Jeanne Mendell‐Harary

This is a clinical safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) study of a single ascending dose (SAD) and a multiple ascending dose (MAD) of the oral direct factor Xa inhibitor edoxaban in healthy males. The placebo-controlled, single-blind, randomized, 2-part study consists of a SAD arm with 85 subjects (10, 30, 60, 90, 120, 150 mg) and a MAD arm with 36 subjects (90 mg daily, 60 mg twice daily, 120 mg daily). Effects of food and formulation (tablet vs solution) are assessed in a crossover substudy. In the SAD, doses are well tolerated up to 150 mg. Exposure is proportional to dose. PK profiles are consistent across dose with rapid absorption, biphasic elimination, and terminal elimination half-life of 5.8 to 10.7 hours. In the MAD, mean accumulation after daily dosing is 1.10 to 1.13 and consistent with elimination half-life of 8.75 to 10.4 hours. Intrasubject variability ranges from 12% to 17% for area under the curve. In general, plasma edoxaban concentrations are linearly correlated with coagulation parameters. Edoxaban is safe and well tolerated with no dose-dependent increases in adverse events. It is concluded that single and multiple doses of edoxaban are safe and well tolerated up to 150 mg with predictable PK and PD profiles.

11514 Background: Inactivation of p53 is the most frequent event in cancer driven by mutations in TP53 or overexpression of MDM2, a negative regulator of p53. DS-3032b is an oral small molecule that disrupts the MDM2-p53 interaction, resulting in reactivation of wild type p53 and causing growth arrest/apoptosis. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics (PD) and preliminary efficacy of DS-3032b. Methods: Patients (pts) received DS-3032b orally in 28 days cycle as per Table. TP53 status was confirmed post-enrollment. Results: 94 pts were enrolled with ST (50, 53%), WD/DD LPS (40, 43%), L (4, 4%). Doses, schedules (Sch), MTDs and responses are tabulated below. Median age was 60.5 years, 50% male, 63% had ≥ 3 prior therapies. 73/84 (87%) pts tested had WT TP53. The most common ( > 10%) TEAEs were nausea 71%, vomiting 31%, diarrhea 40%, decreased appetite 37%, abdominal pain 16%, dry mouth 11%, thrombocytopenia 61%, neutropenia 28%, anemia 43%, fatigue 55%, dysgeusia 18%, headache 19%, cough 19% and peripheral edema 14%. There were 8 dose limiting toxicities (DLT): six Gr 2-4 thrombocytopenia +/- neutropenia; 3 events resolved, 3 unresolved. One Gr 3 nausea, vomiting and anorexia and another Gr 2 fatigue. Sch D (3/14 days) had the best safety profile. In 79 efficacy-evaluable pts, 47 (60 %) achieved stable disease (SD). Median duration of SD was 6.7 (1.6 to 36.4) months. Partial responses (PR) were seen in DDLPS, synovial sarcoma and lung ca (SC).PK parameters AUC0-24h and Cmax were dose proportional with median Tmax 3 hours. PD biomarker MIC-1 correlated with drug exposure. In paired biopsies, MDM2 inhibition resulted in increase of nuclear p53 levels (IHC) in 5/6 pts (83%). Conclusions: DS-3032b has acceptable safety profile with intermittent dosing. Objective responses and durable SD were seen in MDM2 amplified ST and DDLPS warranting further studies Clinical trial information: NCT01877382.Schedule, days Doses, mg N = 94 pts Histology MTD, mg Best Response A – 21/28 15 – 240 40 ST/L 120 SD A – 21/28 120 20 120 B – 28/28 90 9 90 C – 7/28 120, 200 9 Progressing WD/DD LPS and MDM2 amp ST Not achieved 1 PR DDLPS D – 3/14 – 3/14 120, 200, 260, 340 16 260 2 PR: synovial sarcoma & SCLC

8045 Background: P is a fully human anti-HER3 antibody that inhibits HER3 binding with its ligand heregulin (HRG). Preclinically, P enhances anti-tumor activity with EGFR inhibitors, prevents HER3 reactivation after anti-EGFR treatment, and inhibits HRG-dependent activation. Phase Ib showed that P, with E (150mg/day PO), was tolerated at 18mg/kg IV q3w. Methods: This Ph2 randomized, placebo-controlled double-blind study assessed safety and efficacy of P+E vs. placebo (Pbo)+E in E-naïve sbjs with advanced NSCLC (2nd or later line). 215 sbjs were randomized to: 1) High Dose [HD]: P 18 mg/kg IV q3w; 2) Low Dose [LD]: P: 18 mg/kg IV X 1, 9 mg/kg IV q3w maintenance; or 3) Pbo q3wk. All subjects received E 150 mg/day PO. Endpoints included PFS (primary), and OS and safety (secondary). HRG, measured as mRNA, was prospectively hypothesized to be the primary predictive biomarker before database lock. High/Low HRG cutoff was set at the median of the blinded data. Results: 212 sbjs comprised the ITT. Median (m) PFS for ITT for HD, LD, and Pbo arms was 1.4 mos (HR 0.98), 2.5 mos (HR 0.77), and 1.6 mos, respectively (p=NS). 101 sbjs (51 HRG high) had adequate tissue for HRG testing. PFS was significantly improved in the HRG high subgroup (Table). HRG low subgroup showed no improvement in PFS (HR 0.92) and OS (HR 1.05) vs. Pbo. Grade >3 AE’s (HD, LD, Pbo) included: diarrhea (11.4%, 8.5%, 4.2%) and rash (5.7%, 7.0%, 2.8%). Conclusions: P showed improved PFS in the HRG high, but not in the ITT population. P safety was similar to Pbo with the exception of manageable rash and gastrointestinal effects. HRG appears to be a predictive biomarker for P, confirming preclinical findings (Schneider et al, Yonesaka et al, ASCO 2014). HERALD is the first randomized Pbo controlled trial in NSCLC to report a predictive biomarker for HER3. Based on these results, a 2-part (A, confirmation of HRG predictive value; B, pivotal HRG high only) Phase 3 study was initiated. Clinical trial information: NCT01211483. High dose P + E Low dose P + E Pooled doses P + E E alone (Pbo) mPFS (mos) 3.4 3.0 3.0 1.4 PFS HR (95% CI) 0.37 (0.16, 0.85)* 0.29 (0.13, 0.66)† 0.32 (0.16, 0.67)† mOS (mos) 6.1 10.7 9.7 5.0 OS HR (95% CI) 1.15 (0.50, 2.61) 0.60 (0.25, 1.41) 0.81 (0.39, 1.67) Log-rank p value: *<0.03, †<0.003).