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Ref Type Journal Article
PMID (30229512)
Authors Jimeno A, Moore KN, Gordon M, Chugh R, Diamond JR, Aljumaily R, Mendelson D, Kapoun AM, Xu L, Stagg R, Smith DC
Title 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.
Journal Investigational new drugs
Vol 37
Issue 3
Date 2019 Jun
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Navicixizumab Navicixizumab 6 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Navicixizumab OMP-305B83|OMP 305B83|OMP305B83 DLL4 Antibody 6 VEGF Antibody 11 Navicixizumab (OMP-305B83) is a bispecific antibody that binds both DLL4 and VEGF, which inhibits NOTCH and VEGFR signaling and may prevent angiogenesis and tumor growth (PMID: 30229512).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown uterine carcinosarcoma not applicable Navicixizumab Case Reports/Case Series Actionable In a Phase I trial, Navicixizumab (OMP-305B83) treatment resulted in partial response in a patient with uterine carcinosarcoma (PMID: 30229512). 30229512
Unknown unknown Advanced Solid Tumor not applicable Navicixizumab Phase I Actionable In a Phase I trial, Navicixizumab (OMP-305B83) treatment resulted in partial response in 6% (4/66) and stable disease in 26% (17/66) of patients with advanced solid tumors, with 19 patients having a reduction of target lesions (PMID: 30229512). 30229512
Unknown unknown ovarian cancer not applicable Navicixizumab Case Reports/Case Series Actionable In a Phase I trial, Navicixizumab (OMP-305B83) treatment resulted in partial response in 3 patients with advanced ovarian cancer, and 7 of the 11 ovarian cancer patients had a reduction of target lesions (PMID: 30229512). 30229512