Citations

Abstract Abstract 2477 Background: Aurora A kinase (AAK) is a key mitotic regulator, inhibition of which results in mitotic spindle defects, mitotic delay, and apoptosis. AAK is amplified or overexpressed in a number of heme-lymphatic malignancies. This phase 1, multicenter study (NCT00697346) is the first to assess safety, tolerability, and pharmacokinetics (PK) of the investigational AAK inhibitor alisertib (MLN8237) in patients with advanced hematologic malignancies. Methods: Patients aged ≥18 years with relapsed/refractory hematologic malignancy, confirmed radiographically or clinically evaluable disease, and ECOG performance status 0–2, were eligible for inclusion. Patients with prior allogeneic transplant were excluded; there was no restriction on the number of prior therapies. Patients received escalating doses (standard 3+3 design) of alisertib as either a powder-in-capsule (PIC) or enteric coated tablet (ECT) formulation. Alisertib PIC was administered as a twice-daily (BID) loading dose on Day 1, then once daily (QD) on Days 2–14 or 2–21, followed by 14 or 7 days' rest, respectively, in 28-day cycles. Alisertib ECT administration followed the same scheme in the first dose group, and subsequent groups received divided (BID) doses for 7 days plus 14 days' rest in 21-day cycles. Endpoints included maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, PK, and response. Results: 55 patients were included (PIC n=28, ECT n=27); median age was 61 years (range 27–82), 42% had prior ASCT, and 78% had received ≥3 prior therapies. 60% of patients had non-Hodgkin's lymphoma, 35% multiple myeloma, and 5% chronic lymphocytic leukemia/small lymphocytic lymphoma. Patients received a median of 2 cycles (range 1–14); 8 patients are ongoing. The MTD on the alisertib PIC 14-day + 14 days' rest schedule was 45 mg QD, established following occurrence of DLTs in four patients at higher dose levels: Gr 4 thrombocytopenia, Gr 4 neutropenia (65 mg QD); Gr 3 febrile neutropenia, Gr 4 thrombocytopenia (90 mg QD). In patients receiving alisertib ECT, the MTD was determined as 50 mg BID on a 7-day + 14 days' rest schedule; four DLTs were observed in three patients: at 40 mg QD for 14 days, one patient had Gr 4 febrile neutropenia, and one patient had Gr 4 bullous dermatitis and Gr 4 neutropenia; at 50 mg BID for 7 days, one of nine patients had Gr 4 neutropenia. The most common drug-related adverse events (AEs) were neutropenia (PIC 46%, ECT 63%), thrombocytopenia (39%, 41%), and diarrhea (29%, 41%); most common Gr ≥3 drug-related AEs were neutropenia (PIC 36%, ECT 52%), thrombocytopenia (29%, 26%), and anemia (14%, 26%). 24 patients (PIC n=12, ECT n=12) had serious AEs; the most common was febrile neutropenia (PIC n=1, ECT n=4). Tolerability appeared generally similar between the PIC and ECT formulations. Six patients (PIC n=3, ECT n=3) died during the study (PIC: renal failure, airway obstruction, progressive large cell lymphoma; ECT: progressive myeloma [n=2], hypercalcemia); no deaths were considered to be related to alisertib. Alisertib absorption was rapid with an overall median Tmax of 2 hours. The overall mean terminal half-life following multiple dosing was 19 hours. The mean peak/trough (P/T) ratio was 5 following QD dosing as PIC. The mean accumulation ratio and P/T ratio were 2.5 and 2.1, respectively, following BID dosing as ECT. At data cut-off (29 March, 2011), 42 patients were evaluable for response. Antitumor activity was observed in five patients (PIC n=3, ECT n=2) who had partial responses; 11 patients had a best response of stable disease (PIC n=6, ECT n=5) and 26 had progressive disease (PIC n=14, ECT n=12). Seven patients received ≥5 cycles of therapy, including one patient (PIC group; post-transplant grade 3B follicular lymphoma) with resolution of B symptoms who received alisertib for >1 year. Conclusions: The MTDs of the PIC and ECT formulations of alisertib are 45 mg QD for 14 days (+14 days' rest) and 50 mg BID for 7 days (+ 14 days' rest), respectively, in patients with advanced, non-leukemic hematologic malignancies. AEs were generally manageable and were consistent with inhibition of AAK in highly proliferative tissues (gastrointestinal and hematologic AEs). Current data support further investigation and expansion at the MTDs is ongoing. Data from PK, safety, and tolerability collectively support the progression of ECT formulation at 50 mg BID for 7 days in a 21-day cycle into phase 2 development. Disclosures: Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies and solid tumors. Goy:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Reeder:Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding; Celgene: Institutional research funding. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Danaee:Millennium Pharmaceuticals, Inc.: Employment. Xiao:Millennium Pharmaceuticals, Inc.: Employment. Benaim:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Shea:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 621 Background: Two- and three-drug regimens incorporating bortezomib (Velcade®, V), lenalidomide (Revlimid®, R), dexamethasone (D), or cyclophosphamide (C) have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining all four drugs in a single regimen (VDCR) may further enhance efficacy. Published results from the phase 1 dose-escalation portion of the non-comparative, multi-center EVOLUTION study showed that the VDCR regimen was highly active and generally well tolerated (Kumar et al Leukemia 2010). Here we present updated results from the phase 2 portion of the trial, focusing on efficacy and safety of the VDCR, VDR, and VDC regimens. Methods: Previously untreated patients with measurable disease were randomized to one of four treatment groups receiving up to eight 21-d cycles of VDCR (V 1.3 mg/m2 d 1, 4, 8, 11; D 40 mg d 1, 8, 15; R 15 mg d 1–14; C 500 mg/m2 d 1, 8), VDR (VD as in VDCR but with R 25 mg d 1–14), VDC (VDC as in VDCR), or VDC-mod (as for VDC but with an additional dose of C on d 15) as induction therapy, followed by four 42-d maintenance cycles of V 1.3 mg/m2 (d 1, 8, 15, 22) (all treatment arms). Patients eligible for autologous stem cell transplant (SCT) could undergo stem cell mobilization any time after cycle 2 and SCT any time after cycle 4. The primary endpoint was the combined complete response (CR) + very good partial response (VGPR) rate; secondary endpoints included safety/tolerability, time to response, duration of response, progression-free survival, and rate of minimal residual disease (MRD) negativity. Responses were assessed according to International Myeloma Working Group (IMWG) uniform criteria using an automated computer algorithm. Adverse events (AEs) were graded using the CTCAE v3.0. Results: Patient characteristics were similar among the groups with respect to age, performance status, ISS stage, and proportion of patients with high-risk cytogenetic features. Patients received a median of 5, 6, 6, and 6 treatment cycles in the VDCR, VDR, VDC, and VDC-mod arms, respectively; 65%, 60%, 52%, and 47% of patients had dose reductions of any drug. In the VDCR, VDR, VDC, and VDC-mod arms, respectively, 52%, 62%, 58%, and 65% of patients completed treatment; 31%, 43%, 24%, and 41%, respectively, underwent SCT. In the phase 2 response-evaluable patients (n=132), all treatment regimens showed substantial efficacy, with CR+VGPR rates of 59% (VDCR), 50% (VDR), 41% (VDC), and 59% (VDC-mod) (Table) (includes pre-transplant responses only in SCT patients). Of MRD-assessed patients, 46% (21/46) of those who achieved CR (including sCR) or nCR were MRD-negative; 48% (10/21), 75% (9/12), 0% (0/7) and 33% (2/6) in the VDCR, VDR, VDC and VDC-mod arms, respectively. Median time to first response was similar across arms (range 1.6–1.8 months); median time to best response of CR+VGPR was 4.0 months (VDCR), 3.4 months (VDR), 5.1 months (VDC), and 3.1 months (VDC-mod). Median duration of response has not been reached in any arm to date. All treatment regimens were generally well tolerated. In the VDCR, VDR, VDC, and VDC-mod arms, at least one grade ≥3 AE was observed in 81%, 76%, 79%, and 88% of enrolled patients, respectively; serious AEs were experienced by 42%, 40%, 21%, and 41% of patients, and AEs resulting in study discontinuation were reported for 19%, 17%, 12%, and 6% of patients. The five most common all-grade AEs across all treatment groups were fatigue (range 47–67%), nausea (36–67%), constipation (40–62%), diarrhea NOS (42–65%), and neutropenia (19–52%). The incidence of grade ≥3 (grade ≥2) peripheral neuropathy (PN) was 13% (40%) in the VDCR arm, 14% (45%) VDR, 9% (48%) VDC, and 18% (41%) VDC-mod; there was no grade 4 PN. Rates of grade ≥3 neutropenia/thrombocytopenia were 42%/10% for VDCR, 7%/7% VDR, 36%/12% VDC, and 65%/18% VDC-mod. Conclusions: All regimens appear highly active and generally well tolerated in previously untreated MM patients. The four-drug combination did not result in a substantial increase in response rate and was associated with a modest increase in the incidence of hematologic toxicities. Continuous weekly C in the VDC regimen was associated with high response rates and rapid responses, comparable to the VDR and VDCR arms. Outcome data will be presented following longer follow-up. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Richardson:Celgene, Millennium, Novartis, Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Research Funding. Callander:Millennium Pharmaceuticals, Inc.: Research Funding. Noga:Amgen: Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ortho-Centicor: Honoraria, Speakers Bureau; Cephalon: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Stewart:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding; Celgene: Honoraria. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Wolf:Millennium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Genentech and Multiple Myeloma Research: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Estevam:Millennium Pharmaceuticals: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals: Employment. Webb:Millennium Pharmaceuticals: Employment.

Abstract Abstract 2799 Background: Aurora A kinase (AAK) is important in a diverse set of mitotic processes and is amplified or overexpressed in a number of heme-lymphatic malignancies. MLN8237 is an investigational, orally administered, selective AAK inhibitor in clinical development for the treatment of hematologic and solid tumors. This multicenter study (NCT00697346) is the first phase 1 program to assess safety and pharmacology of MLN8237 in patients with advanced hematologic malignancies. Methods: Eligible patients were aged ≥18 yr, had response-evaluable, relapsed or refractory hematologic malignancies, and had ECOG performance status 0–2; there was no restriction on the number of prior therapies, but prior allogeneic transplant was excluded. Patients received escalating doses of MLN8237 as powder-in-capsule formulation in a 3+3 design. Endpoints included safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics, and response. Results: Twenty-eight patients were included; median age was 62 yr (range 41–74), 50% were male, 86% were white, and 43% had prior transplant. Diagnoses were non-Hodgkin's lymphoma (68%), including diffuse large B-cell (DLBCL), mantle cell, follicular, and small lymphocytic lymphoma; multiple myeloma (29%); and chronic lymphocytic leukemia (4%). Seventy-nine percent of patients had received ≥3 prior therapies. Patients initially received a 21-day treatment schedule of MLN8237 25 or 35 mg (BID loading dose on Day 1, then QD on Days 2–21) followed by a 7-day rest period (28-day cycles). Based on results with the first two cohorts, subsequent cohorts received a 14-day treatment schedule of MLN8237 35, 45, 65, or 90 mg (BID loading dose on Day 1, then QD on Days 2–14) followed by a 14-day rest period (28-day cycles). Median number of cycles administered was 2 (range 1–14+). After escalation to 90 mg (maximum administered dose), two DLTs per cohort led to de-escalation to 65 mg and then 45 mg, which was the MTD on the 14-day schedule. The most common treatment-related adverse events (AEs) were neutropenia (46%), thrombocytopenia (36%), and asthenic conditions (32%); grade ≥3 treatment-related AEs were reported in 14 (50%) patients, and 13 (46%) had a serious AE. DLTs included grade 3–4 myelosuppression associated with infection or delay in treatment, which were generally manageable by reduction in dose or schedule. AEs were generally reversible and manageable, although 5 (18%) patients discontinued due to AEs. Three patients died, from causes (renal failure; airway obstruction; progressive large cell lymphoma) not considered related to MLN8237. Following multiple doses, an overall median Tmax of 2 hr, a mean t1/2 of 23 hr, and a peak/trough ratio of 5 were observed. The geometric mean of steady-state AUC increased from 19,534 to 30,811 nM*hr when the daily dose was increased from 25 to 65 mg. With the 14-day schedule, antitumor activity was observed in a patient with relapsed DLBCL treated with 65 mg and reduced to 45 mg, who enrolled after disease progression following ifosfamide-carboplatin-etoposide (ICE) salvage therapy. A durable PR coupled with resolution of B symptoms sustained for >1 yr was observed in a patient with post-transplant grade 3B follicular lymphoma treated with 35 mg, escalated per protocol to 45 mg and then 65 mg. Stable disease (SD; 5 months) was observed in a patient with myeloma treated at 90 mg. Conclusions: MLN8237 toxicities were consistent with AAK inhibition in proliferating tissue (chiefly bone marrow), and were generally manageable. The MTD was 45 mg on the 14-day schedule in these patients with advanced hematologic malignancies. Antitumor activity was observed, and repeat cycles were tolerable over 6–12 months in some patients who achieved PR or SD. The results support further investigation of MLN8237 in heme-lymphatic malignancies, and ongoing clinical development includes alternative schedules and formulations. Disclosures: Padmanabhan: Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of advanced hematologic malignancies. Shea:Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Vose:Millennium Pharmaceuticals, Inc.: Research Funding. Goy:Millennium Pharmaceuticals, Inc., Celgene, GSK, Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Fowler:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Research Funding; Cephalon: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Honoraria.

Abstract Background: Classical Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The standard of care for patients (pts) with relapsed or refractory (R/R) HL is salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant (auto-SCT). Approximately 50% of these pts will experience relapse or progression of HL after auto-SCT. For these individuals, outcomes have historically been poor, with median overall survival (OS) from time of relapse ranging from 10.5 to 27.6 mos (Crump, 2008; Fanale, 2013). A pivotal phase 2 study evaluated brentuximab vedotin, a CD30-directed antibody-drug conjugate, in pts with R/R HL after auto-SCT (ClinicalTrials.gov #NCT00848926). Primary results and 3-year follow-up data have been previously reported (Younes, 2012; Gopal, 2015). Here, we summarize final data from the 5-year follow-up period. Methods: Pts received 1.8 mg/kg brentuximab vedotin once every 3 wks as a 30-min outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Assessments of response and durability of response per an independent review facility (IRF) have been previously reported. Following a protocol amendment that removed the requirement for routine CT scanning during the follow-up period, disease status was only assessed per the investigator. Survival and disease status were assessed every 3 mos for 2 yrs and then every 6 mos through Year 5. CT scans were required if progression was suspected clinically. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months. Results: The enrolled population of 102 pts (53% female) was heavily pretreated and had a median age of 31 yrs (range, 15-77 yrs). Pts received a median of 9 cycles (range, 1-16) of brentuximab vedotin. Per investigator, the ORR to brentuximab vedotin was 72% and complete remission (CR) rate was 33%. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events of Grade 3 or higher that occurred in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. At study closure, which occurred approximately 5 yrs after the last patient's end-of-treatment visit, the median observation time for all enrolled patients from first dose was 35.1 mos (range, 1.8 to 72.9). The estimated 5-year overall survival rate was 41% (95% CI: 31 %, 51%) and the median OS was 40.5 mos (95% CI: 28.7, 61.9 [range, 1.8 to 72.9+]). Median OS by best clinical response was CR (n=34): median not reached; partial remission (PR, n=39): 39.4 mos; and stable disease (SD, n=28): 18.3 mos. The median PFS was 9.3 months overall, but was not reached in CR pts. Of the 102 enrolled patients, 15 remained in follow-up and in remission at study closure. Among these 15 pts, 6 received consolidative allo-SCT and 9 have received no further therapy since completing brentuximab vedotin. Conclusions: These end-of-study results demonstrate that single agent brentuximab vedotin can induce durable remissions and long-term survival in a subset of heavily pretreated patients with relapsed/refractory HL, particularly in pts that achieve CR. A randomized phase 3 study is being conducted to evaluate brentuximab vedotin in combination with AVD (doxorubicin, vinblastine, and dacarbazine) versus ABVD (A, bleomycin, VD) for frontline treatment of advanced HL (ECHELON-1 trial, ClinicalTrials.gov #NCT01712490). Figure 1. Overall Survival Figure 1. Overall Survival Disclosures Chen: Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Gopal:BMS: Research Funding; Piramal: Research Funding; Emergent/Abbott: Research Funding; Millenium: Honoraria, Research Funding; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; BioMarin: Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-Aventis: Honoraria; Merck: Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Rosenblatt:Seattle Genetics: Research Funding. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Engert:Takeda Millenium: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Larsen:Seattle Genetics Inc.: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Fong:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Janssen: Honoraria; Novartis: Research Funding; Incyte: Honoraria; Takeda Millenium: Honoraria; Celgene: Honoraria; Bristol Meyer Squibb: Honoraria; Curis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria; Johnson and Johnson: Research Funding.

Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 479 Background: MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor, which immediately hydrolyzes to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 has shown faster proteasome dissociation and greater tissue penetration than bortezomib. Current phase 1 data indicate that oral administration of single-agent MLN9708 was generally well tolerated, with no grade ≥3 peripheral neuropathy, and showed signs of antitumor activity in some patients with relapsed and/or refractory MM. Bortezomib in combination with lenalidomide and dexamethasone demonstrated a 100% partial response or better (≥PR) rate in patients with previously untreated MM, providing the rationale for evaluating oral MLN9708 in place of bortezomib in this combination. Here we report phase 1 data from the first combination study of MLN9708 (ClinicalTrials.gov: NCT01217957). Methods: Primary phase 1 objectives were to determine the safety, tolerability, and maximum tolerated dose (MTD) of weekly MLN9708 in combination with lenalidomide and dexamethasone; secondary objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN9708, assessment of PK interaction and response. Adults aged ≥18 years with ECOG performance status of 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients with grade ≥2 peripheral neuropathy or prior/concurrent deep vein thrombosis (DVT)/pulmonary embolism were excluded. Patients received oral MLN9708 weekly on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, for up to twelve 28-day cycles. Patients received thromboprophylaxis with aspirin or low molecular weight heparin. Transplant-eligible patients could undergo stem cell transplant after six cycles. MLN9708 dose escalation, from a starting dose of 1.68 mg/m2, followed a 3+3 scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to modified EBMT criteria. Results: At data cut-off (June 29, 2011), 10 patients have been enrolled and treated: three each at 1.68, 2.23, and 2.97 mg/m2 and one at 3.95 mg/m2; median age was 66 years (range 59–77). Patients completed a median of 3 cycles (range 1–6), with three having received 6 cycles; treatment is ongoing in six patients. A DLT of grade 3 fainting was observed in a patient treated at 3.95 mg/m2. The MTD has not yet been reached; the current cohort is receiving 3.95 mg/m2. Drug-related AEs included rash in four patients (two maculopapular, two erythematous); vomiting and fatigue in three patients each; and diarrhea, constipation, and nausea in two patients each. Grade 1 treatment-related peripheral neuropathy was reported in one patient. Serious AEs were seen in four patients: one at 3.95 mg/m2 (DLT of grade 3 fainting), one at 2.23 mg/m2 (grade 3 DVT) unrelated to MLN9708, and two unrelated at 1.68 mg/m2 (grade 3 hypotension; grade 3 gastrointestinal hemorrhage resulting in discontinuation). Two patients required lenalidomide dose reductions to 15 mg due to erythematous rash; no dose reductions were required for MLN9708 or dexamethasone. There were no on-study deaths. Of nine response-evaluable patients, all nine achieved ≥PR, including three very good PR (VGPR) and one complete response. Time to response was rapid; all responders achieved a ≥50% decrease in M-protein in cycle 1, and best response was reached by the end of cycle 4. No patient has progressed to date. One patient with confirmed VGPR discontinued at cycle 6 to undergo stem cell transplant. Conclusions: MLN9708 administered weekly in combination with lenalidomide and dexamethasone appears to be generally well tolerated in previously untreated MM patients at the MLN9708 dose levels studied, with evidence of antitumor activity in the dose-escalation cohorts. Evaluation continues to determine the MTD of MLN9708 in this combination. Updated results, PK data, assessment of PK interaction, and PD data will be presented. Disclosures: Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

Abstract Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of btz at 2 doses (1.0, 1.3mg/m2) after single- and multiple-dose administration, and evaluated their relationship. 24 pts with relapsed MM and creatinine clearance ≥50mL/min were randomized to btz 1.0 (n=12) or 1.3mg/m2 (n=12) on D 1, 4, 8 and 11 of a 21-D cycle (C). Pts could continue therapy for ≥8 Cs if beneficial. PK/PD samples were drawn at multiple time points on D1 and D11 of C1 and C3 over 48h. Plasma concentrations of btz were similar following administration of 1.0 and 1.3mg/m2; differences in mean plasma Cmax and AUC values were within the degree of intersubject variability (Table). There was a decrease in clearance and an increase in terminal half-life of btz on D11 vs D1 of C1.The volume of distribution of btz suggests extensive peripheral tissue distribution. After single or repeat administration, mean maximum percent inhibition of 20S proteasome activity (vs baseline) in whole blood was 70–84% and 73–83% for the 1.0 and 1.3mg/m2 doses, respectively. The percentage of pts who had >90% inhibition was greater in subsequent doses vs first dose. Reversibility of 20S proteasome inhibition in whole blood was demonstrated. PK/PD modeling revealed an exposure-response relationship, with Emax and EC50 values consistent across study days. These results confirm btz is a potent inhibitor of the 20S proteasome. The efficacy of single-agent btz has been explored and validated in the pivotal phase 2 SUMMIT and phase 3 APEX trials at 1.3mg/m2, and explored in the phase 2 CREST trial at 1.0mg/m2. Complete safety and efficacy data by dose will be presented. Mean±SD PK parameters of btz in plasma 1.0mg/m2 1.3mg/m2 1.0mg/m2 1.3mg/m2 D1/C1 (n=11) D11/C1 (n=12) an=5;bn=11;cn=10;dn=7;en=11;fn=9 Tmax (h) 0.13±0.13 0.11±0.06 0.07±0.03 0.20±0.29 Cmax (ng/mL) 56.7±36.3 112±122 106.2±46.7 88.6±47.6 AUC48h(ng·h/mL) 26.5±12.4 34.6±19.8 82.8±35.9b 82.4±28.6b AUClast (ng·h/mL) 22.6±12.6 31.5±18.6 137±106 122.2±67.4 CL (L/h) 102.1±48.1 111.6±73.6 23.2±17.8 28.0±19.8 Vβ (L) 1976±2498a 2015±2974d 1659±752c 2415±1711 t1/2λz(h) 30.7±44.8a 11.5±12.7d 78.9±50.9c 75.6±49.9 D1/C3 (n=12) D11/C3 (n=12) Tmax (h) 0.12±0.12 0.10±0.05 0.16±0.17 0.10±0.05 Cmax (ng/mL) 66.5±42.6 120.3±70.7 83.9±69.3 114.9±98.3 AUC48h(ng·h/mL) 66.4±24.1 79.4±24.5b 101.6±58.2b 85.2±18.7f AUClast (ng·h/mL) 74.8±35.8 86.0±27.6 227±181 160.7±67.1 CL (L/h) 32.2±19.0 32.1±15.4 15.1±13.9 18.2±9.2 Vβ (L) 1852±951d 2059±1231 3294±2993e 2505±1641 t1/2λz (h) 39.9±14.4d 49.1±34.6 193±169e 108.6±64.8

Abstract Background: Triplet regimens combining a proteasome inhibitor, an immunomodulatory drug, and a steroid have been shown to be active and well tolerated in previously untreated MM pts. Extended treatment represents an alternative paradigm to induction followed by ASCT in this setting; however, agents for continuous therapy need to be convenient and well tolerated. The investigational agent ixazomib is the first oral proteasome inhibitor to be studied clinically. Phase 1 studies have indicated single-agent activity in relapsed/refractory MM and shown ixazomib to be well tolerated with a manageable safety profile, including limited peripheral neuropathy (PN) (Richardson PG et al, Blood 2014; Kumar SK, et al, Blood 2014). Weekly ixazomib plus lenalidomide-dexamethasone has been investigated in a phase 1/2 study in previously untreated MM pts (NCT01217957); treatment comprised triplet induction therapy followed by single-agent ixazomib maintenance therapy. Results of induction therapy have been previously reported (Kumar SK, et al, ASH 2012). Here we report phase 2 efficacy and safety data in pts receiving ixazomib maintenance. Methods: In phase 2, pts aged ≥18 yrs with measurable disease and no grade ≥2 PN received oral ixazomib 4.0 mg on d 1, 8, 15, lenalidomide 25 mg on d 1–21, and dexamethasone 40 mg on d 1, 8, 15, 22, for up to twelve 28-d induction cycles, followed by maintenance ixazomib on d 1, 8, 15 every 28 d until progression at the dose last tolerated during induction. Transplant-eligible pts could discontinue from study for ASCT after 6 cycles. The primary objective was CR+VGPR rate. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: Fifty pts were enrolled in phase 2; 29 discontinued during induction (cycles 1–12), primarily to undergo ASCT (n=14) or due to AEs (n=6) or pt withdrawal (n=4). Twenty-one pts received ixazomib maintenance therapy (cycle ≥13); 13 (62%) were male, and median age was 68 (range 34–77) years. At data cut-off (June 11, 2014), pts had received a median of 27 treatment cycles (range 15–32), including both induction and maintenance, with a median treatment duration of 26.6 mos (range 13.4–29.6). Mean ixazomib relative dose intensity was 95% and 89% in the induction and maintenance phases, respectively. The mean ixazomib dose administered during maintenance was 3.6 mg weekly. At data cut-off, 11 (52%) pts remained on ixazomib maintenance. Among 49 evaluable phase 2 pts, 44 (90%) achieved ≥PR, including 29 (59%) ≥VGPR. All 21 pts who received ixazomib maintenance had responded to induction therapy. Overall best confirmed/unconfirmed responses in the 21 pts included ≥CR in 11 (52%, of which 4 [19%] were stringent CRs [sCR]), ≥near-CR in 13 (62%), and ≥VGPR in 15 (71%), plus 6 (29%) PR. Responses were rapid and improved during treatment. Median time to first response (≥PR) was 0.99 mos (range 0.92–5.78) and to best response was 7.46 mos (range 1.02–24.74); 33% of pts improved their response during maintenance, including 2 VGPR to near-CR, 3 VGPR to CR, 1 VGPR to sCR, and 1 CR to sCR. At data cut-off, median duration of response was 26.5 mos (range 5.6–26.6+). Among 15 pts achieving ≥VGPR, 5 (33%) had progressed; median duration of ≥VGPR was 23.0 mos (range 3.7–26.1+). All pts were alive after follow-up of 24.6–30.3 mos, including a median follow-up from start of maintenance of 16.9 mos (range 12.9–18.9). Ixazomib maintenance was well tolerated; 15 (71%) pts had drug-related AEs, with only 2 (10%) pts with grade 3 drug-related AEs (hypokalemia, thrombocytopenia) and no grade 4 AEs. The most common (>1 pt) grade 1–2 drug-related AEs were diarrhea (n=8, 38%), nausea, pain in extremity (each n=3, 14%), anemia, and headache (each n=2, 10%). No PN was reported. Serious AEs were reported in 3 (14%) pts during maintenance, including grade 3 acute myocardial infarction, grade 3 pneumonia, and grade 3 orthostatic hypotension; all were considered not related to treatment. Only 1 pt required an ixazomib dose reduction due to an AE (neuralgia). Conclusions: These data indicate that single-agent ixazomib maintenance for up to 1.5 yrs was feasible and generally well tolerated, improved responses following ixazomib-lenalidomide-dexamethasone induction, and contributed to durable responses (median >2 yrs) in previously untreated MM pts not undergoing ASCT. The results support the ongoing phase 3 trial of ixazomib in the maintenance setting (NCT02181413). Disclosures Kumar: Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone and as maintenance therapy for patients with previously untreated multiple myeloma.. Niesvizky:Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Hamadani:Millennium: The Takeda Oncology Company: Research Funding. Stewart:Takeda Pharmaceuticals International Co.: Research Funding; Sanofi: Consultancy; Array BioPharma: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Hari:Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding. Vescio:Celgene: Speakers Bureau; Millennium: The Takeda Oncology Co.: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Kaufman:Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Berg:Takeda Pharmaceuticals International Co.: Employment. Liao:Takeda Pharmaceuticals International Co.: Employment. Hui:Takeda Pharmaceuticals International Co.: Employment. Richardson:Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Pev (TAK-924/MLN4924), a novel investigational NAE inhibitor, enhances the anti-leukemic effects of aza in AML cell lines and murine xenografts (Smith et al, Blood 2011). Single-agent pev activity was confirmed in relapsed/refractory AML pts (Swords et al, Br J Haematol 2015). This open-label, multi-center, dose-escalation study (NCT01814826) investigated pev + aza in treatment-naïve older AML pts. Dose-limiting toxicities (DLTs)includedG2 hyperbilirubinemia and G4 AST elevation (n=1 each) at pev 30 mg/m2. The maximum tolerated dose (MTD) for the combination was pev 20 mg/m2 + aza 75 mg/m2 (Swords et al, ASH 2014).We present updated safety/efficacy results for the MTD cohort (fully enrolled). Methods: Primary objectives included safety and tolerability assessments of pev + aza in addition to defining the MTD. Secondary objectives included pharmacokinetics (PK) and disease response assessments. Treatment-naïve pts ≥60 yrs unlikely to benefit from standard induction therapy (defined by ≥1 of: antecedent hematologic disease; known adverse cytogenetic risk; ECOG PS 2; ≥75 yrs), received pev 20 or 30 mg/m2 IV on d 1, 3 and 5, + fixed-dose aza (75 mg/m2 IV/SC) on d 1-5, 8 and 9, every 28 d until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed per NCI-CTCAE v4.03; response per IWG criteria for AML. Bone marrow samples were collected at screening to assess cytogenetic risk (CALGB) and mutation profile; serial samples for PK analysis were drawn in cycle 1. Results: Demographics:As of May 17 2016, 61 pts (median age 75 yrs [range 61-89]; 54% male; 77% ECOG PS 0/1, 23% ECOG PS 2; 57% de novo, 43% secondary AML; median marrow blasts 36% [range 5-92]) had received pev 20 mg/m2, of whom 48% had intermediate-, 30% adverse-, and 3% favorable-risk cytogenetics. Safety/PK: Pts received a median of 4 cycles (range 1-33), and 23/61 pts (38%) received ≥6 cycles of pev + aza. The most common AEs were constipation (46%), nausea (44%), fatigue (43%), and anemia (39%). Fifty pts (82%) experienced ≥G3 AEs; the most frequent (≥15%) were anemia, febrile neutropenia (each 28%), thrombocytopenia (21%), neutropenia (18%), and pneumonia (15%). ≥G3 AST/ALT elevations were reported in 5% of pts. Forty-one pts (67%) experienced serious AEs; the most frequent (≥10%) were febrile neutropenia, neutropenia (each 25%), and pneumonia (11%). Two pts discontinued due to pev related toxicity (G3 febrile neutropenia). There were 11 on-study deaths unrelated to study therapy. In the MTD expansion phase (n=55), 2 pts experienced DLTs of transient G3/4 transaminase elevations, and were successfully re-challenged following dose reduction to remain on study. Pev PK was not altered by the addition of aza. Responses: Overall response rate (ORR) in 52 response-evaluable pts was 60% (18CR, 5CRi, 8PR; Figure 1), with a median duration of remission of 8.3 mos (95% CI: 5.75, 12.06); 19/31 (61%) responses occurred within the first 2 cycles.Of the 23 pts with CR/CRi, 14 had responses lasting ≥4 cycles, 2 went on to have allogeneic stem cell transplant, 9 had intermediate-, 7 adverse-, and 1 favorable-risk cytogenetics. ORR was: 64% (14/22; 7CR, 3CRi, 4PR) vs 57% (17/30; 11CR, 2CRi, 4PR) for pts with low- (<30%) vs high- (≥30%) marrow blasts; 58% (18/31; 11CR, 3CRi, 4PR) vs 62% (13/21; 7CR, 2CRi, 4PR) for de novo vs secondary AML pts; 61% (14/23; 8CR, 1CRi, 5PR) vs 50% (8/16; 5CR, 2CRi, 1PR) for intermediate- vs adverse-risk cytogenetic pts; 83% (19/23; 14CR, 2CRi, 3PR) vs 41% (12/29; 5CR, 3CRi, 4PR) for pts who received ≥6 cycles vs <6 cycles of aza, respectively. Responses were seen in pts with typically refractory disease; 7/11 pts with TP53 mutations achieved either a CR/CRi (n=3) or PR (n=4); 4 stayed on study for >10 cycles. After a median follow-up of 16.4 mos, 6-mo survival was 52%. Median overall survival was: 7.0 mos for the MTD cohort; 8.5 vs 5.2 mos for pts with low- (<30%) vs high- (≥30%) marrow blasts (Figure 2); 5.6 vs 11.2 mos for de novo vs secondary AML pts (Figure 3); and 16.1 vs 5.3 mos for pts aged 65-74 vs ≥75 yrs, respectively. Conclusion: Pev + aza was well tolerated. Response rates and durable remissions were observed with limited additional toxicity beyond what is expected for aza alone. The timing and frequency of responses suggests benefit from the addition of pev compared to aza alone (Dombret et al, Blood 2015). At the time of writing, a randomized phase 2 study in low-blast AML/high-risk myelodysplastic syndromes is ongoing. Disclosures Coutre: Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Zeidner:Tolero: Research Funding; Merck: Research Funding; Takeda: Research Funding; Otsuka: Consultancy; Agios: Honoraria. Foran:medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; pfizer: Honoraria; karyopharm: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Cruz:Millennium Pharmaceuticals, Inc.: Honoraria; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Erba:Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Ariad: Consultancy; Jannsen: Consultancy, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Vardhanabhuti:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dobler:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faessel:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sedarati:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dezube:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Savona:Takeda: Research Funding; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.