1473P - Phase 1b trial of anti-notch 2/3 antibody OMP-59R5 in combination with etoposide and cisplatin (EP) in patients (pts) with untreated extensive-stag...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer agents
Small Cell Lung Cancer
Therapy
Biological Therapy
Presenter Maria Catherine Pietanza
Citation Annals of Oncology (2014) 25 (suppl_4): iv511-iv516. 10.1093/annonc/mdu355
Authors M.C. Pietanza1, A. Spira2, R. Jotte3, S. Gadgeel4, A. Mita5, S. Liu6, W.L. Gluck7, G.P. Kalemkerian8, A. Chiang9, L. Hart10, A. Kapoun11, L. Xu11, D. Hill11, L. Zhou11, J. Dupont11, D.R. Spigel12
  • 1Medicine/thoracic Oncology, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 2Medical Oncology, Virginia Cancer Specialists, PC, Fairfax/US
  • 3Thoracic Oncology, Denver Divison, Rocky Mountain Cancer Centers, LLP, Denver/US
  • 4Medical Oncology, Karmanos Cancer Center, 48201 - Detroit/US
  • 5Oncology/hematology, Cedars Sinai Medical Center, 90048 - Los Angeles/US
  • 6Division Of Hematology/oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC/US
  • 7Clinical Trials Unit, Greenville Hospital System, Greenville/US
  • 8Division Of Hematology/oncology, University of Michigan Medical School, 48109-5848 - Ann Arbor/US
  • 9Medicine/medical Oncology, Yale University School of Medicine, New Haven/US
  • 10Research Department, Florida Cancer Specialists, Fort Myers/US
  • 11Clinical Research, OncoMed Pharmaceutical, 94063 - Redwood City/US
  • 12Sarah Cannon Research Institute, Tennessee Oncology PLLC, Nashville/US

Abstract

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.