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Figure S1. EPO and plasma chemokine expression following treatment with ARRY-614 at 1200 mg QD. Figure S2. Comparison of EPO in IWG2006 Responders and Non-Responders.

Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria.Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI.Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study. Clin Cancer Res; 21(5); 985–94. ©2014 AACR.

Supplemental Table 2. Dose escalation PK parameters for ARRY-614

Supplemental Table 1. Treatment-emergent AEs (safety population)

Background: ZN-c5 is an orally bioavailable selective estrogen receptor degrader (SERD) that binds potently to the estrogen receptors alpha and beta. It shows improved activity over fulvestrant in human tumor xenograft models and activity in tumor models that are resistant to tamoxifen. This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of ZN-c5 in subjects with advanced/metastatic estrogen receptor (ER) positive/ human epidermal growth factor receptor (HER2) negative breast cancer, both as monotherapy and in combination with palbociclib. The results from the ongoing monotherapy dose escalation are reported. Methods: Single agent ZN-c5 is being evaluated at sequentially escalating doses starting at 50 mg/day, administered orally, once daily (QD). The endpoints are to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), preliminary clinical activity and to characterize the PK profile. Subjects must be intolerant to or have breast cancer refractory to established therapies and to have received up to 2 prior lines of chemotherapy for the treatment of advanced breast cancer. Subjects must have a documented prior response to endocrine therapy for advanced/metastatic disease (SD, PR, or CR) lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment. Results: A total of 15 female subjects (median age 57 years, range 51 - 89 years) were enrolled across 5 cohorts (3 subjects/dose level). The dose levels were 50, 75, 100, 150, and 300 mg/day. The subjects had a median of 4 prior therapies for advanced/metastatic disease, with a median of 3 prior hormonal-based therapies and a median of 1 prior chemotherapy. Eleven of 15 subjects (73%) received prior fulvestrant. The cut off-date for this analysis was 30 June 2020. There was no increase in incidence or severity of TEAEs with increase in dose level. The most frequent TEAEs reported in > 1 subject were nausea (33%), arthralgia, cough, musculoskeletal pain and vomiting (20% each), alanine aminotransferase increased, anemia, back pain, blood alkaline phosphatase increased, breast pain, diarrhea, fatigue, gamma-glutamyl transferase increased, headache, hypophosphatemia, myalgia and skin mass (13% each). Grade 3 events were COVID-19, hypercalcemia, arthralgia, back pain musculoskeletal chest pain, pain in extremity and hypertension, none were deemed related to ZN-c5. Grade 4 events were not reported. No bradycardia was observed. A single subject reported a Grade 1 visual field defect, not deemed related to ZN-c5. No DLTs were reported. ZN-c5 demonstrated a best response of stable disease (SD) in 10/15 subjects (66.5%), while progression of disease (PD) was reported in 5/15 subjects (33.5%). The clinical benefit rate (CBR, SD ≥ 24 weeks) was 40%. In addition, the progression free survival (PFS) was a median of 3.8 months (95% [CI], 1.6 to 6.3). The preliminary PK was characterized by fast absorption with median Tmax values of 1 - 2 hrs. The exposures were approximately dose-proportional at the dose levels of 50 - 100 mg and less than dose-proportional between 100 - 300 mg. No ZN-c5 accumulation after 15 days of QD dosing was observed. The estimated mean elimination half-lives ranged between 11 - 18 hrs. Conclusion: This monotherapy dose escalation study demonstrates that ZN-c5 is very well-tolerated and has promising clinical activity in patients with ER+/HER2-negative advanced breast cancer who have disease that progressed on standard therapies. The trial with ZN-c5 in monotherapy and with palbociclib is ongoing and the RP2D has not been determined yet. Citation Format: Pavani Chalasani, Vandana Abramson, Joanne Mortimer, Julie R Nangia, Jose Suarez, Matt Suster, Mieke Ptaszynski, Kevin Kalinsky. A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-20.

Background: FGFR1 gene amplifications occur in ~15% of invasive breast cancers (BCs) andhave been shown to be associated with endocrine therapy resistance, whereas FGFR2 amplifications occur in ~2% of invasive BCs (4% of triple-negative BCs [TNBCs]). Futibatinib is an oral, highly selective, irreversible FGFR1-4 inhibitor that has been shown to inhibit both mutant and wild-type FGFR isoforms. In a phase 1 study, futibatinib showed promising clinical activity and tolerability across tumor types, including BC. This phase 2 trial (FOENIX-MBC2) is designed to evaluate futibatinib alone or in combination with fulvestrant (a selective estrogen receptor down-regulator administered intramuscularly) in patients with metastatic BC. Trial design: FOENIX-MBC2 is a multicenter, phase 2, open-label, non-randomized study planned to be conducted in patients with locally advanced/metastatic BC harboring FGFR1/2 amplifications who have experienced disease progression after prior therapy for advanced/metastatic disease. Eligibility criteria include an Eastern Cooperative Oncology Group performance status of 0 or 1 and no prior FGFR inhibitor treatment. Approximately 168 patients are planned to be enrolled in one of four cohorts based on a recurrent BC diagnosis and FGFR amplification status (table) as determined by local testing. Patients will receive single-agent futibatinib (cohorts 1-3) or futibatinib plus fulvestrant (cohort 4) until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Primary and secondary endpoints are detailed in the table. Sample sizes for cohorts 1, 2, and 3 are based on a Simon’s optimal 2-stage design; that for cohort 4 is based on a proof-of-concept phase 2 design. The anticipated start date is August 30, 2019. Patients, treatment, and endpoints in cohorts 1-4 of FOENIX-MBC2 CohortApprox. target enrollment (n)TreatmentKey patient inclusion criteriaEndpointsa1≤55FutibatinibHR+ HER2– BC, measurable disease per RECIST v1.1, FGFR2 amplification, and 1–3 prior endocrine therapies and ≤2 prior chemotherapy regimens for advanced/metastatic diseasePrimary: ORR Secondary: CBR, DOR, OS, PFS, 6-month PFS rate, safety2≤55FutibatinibTNBC, measurable disease per RECIST v1.1, FGFR2 amplification, and ≥1 prior chemotherapy or chemotherapy/immunotherapy regimen for advanced/metastatic diseasePrimary: ORR Secondary: CBR, DOR, OS, PFS, 6-month PFS rate, safety3≤24FutibatinibHR+ HER2– BC or TNBC; non-measurable, evaluable disease; FGFR2 amplification; and prior therapy as per cohort 1 (HR+ HER2– BC) or cohort 2 (TNBC)Primary: CBR Secondary: CR rate, DOR, OS, PFS, 6-month PFS rate, safety4≤34Futibatinib + fulvestrantHR+ HER2– BC, measurable disease per RECIST v1.1, high levels of FGFR1 amplification (FGFR1:CEN8 ratio ≥5.0 or FGFR1 copy number ≥10), and 1–2 prior endocrine-containing regimens and ≤1 prior chemotherapy regimen for advanced/metastatic disease, but no prior fulvestrantPrimary: 6-month PFS rate Secondary: ORR, CBR, DOR, OS, PFS, safetyCBR, clinical benefit rate; CR, complete response; DOR, duration of response; HER2-, human epidermal growth factor-negative; HR+, hormone-receptor-positive; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1aORR is defined as the proportion of all treated patients with a best overall response of CR or PR; CBR is defined as the proportion of all treated patients with a best overall response of CR, PR, or SD ≥24 weeks. ORR and CBR will be summarized descriptively. The 6-month PFS rate is the percentage of patients who remain alive and progression-free at 6 months estimated using the Kaplan-Meier method. This study is funded by Taiho Oncology, Inc. and Taiho Pharmaceutical Co., Ltd. Citation Format: Nick C. Turner, Ian E. Krop, Aditya Bardia, Senthil Damodaran, Miguel Martin, Karim A. Benhadji, Yaohua He, Mieke Ptaszynski, Carlos L. Arteaga. A phase 2 study of futibatinib (TAS-120) in metastatic breast cancers harboring fibroblast growth factor receptor (FGFR) amplifications (FOENIX-MBC2) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-07-01.

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. © 2017 American Cancer Society.

BACKGROUND Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2/day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2/day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2/day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m2 (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016. © 2016 American Cancer Society.

Purpose Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle protein (KSP) inhibitor that induces mitotic arrest and subsequent tumor cell death. This first-in-human Phase 1 study evaluated dose-limiting toxicities (DLTs) and determined a maximum tolerated dose (MTD) for filanesib administered as a 1-h intravenous infusion on 2 treatment schedules in patients with advanced solid tumors. The pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of filanesib were also evaluated. Methods Filanesib was administered on Day 1 of each 3-week cycle (Initial Schedule) or Days 1 and 2 of each 2-week cycle (Alternate Schedule). A standard 3 + 3 dose-escalation design was employed. An expansion cohort was conducted at the MTD of the Initial Schedule. Filanesib PK was evaluated in plasma (both schedules) and urine (Initial Schedule only). Monopolar spindle formation was evaluated in biopsies taken from patients in the expansion cohort. Results Forty-one patients received filanesib. The MTD was equivalent for both the Initial and Alternate Schedules (2.50 mg/m(2)/cycle). The prevalence of neutropenia as a DLT for both schedules necessitated adding prophylactic filgrastim to another dose escalation on the Alternate Schedule (highest tolerated dose 3.20 mg/m(2)/cycle). Neurotoxicity related to filanesib was not observed. Dose-proportional increases in filanesib exposure were observed. The half-life for filanesib was ~70 h. Monopolar spindles in patient biopsy samples indicated KSP inhibition. Stable disease was the best tumor response observed in 18 % (7/39) of evaluable patients. Conclusion Filanesib provided exposures with acceptable tolerability and evidence of target-specific pharmacodynamic effects.

BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The current study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of prophylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m(2)/day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m(2)/day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m(2)/day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (≤11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of ≥1.25 mg/m(2) (duration of response, 5.2 to ≥21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezomib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma.

BACKGROUND: ARRY-520 selectively inhibits the mitotic kinesin spindle protein (KSP), which leads to abnormal monopolar spindle formation and apoptosis. METHODS: A phase 1 trial was conducted to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 given as a 1-hour infusion in either a single dose or on a day 1, 3, and 5 divided-dose schedule per cycle in patients with advanced or refractory myeloid leukemias. Additional objectives were to characterize pharmacokinetics, assess preliminary clinical activity, and explore biomarkers of KSP inhibition with ARRY-520. A total of 36 patients with acute myelogenous leukemia (n = 34) or myelodysplastic syndromes (n = 2) with a median age of 66 years (range, 21-88 years) were enrolled: 15 in the single-dose schedule (dose levels: 2.5, 3.75, 4.5, and 5.6 mg/m2) and 21 in the divided-dose schedule (dose levels: 0.8, 1.2, 1.5, and 1.8 mg/m2/day). RESULTS: The MTD was 4.5 mg/m2 total dose per cycle for both dose schedules. Dose-limiting toxicities included mucositis, exfoliative rash, hand-foot syndrome, and hyperbilirubinemia. Grades 3 or 4 reversible drug-related myelosuppression were observed in 33 of 36 patients. Plasma pharmacokinetic analyses revealed low clearance of ARRY-520 (∼3 L/hour), a volume of distribution of ∼450 L, and a median terminal half-life of >90 hours. Monopolar spindles were observed in blood mononuclear cells, through use of 4′,6-diamidino-2-phenylindole nucleic acid stain and antitubulin antibodies. CONCLUSIONS: On the basis of the relative lack of clinical activity, further development of ARRY-520 as an antileukemic agent was halted. (Clinicaltrials.gov identifier NCT00637052). Cancer 2012;3556–3564. © 2011 American Cancer Society.

Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria. Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts. Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study. Clin Cancer Res; 21(5); 985–94. ©2014 AACR.

Prolonging tumor exposure to topoisomerase I inhibitors has been correlated to enhance the efficacy of those agents. Lurtotecan, a water-soluble camptothecin analog, was formulated as a liposomal drug, NX211, to enhance the delivery of drug to tumors. Tumor-bearing mice were treated with either [14C]NX211 containing [14C]lurtotecan, [3H]NX211 containing [3H]phosphatidylcholine or [14C]lurtotecan, euthanized at selected times post-injection, and tissues, plasma, urine and feces were collected. These studies demonstrated that KB tumors of [14C]NX211-treated mice had approximately 70-fold greater concentrations of [14C]lurtotecan at 24 h, respectively, compared to concentrations of [14C]lurtotecan of the KB tumors of [14C]lurtotecan-treated mice. The area under curve (AUC) from 0 to 48 h of [14C]lurtotecan for the KB tumors of [14C]NX211-treated animals was over 17-fold greater than the AUC of [14C]lurtotecan for the tumors of [14C]lurtotecan-treated animals. Treatment with [3H]NX211 demonstrated that the lipid component continually accumulated over 24 h in the tissues. HPLC analysis of extracted material from tumors of [14C]NX211-treated mice showed that more than 95% of the radioactive material was intact [14C]lurtotecan. These findings are one of the keys justifying the development of a liposomal formulation of lurtotecan, which has the intent to increase tumor exposure and increase antitumor efficacy.

Background Pomalidomide and dexamethasone (Pom-Dex) represents a standard of care for relapsed and refractory MM patients, with a 30% response rate and a PFS of approximately 4 months (San Miguel Lancet Oncol. 2013). These data have prompted the search for novel combinations with standard and novel agents using Pom-Dex as backbone therapy in order to improve its efficacy. Filanesib (ARRY-520) is a kinesin spindle protein inhibitor, with clinical activity as monotherapy in heavily pretreated MM patients (Lonial ASH 2013). Our group previously demonstrated the preclinical synergy of this therapeutic with Pom-Dex (Hernandez-Garcia ASH 2015), providing the basis for the present trial. Materials and Methods MM patients with disease in progression after at least two prior lines of therapy including bortezomib and lenalidomide, who were refractory or intolerant to lenalidomide and refractory to their last line of therapy were treated until progression with 28-day cycles of filanesib (iv on days 1, 2, 15 & 16), pomalidomide (po days 1-21), and dexamethasone (at a fixed dose of 40 mg po days 1, 8, 15, & 22). Prophylaxis with G-CSF with two 7-day courses starting at day +3 and day +17 was mandatory. A Phase Ib study was initially conducted, that defined the recommended dose of filanesib as 1.25 mg/m2 and pomalidomide as 4 mg QD. Recruitment was continued in the phase II using these doses, and the compiled data of all patients included to date is the focus of the present abstract. Baseline AAG levels were collected in patients included in the Phase II to be correlated with response. Results Thirty-three patients have been enrolled in the trial, 14 in the Phase I (7 of them treated at 1 mg/m2 of filanesib) and 19 patients in the phase II. Median age was 65 years (52-83). The patients had received a median of 3 prior lines of treatment (range: 2-6); 66% were refractory to bortezomib; 94% refractory to lenalidomide, 61% were double refractory to PI and lenalidomide; and 22% had received prior daratumumab. The most frequent treatment-related AEs were hematological: with anemia in 40% of patients (28% G3/4), neutropenia in 76% (60% G3/4), and thrombocytopenia in 56% (28% G3/4). Eighteen patients (76%) had infections, being 10 of them grade 3: febrile neutropenia (n=4), and respiratory infections (n=6). Other non-hematological related AEs were generally low grades, the most frequent-ones being asthenia in 36%, diarrhea in 16% and rash in 12%. A total of 49 SAEs were reported; 24 were considered related to the study drugs. The most frequent ones were G4 neutropenia in 6 cases and infections in 10 cases. Dose reductions were required in 8 patients for filanesib, in 6 patients for pomalidomide and in 1 patient for dexamethasone. Among the 26 patients evaluable for efficacy (7 patients are not evaluable as they are in the 1st two cycles of treatment), 3 (12%) have achieved VGPR and 14 (54%) PR, for an overall response rate (ORR) of 65%; one additional patient (4%) achieved MR and the disease was stabilized in 6 more patients (23%), lasting for at least 3 cycles, for a disease control rate (DCR) of 92%. Median time to first response (MR) was 1 (1-5) months and 3 (1-13) months for 1st PR. After a median follow-up of 7 months, the median PFS was 7 months (CI95 4.2-9.7). Overall survival at 24 months is 75%; five patients have died, one due to influenza A infection (considered non-related) and 4 patients due to progressive disease. Conclusion The results of this ongoing Phase Ib-II trial confirm the preclinical synergy observed with filanesib when combined with pomalidomide and dexamethasone. The combination induces a 65% response rate in this refractory population and a PFS of 7 months. The main toxicity was haematological, particularly neutropenia, which was manageable. Updated results as well as the influence of baseline AAG levels on response will be presented at the meeting. Disclosures Ocio: Array Pharmaceuticals: Research Funding; BMS: Honoraria; Seattle Genetics: Consultancy; Janssen: Honoraria; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Amgen: Honoraria, Research Funding; MSD: Research Funding. Rodriguez-Otero: Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. de la Rubia: Amgen: Other: Honoraria; Janssen: Other: Honoraria; Celgene: Other: Honoraria. Oriol: Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: sponsored symposia; Celgene: Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau. Lahuerta: Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria. San Miguel: Sanofi: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Roche: Membership on an entity9s Board of Directors or advisory committees. Mateos: Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Table. Efficacy evaluable pts (potential to have received ≥ 2 cycles of treatment) CFZ (N = 20) CFZ + FIL (N = 30) Prior regimens, median (range) 4 (2,11) 5 (2,11) N cycles on study, median (range) 4 (1 - 16) 4 (1 - 15+) % ORR (≥ PR) 10 30 % CBR (≥ MR) 20 37 N (%) IMiD & BTZ Refractory 14 (70) 20 (67) % ORR (≥ PR) 14 35 % CBR (≥ MR) 21 40 CBR = clinical benefit rate Disclosures Zonder: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

TPS8612 Background: Immunomodulatory agent (IMiD)/bortezomib (BTZ) combinations are common frontline therapy in patients with multiple myeloma (MM). Despite high initial objective response rates (O...

Background Emerging data support a role for both p38 MAPK (p38) and Tie2 in the molecular mechanisms underlying MDS pathophysiology and suggest that inhibition of p38/Tie2 has the potential to improve hematopoiesis. ARRY-614 is an orally bioavailable, dual inhibitor of p38 and Tie2 that has demonstrated multi-lineage hematologic improvement (HI) and acceptable tolerability with a powder-in-capsule (PIC) formulation. However, due to suboptimal PK properties of the PIC, a Phase 1 study in patients (pts) with MDS was initiated to evaluate an optimized formulation of ARRY-614. Methods The aims of this study were to determine the MTD, establish a recommended Phase 2 dose and evaluate the safety, PK profile and PD effects of a formulated capsule of ARRY-614 administered once daily (QD) and twice daily (BID) in continuous 28-day cycles. Pts with IPSS low/intermediate-1 risk MDS, ≥ 1 cytopenia (per IWG 2006 criteria) and adequate ECOG performance status, hepatic and renal function were eligible. Prior therapy for MDS was permitted; CMML per FAB criteria and secondary MDS were allowed. The study used a 3+3 dose escalation design modified to allow additional pt accrual at lower dose levels already determined to be tolerable. Additional expansions were permitted at selected dose levels to determine the recommended Phase 2 dose. Response was assessed using IWG 2006 criteria. In addition, platelet transfusion dependent pts (TD, ≥ 1 platelet transfusion within 8 weeks prior to starting treatment) were assessed for transfusion independence (TI) or transfusion reduction (TR, 50% decrease). Results At the time of this analysis (01 May 2013), 62 pts with IPSS low (n = 16) or intermediate-1 (n = 46) risk MDS were enrolled (median age 72 years, range 46-85). Patients had received a median of 3 prior regimens (range 0-6); 5 pts had no prior therapy. Prior regimens included: hypomethylating agents (HMAs; 85%), erythropoiesis-stimulating agents (65%) and lenalidomide (32%). ARRY-614 was administered at doses of 200-1000 mg QD (n=50) and 100-200 mg BID (n=12), with a median treatment duration of 13 weeks (range 1 day to 65 weeks). The MTD of the QD schedule was determined to be 800 mg QD after 2/6 pts experienced dose limiting toxicities (DLTs) of atrial fibrillation at the 1000 mg QD dose. The 200 mg BID dose was deemed not tolerable after 3/8 pts developed DLTs of Grade 3 rash (2 pts) and Grade 3 ECG QT prolongation (1 pt). The most common treatment-related adverse events (> 5% of total pts) included rash, nausea, atrial fibrillation, decreased appetite, fatigue, asthenia and vomiting. The majority of these events were mild or moderate. Nineteen pts remain on study (median time on treatment of 10 weeks). To date, 12 of 54 (22%) evaluable pts and 9 of 31 (29%) pts on treatment ≥ 16 weeks experienced HI per IWG 2006 criteria and/or achieved platelet TR or TI. Responses were observed at all dose levels. HI-E, HI-P, and HI-N responses were observed in 6% (3/49), 21% (7/34) and 31% (5/16) of the pts, respectively. In addition, of the 12 pts who were platelet TD, a total of 50% (6/12) achieved at least a TR, and 33% (4/12) achieved complete TI. All pts who experienced a response had received prior treatment with an HMA. ARRY-614 and its metabolite AR00451575 demonstrated increasing exposure with increasing dose, which was approximately dose proportional based on Cmax and AUC. At doses ≥ 400 mg QD, the plasma concentrations exceeded the predicted p38 and Tie2 IC50 values (113 ng/mL and 1150 ng/mL, respectively, plasma protein binding corrected). Preliminary biomarker analyses demonstrated primary target inhibition with persistent reduction in phospho-p38 levels in the bone marrow as compared to baseline during the course of treatment. In addition to primary target inhibition, observed decreases in plasma chemokines during the course of treatment were consistent with functional inhibition of p38. Conclusions The ARRY-614 formulated capsule demonstrates good tolerability and on-target activity at doses up to 800 mg QD, as well as a more favorable PK profile than the previous formulation. In addition, HI responses were seen across dose levels and across lineages in pts previously treated with HMAs, suggesting ARRY-614 may provide a treatment option for pts with lower-risk disease failing standard therapies. Next steps will be to explore the 400 mg and 800 mg dosing schedules further. Disclosures: Garcia-Manero: Array BioPharma: steering committee participation Other. Sekeres:Amgen: data safety monitoring board, data safety monitoring board Other; Celgene: advisory board Other. List:Array BioPharma: Member of advisory board on MDS Other. Khoury:Array BioPharma: steering committee participation Other. Kantarjian:Array BioPharma: Research Funding. Cable:Array BioPharma: Employment. Guthrie:Array BioPharma: Employment. Hogeland:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Maloney:Array BioPharma: Employment. Corson:Array BioPharma: Employment. Komrokji:Array BioPharma: steering committee participation Other.

Abstract 2047 Poster Board II-24 Introduction: The mitotic kinesin spindle protein (KSP) is required for the assembly of a normal bipolar spindle and cell cycle progression through mitosis. ARRY-520 is a potent, selective inhibitor of KSP that arrests cells in mitosis forming an abnormal monopolar spindle with subsequent onset of apoptosis. ARRY 520 has shown potent activity in preclinical models of hematological malignancies which support clinical investigation of this novel targeted antimitotic therapy in patients with leukemias. ARRY-520 was evaluated in a Phase 1 trial, administered as an intravenous (IV) infusion on Day 1 or on Days 1, 3 and 5 in patients with advanced/refractory leukemias. Objectives: The primary objectives of this study were to establish the safety and the maximum tolerated dose (MTD) of ARRY-520 when given as a 1-hour infusion in either a single dose or on a Days 1, 3 and 5 divided-dose schedule per cycle. Secondary objectives were to characterize the pharmacokinetics (PK) of ARRY-520 when given on these schedules, to assess evidence of preliminary clinical activity, and to explore potential biomarkers of KSP inhibition. Methods: ARRY-520 was administered as a 1-hour IV infusion as a single dose per cycle or on a divided dose schedule, in a “3 + 3” Phase 1 design. PK analyses for ARRY-520 were performed on plasma samples collected during Cycle 1 and Cycle 2. Results: A total of 33 patients with acute myelogenous leukemia (AML) and with a median age of 66 years (range 21-88 yrs) were enrolled: 15 in the single-dose schedule (dose levels 2.5, 3.75, 4.5 and 5.6 mg/m2) and 18 in the divided dose schedule (dose levels 0.8, 1.2, 1.5 and 1.8 mg/m2/day). All but one patient had disease refractory to and/or relapsed from prior therapy with a median of 4 prior regimens (range 0-7). The MTD was 4.5 mg/m2 for the single-dose schedule with the dose-limiting toxicity (DLT) of Grade 3 mucositis and was 1.5 mg/m2/day (cumulative dose per cycle of 4.5 mg/m2) for the divided dose schedule, with DLTs of Grade 3 mucositis, hand-foot syndrome and hyperbilirubinemia. ARRY-520 was well tolerated at the MTD and doses below. At the MTD, Grades 3 or 4 reversible drug-related leukopenia were observed in 4/8 evaluable patients (Grade 0 or 1 WBC at baseline) with a median nadir occurring on Day 7. In both schedules ARRY-520 showed promising signs of clinical activity as measured by significant decreases in leukemic blasts in both the peripheral blood and bone marrow. Four of 33 patients (12%) showed at least 50% reduction in bone marrow blasts and 12/33 patients (36%) showed > 1 log reduction in blasts in the peripheral blood. Preliminary plasma PK analyses revealed increasing ARRY-520 concentrations with increasing dose, a mean terminal t1/2 of ∼90 hours, with clearance values ranging from 1.6 to 8.0 L/hr. Conclusions: ARRY-520 showed promising signs of clinical activity and has been well tolerated in both schedules investigated in patients with AML. The most prominent DLTs were mucositis and hand-foot syndrome. The MTD was determined to be the same total dose per cycle for the single-dose and the divided-dose schedule. Data including the safety, PK, pharmacodynamics and preliminary activity of ARRY 520 from this study will be presented. Disclosures: Bethelmie-Bryan: Array BioPharma: Employment. Rush:Array BioPharma: Employment. Freeman:Array BioPharma: Employment. Simmons:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment.