688P - Final 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 pati...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Pancreatic Cancer
Presenter Johanna Bendell
Citation Annals of Oncology (2014) 25 (suppl_4): iv210-iv253. 10.1093/annonc/mdu334
Authors J. Bendell1, A.L. Cohn2, L. Smith3, J.H. Strickler4, W.L. Gluck5, W.G. Schmidt6, A. Kapoun7, L. Xu7, D. Hill7, L. Zhou7, J. Dupont7, E.M. O\'Reilly8
  • 1Drug Development Unit, Sarah Cannon Research Institute / Tennessee Oncology, 37203 - Nashville/US
  • 2Oncology, Rocky Mountain Cancer Centers, Denver/US
  • 3Oncology And Hematology, South Texas Accelerated Research Therapeutics, San Antonio/US
  • 4Duke University Medical Center, Duke University, Durham/US
  • 5Clinical Trials Unit, Greenville Hospital System, Greenville/US
  • 6Oncology, Bend Memorial Clinic, Bend/US
  • 7Clinical Research, OncoMed Pharmaceutical, 94063 - Redwood City/US
  • 8Gastro-intestinal Medical Oncology, Memorial Sloan-Kettering Cancer Center, US-10128 - New York/US

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.