Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that selectively and irreversibly binds to its target. Preliminary findings of OPZ in pts with hematologic malignancies (HM) have been reported previously (Savona, ASH 2012, 203; Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with MM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives (phase 1b portion) are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective (phase 2 portion) is to determine the best overall response rate (ORR; ≥PR). In the phase 1b portion, OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments up to 330 mg/d. In the phase 2 portion, pts are receiving OPZ (240 mg/d) on the 5/14 schedule (initial phase 2 schedule opened to enrollment). For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 68 pts with MM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with MM are presented in Table 1. Median treatment duration (phase 1b) was 21.3 weeks (range, 0.3–62.1; 2/7 schedule) and 10.1 weeks (range, 0.3–81.1; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 5.4 weeks (range, 0.7–26.7). In all patients with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. Of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule, all 3 DLTs (including hypotension [300 mg/d, n=1], grade 3 diarrhea and grade 4 thrombocytopenia [330 mg/d, n=1 each]) were observed in pts with MM. Of 4 DLTs on the 5/14 schedule, 2 DLTs (grade 3 renal failure [180 mg/d, n=1] and grade 3 tumor lysis syndrome [270 mg/d, n=1]) were observed in pts with MM. The most common adverse events (AEs) in patients with MM are shown in Table 2. Grade 4 AEs included 8 pts (11.8%) with thrombocytopenia, 4 pts (5.9%) with anemia, and 1 pt each (1.5%) with sepsis, leukopenia, decreased platelet count, hyperkalemia, and acute renal failure. Two pts died from upper gastrointestinal bleeding (5/14 schedule, 240 mg/d). One pt (5%) on the 2/7 schedule (phase 1b), 3 pts (15%) on the 5/14 schedule (phase 1b), and 8 pts (30%) on the 5/14 schedule (phase 2) discontinued treatment due to an AE; 6 pts (29%) on the 2/7 schedule (phase 1b), 7 pts (35%) on the 5/14 schedule (phase 1b), and 11 pts (41%) on the 5/14 schedule (phase 2) had their dosage reduced at least once due to an AE. Thirty-four pts in the phase 1b portion were eligible for response. In the phase 1b portion, the ORR in 15 pts on the 2/7 schedule (all were carfilzomib [CFZ]-naïve) was 33.3%; the clinical benefit rate (CBR) was 46.7% (3 very good partial response [VGPR], 2 partial response [PR], and 2 minimal response [MR]). Among 19 pts on the 5/14 schedule (phase 1b portion; all were CFZ-naïve), the ORR was 36.8%; the CBR was 42.1% (1 complete response, 2 VGPR, 4 PR, and 1 MR). In the 5/14 schedule (phase 1b), the ORR among bortezomib [BTZ]-refractory pts (n=7) was 14.3%. On the phase 2 portion (5/14 schedule), the ORR among CFZ-refractory pts (n=11) and CFZ-sensitive pts (n=12) was 27.3% (3 PR) and 33.3% (2 VGPR and 2 PR), respectively; the ORR among BTZ-refractory pts (n=12) was 25.0%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all patients with HM. The most common grade 3 AEs were diarrhea, nausea, and vomiting; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity. Enrollment of pts with MM is continuing on the phase 2 study in both treatment schedules. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Vij: Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Jannsen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Array: Honoraria. Off Label Use: Carfilzomib as treatment in multiple myeloma and solid tumors. Savona:Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Kaufman:Millennium: 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. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other. Paner:Celgene Corporation: Honoraria. Jagannath:Millenium: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Merck: Honoraria; Ortho: Membership on an entity's Board of Directors or advisory committees; im: Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; Optum Health Worldwide: Membership on an entity's Board of Directors or advisory committees; PER group: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:BMS: Advisory Board Other, Consultancy, Honoraria; Celgene: Advisory Board, Speaking, Advisory Board, Speaking Other, Consultancy, Honoraria; Janssen: Advisory Board, Speaking, Advisory Board, Speaking Other, Consultancy, Honoraria; Millennium: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Novartis: Advisory Board Other, Honoraria; Onyx: Advisory Board, Speaking Other, Consultancy, Honoraria; Skyline Dx: Advisory Board Other, Honoraria. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment.

Background: SNS-062 is a potent, noncovalent (reversible) BTK inhibitor in development for B-cell malignancies and other cancers. SNS-062 has the potential for activity in patients whose cancers are sensitive to BTK inhibition, as well as those that are resistant to ibrutinib through acquisition of a BTK Cys481Ser mutation. In vitro studies have demonstrated that SNS-062 antitumor activity in cells with the mutation is unaffected (Binnerts et al, EORTC 2015, Abstract C186), in contrast to the substantially reduced activity seen with ibrutinib and acalabrutinib. This study was designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SNS-062 in healthy subjects. Methods: This was a phase 1a, first-in-human, randomized, double-blind, placebo-controlled, sequential-group, single-dose study conducted in 3 stages. In stage 1, four sequential cohorts of 8 subjects were randomly assigned to receive ascending SNS-062 dose levels (50, 100, 200, and 300 mg; n=6, 3 male, 3 female) or placebo (n=2, 1 male, 1 female) as a single dose administered orally. The primary endpoint was safety, assessed by adverse events (AEs), laboratory parameters, and cardiac monitoring. Secondary endpoints included PK parameters and PD parameters (inhibition of phosphorylation BTK [pBTK] as determined by ELISA in whole blood lysates). Stages 2 and 3 were designed to evaluate the effects of food and CYP3A4 inhibition, respectively, on the PK of SNS-062. Results: In stage 1 (n=32), the median age was 55 years (range: 22-64) among those who received SNS-062 (n=24) and 42.5 years (range: 29-65) among those who received placebo (n=8). Treatment-emergent AEs (TEAEs) were reported for 8 (33%) subjects who received SNS-062 and for 3 (38%) subjects who received placebo. TEAEs reported for subjects who received SNS-062 included headache (n=5) and nausea, constipation, bronchitis, fatigue, orthostatic hypotension, and supraventricular tachycardia (n=1 each) without obvious evidence of dose dependency. AEs in the placebo group included headache (n=2), nausea (n=2), and diarrhea (n=1). AEs were all reported as Grade 1 except for 1 subject (who received 300 mg SNS-062) who experienced Grade 2 headache and fatigue. No Grade 3 or higher AEs and no serious AEs were reported. SNS-062 was rapidly absorbed (median Tmax: 1 hour [range: 0.5-3.0 hours]). SNS-062 concentrations declined in a multiphasic manner. Exposure increased approximately proportional to dose. Mean PK parameters for each cohort are shown in the Table. SNS-062 demonstrated rapid and near complete inhibition of pBTK at all dose levels. Stages 2 and 3 are in progress and results of the completed study will be reported at the meeting. Conclusions: The observed safety, PK, and PD profiles of SNS-062 in this phase 1a study in healthy subjects support further clinical investigation. This study continues to evaluate the effects of food and CYP3A4 inhibition on SNS-062 PK. Mean SNS-062 exposure at 50 mg, the lowest dose level studied, exceeded those reported for ibrutinib (Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics, LLC; 2016) and acalabrutinib (Byrd et al, N Engl J Med 2016;374:323:32) when those drugs are administered at recommended dose levels. The extent of SNS-062 exposure and duration of pBTK inhibition are encouraging and support twice-daily dosing in a planned phase 1b/2 study in patients with advanced B-cell malignancies with and without the BTK Cys481-Ser mutation. This study was sponsored by Sunesis Pharmaceuticals. Disclosures Neuman: Puma Biotechnology: Employment; Sunesis Pharmaceuticals: Employment. Ward:Sunesis Pharmaceuticals: Consultancy, Employment. Arnold:Sunesis Pharmaceuticals: Consultancy. Combs:Sunesis Pharmaceuticals: Consultancy. Gruver:Sunesis Pharmaceuticals: Employment. Hill:Sunesis Pharmaceuticals: Employment. Miller:Sunesis Pharmaceuticals: Consultancy. Fox:Amphivena Therapeutics: Consultancy, Equity Ownership, Patents & Royalties: Patent #9212225; Bispecific CD33 and CD3 Binding Proteins; Sunesis Pharmaceuticals: Consultancy, Equity Ownership, Patents & Royalties: Patent Application #20150202189; Methods of Using SNS-595 for Treatment of Cancer Subjects with Reduced BRCA2 Activity.

Introduction: In order to address the issue of acquired resistance to ibrutinib, we sought to characterize the Bruton agammaglobulinemia tyrosine kinase (BTK) inhibitor SNS-062 in preclinical models of chronic lymphocytic leukemia (CLL). Methods: Primary CLL B cells were isolated from the whole blood of consented patients by ficoll density centrifugation and Rosette-Sep negative selection. Annexin V and propidium iodide flow cytometry was used to measure patient CLL cell viability and 7-AAD was used to measure viability in stromal co-culture. CD40 and CD86 expression was evaluated via flow cytometry subsequent to sustained 3.2uM CpG stimulation. BCR signaling in primary CLL cells was investigated by immunoblot following 1 hour treatment and following 1 hour or 24 hours of incubation with SNS-062 in XLA cell lines. ITK inhibition was investigated via immunoblot after stimulation with anti-CD3 and anti-CD28 and incubation with SNS-062 for 1 hour. SNS-062 was used at a concentration of 1uM in preclinical studies unless otherwise noted. Measurement of kinase activity in human recombinant WT BTK or C481S BTK was performed in a FRET kinase assay. Results: Immunoblots of BTK and ERK phosphorylation of XLA cells transfected with WT or C481S BTK demonstrated that SNS-062 inhibition is comparable to that of ibrutinib in WT BTK and greater than that of ibrutinib in C481S BTK. Using a recombinant kinase assay, we found the IC50 of SNS-062 against WT BTK to be 4.6nM and C481S BTK to be 1.1nM, suggesting that SNS-062 retains activity against the mutated BTK variant. Additionally, SNS-062 was found to be six times more potent than ibrutinib and greater than 640 times more potent than acalabrutinib against C481S BTK. SNS-062 demonstrates dose-dependent inhibition of BTK in primary patient CLL cells comparable to ibrutinib via immunoblot for BTK phosphorylation. The viability of primary patient cells treated with 0.1uM, 1.0uM, and 10.0uM SNS-062 for 48 hours was measured to be 96.7%, 96.1%, and 88.1%, respectively, that of the untreated condition. At 48 hours, SNS-062 decreased viability of primary CLL cells in the presence of HS5 stromal protection by 5.5%. SNS-062 was found to decrease CpG induced CD40 and CD86 expression by 8.7% and 15.7%, respectively. Using an in vitro kinase assay, SNS-062 inhibited ITK with an IC50 value of 24nM. An immunoblot of anti-CD3/CD28 stimulated Jurkat cells revealed that SNS-062 decreased the phosphorylation of ERK, implying inhibition of ITK. Conclusion: Unlike ibrutinib, SNS-062 inhibits BTK signaling in the presence of the C481S mutation and may address acquired resistance to covalent BTK inhibitors. SNS-062 decreases B cell activation markers, viability, and stromal cell protection in primary patient CLL cells and was shown to inhibit ITK, suggesting support of T cell mediated antitumor activities. These data support further investigation of this molecule and advancement into clinical trials. Citation Format: Catherine A. Fabian, Sean D. Reiff, Daphne Guinn, Linda Neuman, Judith A. Fox, Wendy Wilson, John C. Byrd, Jennifer A. Woyach, Amy J. Johnson. SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated Bruton tyrosine kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1207. doi:10.1158/1538-7445.AM2017-1207

Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure‐matching strategy with a wild‐type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60 μg/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6 h, respectively. According to the phase III protocol, if a second dose was required after 3 h because of a lack of efficacy, 90% of the population was observed to be above target 6 h after the initial dose. The model‐informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication.

Background: Oprozomib (OPZ) is a selective oral proteasome inhibitor that binds selectively and irreversibly to its target. In a phase 1b/2 study of single-agent OPZ in patients (pts) with hematologic malignancies, OPZ has shown promising antitumor activity in pts with multiple myeloma (MM) (Savona, ASH 2012, 203; Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). This multicenter, single arm phase 1b/2 study evaluates the safety and tolerability of OPZ with dexamethasone (DEX) in pts with relapsed and/or refractory MM. Initial results from the study are presented. Methods: This is an open-label, phase 1b/2 study (NCT01832727). Pts with relapsed and/or refractory MM who have received 1–5 prior lines of therapy (at least 1 regimen including lenalidomide and/or bortezomib) are eligible for enrollment. Pts are receiving OPZ on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting OPZ dose was 210 mg on both schedules. Doses are being escalated in 30-mg increments using a standard 3+3 dose-escalation scheme. DEX (20 mg) is being given by oral administration on days 1, 2, 8, and 9 of a 14-day cycle. Treatment is being administered until pt withdrawal or progressive disease. The primary objectives of the phase 1b study are to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of OPZ with DEX and to evaluate safety and tolerability. Response is being assessed by IMWG criteria, with inclusion of minimal response and near complete response by modified EBMT criteria to provide an overall response rate (ORR) as reflected by partial response (PR) or better and a clinical benefit rate (CBR) as reflected by minimal response (MR) or better. Results: As of July 7, 2014, 29 pts were enrolled (2/7 schedule, n=14; 5/14 schedule, n=15). Median age was 64 years (2/7 schedule) and 63 years (5/14 schedule). Pts received a median of 3 prior regimens in the 2/7 schedule and 2 prior regimens in the 5/14 schedule. Preliminary median OPZ treatment duration in this ongoing study was 13.3 weeks in the 2/7 schedule (range, 3.3–35.3 weeks) and 5.7 weeks in the 5/14 schedule (range, 0.1–24.7 weeks). No dose-limiting toxicities (DLTs) have occurred in pts on the 2/7 schedule; 3 DLTs were observed on the 5/14 schedule (210 mg cohort; grade 2 subarachnoid hemorrhage, grade 3 transaminitis, and grade 4 thrombocytopenia [n=1 each]). In both treatment schedules combined, the most common adverse events (AEs) were diarrhea (83%), nausea (79%), and vomiting (62%); additional AEs are shown in the table. The most common grade 3 AEs included diarrhea (21%), anemia (14%), pneumonia (14%), and nausea (10%). Grade 4 AEs included thrombocytopenia (n=1, 2/7 schedule; n=2, 5/14 schedule) and decreased lymphocyte count (n=1, 5/14 schedule). Grade 5 sepsis occurred in 1 pt on the 2/7 schedule (240 mg/d) and 1 pt on the 5/14 schedule (210 mg/d). Treatment was discontinued because of AEs in 2 pts on the 2/7 schedule and 7 pts on the 5/14 schedule. Five pts on the 2/7 schedule and 7 pts on the 5/14 schedule had their OPZ dose reduced at least once. In 12 pts enrolled on the 2/7 schedule who had ≥2 assessments for response, 5 pts had a PR, 2 pts had a MR, and 5 pts had stable disease (SD) as their best overall response for an ORR of 41.7% and a CBR of 58.3%. In 7 pts enrolled on the 5/14 schedule who had ≥2 response assessments, 3 pts had a MR and 2 pts had SD as their best overall response for a CBR of 42.9%. Conclusions: Preliminary results suggest that treatment with OPZ and DEX has improved gastrointestinal tolerability in pts with relapsed and/or refractory MM relative to single-agent OPZ (Savona, ASH 2012, 203; Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Additional measures will be taken to improve gastrointestinal tolerability. Encouraging responses have been seen in this heavily pretreated patient population, especially with the 2/7 schedule. Enrollment in the phase 1 portion of the study is ongoing; dose escalation will continue until the MTD and RP2D are determined. Updated results will be presented at the meeting. Disclosures Hari: Genzyme: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Shain:Onyx/Amgen: Speakers Bureau. Voorhees:Millennium/Novartis: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Research Funding; Prolexys Pharmaceuticals: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; GSK: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Abidi:Onyx: Speakers Bureau. Zonder:Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Richardson:Onyx: Membership on an entity's Board of Directors or advisory committees. Neuman:Onyx Pharmaceuticals: Employment. Dixon:Onyz Pharmaceuticals: Employment, Equity Ownership.

Background Oprozomib (OPZ), a structural analog of carfilzomib (CFZ), is an oral, second-generation epoxyketone proteasome inhibitor that selectively and irreversibly binds to its target. Preliminary findings have shown that modified-release OPZ tablets have acceptable safety and tolerability and promising antitumor activity in pts with hematologic malignancies (HM) (Kaufman JL, et al. EHA 2013, P233). Updated results are presented herein. Methods This open-label, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who relapsed after failing ≥1 line of therapy. The primary objectives are to determine the safety profile and maximum tolerated dose (MTD) of OPZ. Secondary end points include response, pharmacokinetics, and pharmacodynamics. OPZ dose escalation began at 150 mg/d. Dose levels are being increased in 30-mg increments; there is no maximal planned dose. Modified-release OPZ tablets are being administered once daily on Days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on Days 1–5 of a 14-day cycle (5/14 schedule). Peripheral blood mononuclear cells (PBMC) and whole blood (WB) samples are being collected for assessment of proteasome inhibition (PI). Results As of July 1, 2013, 42 pts were enrolled, including 15 multiple myeloma (MM) and 4 Waldenström's macroglobulinemia (WM) pts on the 2/7 schedule and 15 MM and 8 WM pts on the 5/14 schedule. Median pt age was 62.0 and 64.0 years (2/7 and 5/14 schedule, respectively). Two-thirds (67%) of pts had prior bortezomib (BTZ) exposure; 43% were refractory to a prior BTZ-containing regimen. Median treatment duration for the 2/7 and 5/14 schedule was 11.3 weeks and 8.7 weeks, respectively. There were 2 dose-limiting toxicities (renal failure [180 mg/d] and tumor lysis syndrome [240 mg/d]; both occurred on the 5/14 schedule). The most common grade 1–2 adverse events (AEs; ≥5 pts) are reported in Table 1. The most common grade 3–4 AEs (≥2 pts) included diarrhea (n=9); anemia, nausea, and neutropenia (n=4 each); hypophosphatemia, thrombocytopenia, and vomiting (n=3 each); and dehydration and fatigue (n=2 each) (Table 2). Two pts experienced grade 1 peripheral neuropathy (PN); both reported PN grade 2 at baseline. No new-onset or worsening of PN was reported. Thirteen pts had their treatments held or delayed; 6 had their dosage reduced at least once. Eleven pts discontinued treatment. Apparent dose-dependent increases in the Day 1 plasma area under the concentration time curve and maximum concentration (Cmax) were observed (150–300 mg/d). The median time to Cmax was 2 hr and the terminal half-life was approximately 0.5–1.5 hr. Pts receiving 240-mg/d OPZ achieved depth and duration of PI that is similar to CFZ (20/27 mg/m2). In WB, ≥90% inhibition of the primary chymotrypsin-like activity was achieved 4 hr following OPZ administration; this inhibition was sustained through Cycle 2. In PBMCs, ≥80% inhibition was observed on the first day of Cycle 1 and showed minimal recovery before dosing on day 1 of Cycle 2. OPZ administration also inhibited the secondary caspase-like and trypsin-like sites of the immunoproteasome (LMP2 and MECL1, respectively). The profile of OPZ target inhibition is similar to previous reports with CFZ. Thirteen MM and 5 WM pts on the 5/14 schedule were included in the response evaluation. The clinical benefit response rate (CBR) was 23.1% (MM) and 80.0% (WM). In pts with MM, 1 (150 mg/d) had a very good partial response, 2 (210 mg/d) had a partial response (PR), 6 (150–240 mg/d) had stable disease (SD), 1 (150 mg/d) had progressive disease (PD), and 3 were not evaluable for response. In WM pts, 4 (150–210 mg/d) had a PR and 1 (180 mg/d) had SD. In 12 MM and 3 WM pts included in the response evaluation (2/7 schedule), the CBR was 16.7% (MM) and 0% (WM). Two MM pts (150–180 mg/d) had a minimal response (MR); 10 MM (150–300 mg/d) and 3 WM (180–240 mg/d) pts had SD. In 14 pts with MM or WM who were refractory to BTZ and eligible for assessment, 3 had a PR, 1 had a MR, 9 had SD, and 1 had PD. Conclusion Once-daily modified release OPZ tablets continue to have acceptable safety and promising antitumor activity in MM and WM pts. The most common grade 3 AE was diarrhea; grade 4 AEs were infrequent. No grade ≥2 PN was reported in pts with baseline PN; no new-onset or worsening of PN was reported. Dose escalation is continuing in the 2/7 (300 mg/d) and 5/14 (270 mg/d) dosing schedules. The phase 2 study will begin once the MTD is reached. Updated data will be presented at the meeting. Disclosures: Ghobrial: Onyx: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi (Genzyme): Research Funding; Noxxon: Research Funding. Kaufman:Jansenn: Consultancy; Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy; Merck: Research Funding. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vij:BMS: Honoraria; Lilly: Honoraria; Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Speakers Bureau. Neuman:Onyx: Employment, Equity Ownership. Wong:Onyx: Employment, Equity Ownership, Patents & Royalties, Research Funding. Anderl:Onyx: Employment, Equity Ownership.

The Dead Sea (barometric pressure: 800 mm Hg) is an important balneotherapeutic centre for chronic dermatologic and arthritic diseases. In the past, hypertensive patients have complained sporadically of weakness and dizziness during a stay in the Dead Sea. It was therefore recommended that hypertensives do not stay at these health centres. The aim of our study was to investigate the changes in blood pressure (BP) parameters of 72 hypertensive and normotensive osteoarthritic and rheumatoid arthritic elderly patients during a 2-week stay in the Dead Sea, and to further evaluate the effect of different balneotherapeutic means on these BP changes. Following a primary BP assessment at the out-patient clinic (Beer Sheva barometric pressure: 745 mm Hg), the patients were divided into four groups: (1) thermomineral pool; (2) Dead Sea water baths; (3) combination of the aforementioned treatments; and

Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that has shown promising antitumor activity in patients (pts) with hematologic malignancies (HM), including WM (Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with WM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, multicenter, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives of the phase 1b portion of the study are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective of the phase 2 portion of the study is to determine the best overall response rate (ORR; ≥minimal response [MR]). In the phase 1b portion, single-agent OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments. In the phase 2 study, pts have received 240 mg/d on the 5/14 schedule, which was the initial phase 2 schedule opened to enrollment. For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 36 pts with WM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with WM are presented in Table 1. For WM patients in the phase 1b portion, median treatment duration was 17.1 weeks (range, 3.1–51.4; 2/7 schedule) and 51.7 weeks (range, 3.9–74.9; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 8.1 weeks (range, 0.7–22.0). In all pts with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. None of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule occurred in patients with WM. Two of the 4 DLTs observed on the 5/14 schedule occurred in pts with WM (grade 4 tumor lysis syndrome [240 mg/d, n=1] and grade 3 vomiting [270 mg/d, n=1]). The most common adverse events (AEs) in pts with WM are shown in Table 2. Grade 4 AEs were thrombocytopenia (n=1; phase 1b; 2/7 schedule) and influenza and tumor lysis syndrome (n=1 each; phase 1b; 5/14 schedule). No on-study deaths occurred in pts with WM. In the phase 1b portion, two pts (25%) in the 2/7 schedule and 1 pt (9%) in the 5/14 schedule discontinued treatment due to an AE; 6 pts (35%) discontinued treatment due to an AE in the phase 2 portion. In the phase 1b portion, 3 pts (38%) (2/7 schedule) and 6 pts (55%) (5/14 schedule) had their dosage reduced at least once due to an AE; 10 pts (59%) in the phase 2 portion had their dosage reduced at least once due to an AE. In the phase 1b portion, all 19 pts were eligible for response and were carfilzomib (CFZ)-naïve. The ORR in 8 pts enrolled on the 2/7 schedule was 38% (3 pts had a partial response [PR]). Among 11 pts enrolled on the 5/14 schedule, the ORR was 73% (1 complete response, 1 very good partial response, 5 PRs, and 1 MR); the ORR for BTZ-refractory pts (n=4) was 75%. All 17 pts enrolled on the phase 2 portion were response-eligible. The ORR in the phase 2 portion was 59% (there were 5 PRs and 5 MRs). The ORR among CFZ-naïve pts (n=16) in the phase 2 portion was 56; the ORR among BTZ-refractory pts (n=3) was 67%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all pts with HM. In pts with WM who received single-agent OPZ, the most common grade 3 AEs were neutropenia and diarrhea; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity in pts with WM. Enrollment of patients on the 2/7 schedule is continuing; the target enrollment for the phase 2 portion of the study is 66 patients. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Disclosures Siegel: Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Off Label Use: Monoclonal antibody/toxin fusion protein. For treatment of multiple myeloma. Kaufman:Millennium: 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. Raje:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Ely Lilly: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Treon:Onyx: Consultancy, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other.