Phase 1B Trial of Anti-Notch 2/3 Antibody Omp-59R5 in Combination with Etoposide and Cisplatin (Ep) in Patients (Pts) with Untreated Extensive-Stage Small-Cell Lung Cancer (Ed-Sclc): the Pinnacle Study

Aim: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers, including SCLC. OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Anti-tumor activity was noted in 7 of 9 pt-derived SCLC xenografts expressing Notch 2 and 3 with OMP-59R5 treatment. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5mg/kg IV every 3 weeks (Smith, EORTC 2012); the main dose-limiting toxicity (DLT) was Grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with EP in ED-SCLC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 was given IV on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2, and 3 and cisplatin 80 mg/m2 on Day 1. After 6 cycles, pts continued OMP-59R5 alone every 21 days in the absence of disease progression or unacceptable toxicities. Results: By April 4, 2014, 11 pts were treated. One DLT of Grade 3 nausea was reported from a subject in the 10 mg/kg dose cohort that lasted more than 48 hours despite daily IV fluids and antiemetics. Frequently reported (≥30%) adverse events (all grades) regardless of relationship were: fatigue (81.8%), nausea (72.7%), anemia (63.6%), diarrhea (63.6%), decreased appetite (54.5%), weight loss (54.4%), hypomagnesemia (45.5%), peripheral edema (45.5%), dehydration (36.4%), neutropenia (36.4%), thrombocytopenia (36.4%), vomiting (36.4%) and elevated creatinine (36.4%). Of these, fatigue (54.5%), anemia (36.4%), diarrhea (36.4%) and nausea (36.4%) were considered related to OMP-59R5. The events were mostly Grade 1 or 2, and managed with supportive care. Additional data are below: OMP-59R5 Dose (mg/kg) 5 (n=3) 7.5 (n=3) 10 (n=5) Etoposide (mg/m2) 100 Cisplatin (mg/m2) 80 DLT evaluable 3 3 5 incidence - - 1 RECIST 1.1 evaluable 3 3 4 Best Response/ Partial Response 3 2 4 Stable Disease - 1 - Progressive Disease - - - pts still on treatment - 2 4 Conclusions: OMP-59R5 with EP is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated safety, PK/PD, and efficacy data will be presented. The Phase 2 part of PINNACLE will start in 2014. Disclosure: A. Kapoun: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Xu: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; D. Hill: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Zhou: Paid consultant for OncoMed Pharmaceuticals (sponsor); J. Dupont: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks. All other authors have declared no conflicts of interest.