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

Invest New Drugs. 2019 Jun;37(3):461-472. doi: 10.1007/s10637-018-0665-y. Epub 2018 Sep 19.


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: DLL4 pathway; Navicixizumab; OMP-305B83; VEGF.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adult
  • Aged
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacokinetics
  • Antibodies, Bispecific / therapeutic use*
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Calcium-Binding Proteins / antagonists & inhibitors*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Prognosis
  • Tissue Distribution
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*


  • Adaptor Proteins, Signal Transducing
  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Calcium-Binding Proteins
  • DLL4 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • navicixizumab