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A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors

  • Antonio Jimeno
  • Kathleen N. Moore
  • Michael Gordon
  • Rashmi Chugh
  • Jennifer R. Diamond
  • Raid Aljumaily
  • David Mendelson
  • Ann M. Kapoun
  • Lu Xu
  • Robert Stagg
  • David C. Smith
PHASE I STUDIES

Summary

Purpose Navicixizumab (OMP-305B83) is a bispecific antibody that inhibits delta-like ligand 4 and vascular endothelial growth factor. This Phase 1a trial assessed escalating doses of navicixizumab in refractory solid tumors patients. Design A 3 + 3 dose escalation design was used followed by the treatment of additional patients in an expansion cohort. Study objectives were determination of the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, immunogenicity and efficacy. Results Sixty-six patients were treated once every 3 weeks in 8 dose-escalation cohorts (0.5, 1, 2.5, 3.5, 5, 7.5, 10, and 12.5 mg/kg) and an expansion cohort (7.5 mg/kg). The median age was 60 years and 68% of the patients were female. The most commonly enrolled tumor types were ovarian (12), colorectal (11) and breast, pancreatic, uterine and endometrial (4 each) cancers. As only 1 dose limiting toxicity occurred, the maximum tolerated dose was not reached, but 7.5 mg/kg was chosen as the dose for the expansion cohort. The treatment related adverse events (≥15% of patients) were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension was mostly asymptomatic at doses ≤5 mg/kg (6 Gr1, 1 Gr2), but was more severe at higher doses (4 Gr2, 1 Gr3). Navicixizumab’s half-life was 11.4 days and there was a moderate (29%) incidence of anti-drug antibody formation. Four patients (3 ovarian cancer, 1 uterine carcinosarcoma) had a partial response and 17 patients had stable disease. Nineteen patients had a reduction in the size of their target lesions including 7/11 patients with ovarian cancer. Four patients remained on study for >300 days and 2 of these patients were on study for >500 days. Conclusions Navicixizumab can be safely administered with manageable toxicities and these data showed preliminary signs of antitumor activity in multiple tumor types, but was most promising in ovarian cancer. As a result these data justify its continued development in combination Phase 1b clinical trials.

Keywords

Navicixizumab OMP-305B83 VEGF DLL4 pathway 

Notes

Financial support

This study was supported by OncoMed Pharmaceuticals through research grants to the author’s Institutions.

Compliance with ethical standards

Conflicts of interest

No conflicts were disclosed by any of the authors not affiliated with OncoMed. AMK, LX, and RS are employees of OncoMed, the study sponsor.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

10637_2018_665_MOESM1_ESM.docx (23 kb)
ESM 1 (DOCX 23 kb)
10637_2018_665_MOESM2_ESM.docx (183 kb)
ESM 2 (DOCX 182 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Antonio Jimeno
    • 1
  • Kathleen N. Moore
    • 2
    • 3
  • Michael Gordon
    • 4
  • Rashmi Chugh
    • 5
  • Jennifer R. Diamond
    • 1
  • Raid Aljumaily
    • 2
    • 3
  • David Mendelson
    • 4
  • Ann M. Kapoun
    • 6
  • Lu Xu
    • 6
  • Robert Stagg
    • 6
  • David C. Smith
    • 5
  1. 1.University of Colorado School of MedicineAuroraUSA
  2. 2.The University of OklahomaOklahoma CityUSA
  3. 3.Sarah Cannon Research InstituteNashvilleUSA
  4. 4.Pinnacle Oncology HematologyScottsdaleUSA
  5. 5.University of MichiganAnn ArborUSA
  6. 6.OncoMed PharmaceuticalsRedwood CityUSA

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