to a prospective intervention study to decrease re-admission rates. Procedure: At a tertiary care center, we performed a retrospective analysis of the medical records, from 2010 to 2013, to determine risk factors for 30-day re-admission in adults with SCD. Initial admission was defined as the first admission associated with uncomplicated vaso-occlusive pain episode in each focus year (2011- 2013). To decrease bias associated with multiple admissions from the same individual, the first admission for vaso-occlusive pain in each year was evaluated as the index admission for each record. Cases and controls were defined as adults with SCD initially admitted for pain and subsequently re-admitted to the hospital within 30 days of the initial admission. A multi-variable logistic regression analysis was performed on seven postulated risk factors. All data was collected and double checked by a single reviewer, and at least 10% of the chart was checked by a medical student for further assurance of accuracy. Results : A total of 158 first admissions and 49 re-admissions (31%) were evaluated. The mean age of the cohort was 30.38 (IQR 13.55 years). The median time to re-admission was 10 days (IQR 19 days). Approximately 50% of the cohort was not evaluated in the outpatient setting by the hematology team within 30 days post-discharge. Upon discharge patients either were not given a follow up appointment (35%) or were given an appointment beyond 30 days of discharge (13%). Only two predictors were significantly associated with re-admission within 30 days: not having a primary care provider listed in the electronic medical record (odds ratio 0.35, 95% CI 0.146-0.858; p = 0.022) and the number of hospital admissions due to vaso-occlusive pain in the prior year (odds ratio 1.28, 95% confidence interval 1.15-1.42; p 〈 0.001), table and figure below. Five covariates were not significantly associated with re-admission within 30 days: age (odds ratio 0.982, 95% CI 0.94-1.02; p = 0.369), sex (odds ratio 0.715, 95% CI 0.28-1.81, p =0.481), hemoglobin phenotype (odds ratio 0.50, 95% CI 0.19-1.287; p = 0.15), median lifetime oxygen saturation (odds ratio 0.892, 95% CI 0.75-1.05; p = .186), and presence of government insurance (odds ratio 1.90, 95% CI 0.67-5.37; p =0.222). Conclusions: Not having a primary care provider listed in the electronic medical record and multiple admissions in the prior year are potentially modifiable risk factors for re-admission within 30 days in adults with SCD. In addition, discharge planning with a hematology visit scheduled within a week of discharge may also impact the 30-day re-admission rate. We recently introduced a strategy focused on improved discharge planning, ensuring a primary care provider for every adult patient with SCD and targeted therapeutic intervention for those with high admissions. Table: Multivariable analysis of risk factors for 30-day re-admission in adults with sickle cell disease over a course of 3 years. A total of 158 admissions were evaluated with 31% being re-admissions within 30 days. Sig. Odds ratio 95% C.I.for EXP(B) Lower Upper Age Upon Admission to the Hospital 0.369 0.982 0.944 1.021 Sex 0.481 0.715 0.281 1.817 Hemoglobin Phenotype 0.152 0.504 0.197 1.287 Median Lifetime Oxygen Saturation Level 0.186 0.892 0.753 1.057 Primary Care Provider 0.022 0.354 0.146 0.858 Government Insurance 0.222 1.907 0.676 5.378 Number of Hospitalizations Due to Vaso-Occlusive Pain in the Prior Year 0.000 1.278 1.148 1.422 Figure. A graph depicting the predicted probablity of a re-admission within 30 days in indivdiuals with and without hospitalization versus the number of hospitalizations in the prior years. Figure. A graph depicting the predicted probablity of a re-admission within 30 days in indivdiuals with and without hospitalization versus the number of hospitalizations in the prior years. Disclosures No relevant conflicts of interest to declare.

Description: Background ARRY-520, a kinesin spindle protein (KSP) inhibitor, has demonstrated promising clinical activity, both as a single agent and combined with dexamethasone in patients (pts) with bortezomib- and lenalidomide-refractory MM with a single agent response rate (≥ MR) of 19-33%. The maximum tolerated dose (MTD) of ARRY-520 as a single agent was 1.5 mg/m2 administered on days 1 and 2 every 2 weeks with minimal non-hematologic toxicity. Carfilzomib, an irreversible proteasome inhibitor (PI), also has demonstrated single agent activity in RRMM and received accelerated approval by the Food & Drug Administration (FDA). Preclinical data demonstrate synergy between the combination of a PI and ARRY-520 and the minimal overlapping side effect profile support the hypothesis that the combination of carfilzomib and ARRY-520 could be an attractive regimen. Methods The primary objective was to determine the MTD and the safety/tolerability of carfilzomib and ARRY-520 in RRMM. Secondary objectives were to determine efficacy as measured by the overall response rate (ORR), time to progression, progression free survival and time to next therapy. Pts had to be ineligible for autologous stem cell transplant (ASCT), have disease refractory/intolerant to bortezomib, and have had prior lenalidomide exposure. ARRY-520 was administered intravenously (iv) on days 1, 2, 15 and 16; carfilzomib was administered intravenously on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. All pts received growth factor support in cycle 1. Dose-escalation used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Four dose levels were studied with ARRY-520 escalated from 0.75 to 1.5 mg/m2 with the approved fixed dose of carfilzomib 20/27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results 20 pts were enrolled in the completed phase 1 dose escalation portion of the study. The median age was 61 (range 43-80), and pts had received a median of 4 lines of prior therapy (range 2-10). 16/20 pts were lenalidomide refractory/intolerant; 20/20 pts were bortezomib refractory/intolerant; and 18/20 pts had prior ASCT. Two pts in cohort 2 were not DLT evaluable due to non-compliance with study-related therapy in cycle 1 and replaced for assessment of DLT. No DLTs were observed in 3 patients dosed in cohort 1, with ARRY-520 at 0.75 mg/m2. In cohort 2, 1/6 patients encountered a DLT with influenza pneumonia and non-neutropenic fever. In cohort 3, 5 patients were enrolled, ARRY-520 was dose escalated to 1.25 mg/m2, 2 patients were unevaluable for assessment of DLT, and no DLTs were encountered in the remaining 3 patients. The final planned cohort 4 was full dose ARRY-520 at 1.5 mg/m2 and carfilzomib 20/27 mg/m2, where 1/6 patients encountered a DLT of non-neutropenic fever and pneumonia. Therefore, the MTD of ARRY-520 with carfilzomib 20/27 mg/m2 was established at 1.5 mg/m2. Among 19/20 patients evaluable for efficacy, for an ORR (≥ MR) was 58%: including nCR (n=1), uPR/PR (n=6), MR (n=4), uSD/SD (n=4) and PD (n=4). Among 20 pts enrolled to date, 10 patients remain on study, 6 discontinued due to progressive disease, 1 pt was lost to follow-up, 1 patient died with febrile neutropenia in cycle 4 related to treatment, and 2 pts withdrew consent after 1 cycle of therapy. Treatment emergent SAEs included 5 pts with 6 incidences of pneumonia (influenza; n=1), 1 patient each with G3 bacteremia, G2 lethargy, G3 febrile neutropenia(FN) and G5 FN. Conclusions MTD has been established at the maximum planned dose level 4, with carfilzomib 20/27mg/m2 and ARRY-520 at 1.5 mg/m2. ARRY-520 can be safely combined carfilzomib in patients with RRMM and the combination is well tolerated with limited hematologic toxicity with growth factor support. The combination is very active in a heavily pretreated patient population with an ORR (≥MR) of 58%. Enrollment in a dose expansion at dose level 4 is underway. In addition a second dose escalation of ARRY-520 and increasing doses of carfilzomib in a 30 minute infusion is also enrolling. Disclosures: Shah: Array biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millennium: Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: ARRY-520 in relapsed/refractory myeloma. Thomas:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Hilder:Array BioPharma: Employment. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

Description: Abstract 1868 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that has demonstrated clinical activity in patients with relapsed and refractory multiple myeloma (MM). Although ARRY-520 is administered IV, it displays variable pharmacokinetics (PK) among patients. The degree of binding of certain drugs to serum proteins can alter their free fraction (fu) and PK, with a possible impact on clinical activity. Alpha 1-acid glycoprotein (AAG) is an acute-phase reactant protein that is often elevated in the blood of patients with cancer, including multiple myeloma. We investigated the significance of the interaction of ARRY-520 with AAG, and other relevant blood proteins, using both in vitro models and clinical data. Methods Compound-protein binding was assessed using several in vitro assays. In addition, the effect of increasing concentrations of AAG on MM cell line viability was measured. Patient data were obtained from 3 clinical studies of ARRY-520: a Phase 1 solid tumor study, a Phase 1/2 AML study, and a Phase 1/2 study in MM. The MM Phase 2 portion consists of 2 separate, 2-stage cohorts. Cohort 1 evaluated ARRY-520 administered as a single agent, and cohort 2 investigated ARRY-520 in combination with low-dose dexamethasone (LoDex). The concentrations of multiple proteins, including AAG, and the degree of ARRY-520 total protein binding, were measured in pre- and post-dose blood samples for patients in the analysis. AAG levels in MM patients were further correlated with time-on-study and clinical response rate. Results ARRY-520 exhibits low micromolar affinity for AAG in in vitro assays, but not for other common serum proteins, such as albumin. To investigate whether AAG binding impacts biological activity, we found that increasing AAG concentrations within a clinically relevant range resulted in increasing IC50 values for ARRY-520 on MM cell line viability. Of other MM agents tested, none exhibited high affinity binding to AAG in vitro, and a range of AAG concentrations did not alter the cellular activity of these compounds. Pre-dose concentrations of AAG were measured using blood samples collected from patients on all 3 ARRY-520 studies (0.4 – 4.1 g/L AAG in solid tumor study; 0.5 – 2.4 g/L in AML study; 0.2 – 2.8 g/L in MM study). Post-dose blood samples from the MM study also indicated that AAG levels do not significantly change with time. The fu of ARRY-520 in blood was meaningfully reduced among patients with the highest AAG concentrations. Furthermore, AAG and fu were correlated with changes in clinical PK: CL and Vd decreased with increasing AAG, trends consistent with a lower fu. Among the MM patients, 72 patients were evaluable for AAG determination (27 from the dose-escalation portion, 27 from Cohort 1, and 18 from Stage 1 of Cohort 2). Across all of these cohorts, the group of patients with AAG above an empirically-determined cutoff of 1.1 g/L showed a decreased median time on study (1.5 months vs 4.7 months) and no clinical responses (0/19 vs 12/53) as compared to patients below this cutoff. For example, as reported separately, ARRY-520 in combination with LoDex showed a promising 22% overall response rate (≥PR) in the 1st-stage of Cohort 2. In this cohort, 6 patients were determined to have AAG concentrations above the empirical cutoff. None of these patients had clinical benefit. Excluding these 6 patients would significantly improve the overall response rate (≥PR) from 22% (4/18) to 33% (4/12). Summary AAG has been proposed as a prognostic marker for MM disease severitya. Our preliminary data suggest that AAG levels can affect the free fraction of ARRY-520 in blood over a clinically relevant range both preclinically and in clinical studies. In retrospective analysis, patients with higher AAG levels show a lower fu and therefore may not achieve sufficient exposure to gain therapeutic benefit from ARRY-520. In preclinical analyses, this effect is specific to ARRY-520, suggesting that AAG levels may be predictive for ARRY-520 activity relative to other MM drugs. We hypothesize that prospective screening for AAG may enable exclusion of patients who may not achieve therapeutic exposure to ARRY-520, increasing the overall activity of ARRY-520 and preventing exposure of non-responders to an ineffective therapeutic dose. Further, experiments are currently underway to investigate the relevance of other acute-phase proteins in blood. Disclosures: Tunquist: Array BioPharma: Employment. Off Label Use: ARRY-520 alone and with dexamethasone for the treatment of relapsed/refractory multiple myeloma. ARRY-520 is not currently approved for any indication. Brown:Array BioPharma: Employment. Hingorani:Array BioPharma: Employment. Lonial:Millennium Pharmaceuticals, Inc.: 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; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Zonder:Celgene: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shah:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Koch:Array BioPharma: Employment. Litwiler:Array BioPharma: Employment. Walker:Array BioPharma: Employment.

Description: This paper presents a new approach for the expected cost-to-go functions modeling used in the stochastic dynamic programming (SDP) algorithm. The SDP technique is applied to the long-term operation planning of electrical power systems. Using state space discretization, the Convex Hull algorithm is used for constructing a series of hyperplanes that composes a convex set. These planes represent a piecewise linear approximation for the expected cost-to-go functions. The mean operational costs for using the proposed methodology were compared with those from the deterministic dual dynamic problem in a case study, considering a single inflow scenario. This sensitivity analysis shows the convergence of both methods and is used to determine the minimum discretization level. Additionally, the applicability of the proposed methodology for two hydroplants in a cascade is demonstrated. With proper adaptations, this work can be extended to a complete hydrothermal system.