688PFINAL RESULTS OF A PHASE 1B OF OMP-59R5 (ANTI-NOTCH2/3/STEM CELL ANTIBODY) IN COMBINATION WITH NAB-PACLITAXEL AND GEMCITABINE (NAB-P + GEM) IN PATIENTS (PTS) WITH UNTREATED METASTATIC PANCREATIC CANCER (MPC): ALPINE STUDY.

ABSTRACT Aim: OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors and targets cancer stem cells. Tumor regressions were seen in Notch3-expressing patient-derived pancreatic cancer xenografts when OMP-59R5 was combined with Nab-P + Gem. For single-agent OMP-59R5, the maximum tolerated dose (MTD) was 7.5mg/kg every other week (Smith, EORTC 2012) and grade 3 diarrhea was the dose-limiting toxicity (DLT). This study was designed to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of OMP-59R5 in combination with Nab-P + Gem in mPC. OMP-59R5 Dose (mg/kg) 2.5 (n = 5) 5 (n = 4) 5 (n = 4) 7.5 (n = 6) 10 (n = 6) 12.5 (n = 3) 15 (n = 7) Gem (mg/m2) 1000 1000 1000 1000 1000 1000 1000 Nab-P (mg/m2) - - 125 125 125 125 125 DLT evaluable 4 4 4 6 6 3 6 incidence - - - - - - - RECIST evaluable 4 4 4 6 6 3 5 Best Response PR - - 2 3 3 - 1 SD 3 3 1 3 1 - 4 PD 1 1 1 - 2 3 - CA19-9 evaluable 4 4 4 6 5 - 3 Responder (≥50% reduction) 2 2 3 5 4 - 3 pts still on treatment - - 1 3 3 1 7 Methods: Cohorts of 3- 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 was given intravenously every other week (Days 1 and 15) with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125mg/m2 and GEM 1000mg/m2 on Days 1, 8 and 15 of every 28-day cycle. Results: Thirty-five patients have been enrolled. No DLTs have occurred. Frequently reported (>20%) adverse events (AEs) regardless of relationship were: thrombocytopenia/platelet count decrease (65.7%), anemia (60.0%), diarrhea (51.4%), fatigue (42.9%), nausea (31.4%), decreased appetite (25.7%), alopecia (22.9%), neuropathy peripheral (22.9%), pyrexia (22.9%) and vomiting (22.9%); most were grade 1 or 2 and managed with supportive care. The combination of Nab-P and GEM did not alter the PK of OMP-59R5. Notch pathway genes were modulated in patient samples at doses of OMP-59R5 ≥7.5mg/kg. Cohort and response data is summarized in the table above. Conclusions: The anticipated recommended phase II dose of OMP-59R5 combined with Nab-P + GEM is 15 mg/kg (a biologically optimized dose). No DLT was observed. Encouraging anti-tumor activity was seen. Updated Safety, PK/PD, and efficacy data will be presented for the phase Ib. A randomized phase II study of Nab-P + Gem + OMP-59R5/placebo will be initiated in the Spring 2014. Disclosure: A. Kapoun, L. Xu and D. Hill: I am an OncoMed employee and own stock in the company; L. Zhou: I am a compensated consultant to OncoMed; J. Dupont: I am the Chief Medical Officer of OncoMed and own stock in the company. All other authors have declared no conflicts of interest.