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.
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