616PDA PH 1B STUDY OF THE ANTI-CANCER STEM CELL AGENT DEMCIZUMAB (DEM) & GEMCITABINE (GEM) +/- PACLITAXEL PROTEIN BOUND PARTICLES (NAB-PACLITAXEL) IN PTS WITH PANCREATIC CANCER

ABSTRACT Aim: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway. DEM is a humanized IgG2 anti-DLL4 antibody that inhibits tumor growth & decreases cancer stem cell frequency in minimally passaged human xenograft models. In addition, DEM has an antiangiogenic effect & synergistic activity when combined with GEM & nab-paclitaxel in human pancreatic tumor-derived xenograft models. Methods: Pts with 1st line pancreatic cancer were enrolled. Pts in cohorts 1-3 received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks including 3 truncated pts) & GEM 1000 mg/m2 7 of 8 wks, then 3 of 4 wks. Pts in cohorts 4 & 5 received truncated DEM (2.5 or 5 mg/kg every 2 wks through Day 70) & nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 3 of 4 weeks. The primary objective was to determine the MTD. Other objectives were safety, efficacy, immunogenicity, PK & biomarkers. Results: Thirty-eight pts were enrolled; 8, 8, 8, 6 & 8 pts received 2.5 mg/kg every 2 wks, 2.5 mg/kg every 4 wks, 5 mg/kg every 4 wks, 2.5 mg/kg every 2 weeks (truncated) & 5 mg/kg every 2 weeks (truncated), respectively. Related AEs in > 20% of pts were nausea (37%), fatigue (34%), nausea, vomiting (32%), decreased appetite (24%) & hypertension (21%). Hypertension was managed with anti-hypertensives. Increased BNP is an early indicator of the cardiac effects of DEM & mildly elevated values are used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One pt who received 5 mg/kg continuously developed reversible pulmonary hypertension & heart failure on day 143. As a result, DEM was limited to 70 days in cohorts 4 & 5. In cohorts 1-3, 4 of 16 (25%) pts had a partial response (PR) & 7 had stable disease (SD). In cohorts 4 & 5, 6 of 14 (43%) pts had a PR & 6 had SD. The median PFS for 2.5 & 5 mg/kg every 4 wks and 2.5 mg/kg, 2.5 mg/kg (truncated) & 5 mg/kg (truncated) every 2 wks were 1.7, 7, 3.4, not reached and 3.5 mos., respectively. The 3 truncated pts in cohort 3 had PFS of 5.4, 7 and 9.1 mos. Conclusions: This therapy was generally well tolerated with fatigue, nausea & vomiting being the most common related AEs. Encouraging early clinical activity was observed. Additional data with truncated DEM will be presented. Disclosure: R. Stagg and J. Dupont: I am an employee of OncoMed and own stock in the company. All other authors have declared no conflicts of interest.