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

Abstract

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.

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

“…Regarding synergy, it must be noted that the closest to clinical success of mAbs in a Notch context to date is when combining DLL4 and VEGF blockade. This is underlined by observations in preclinical studies of enoticumab combined with the anti-VEGF IgG1 Fc-fusion (aflibercept) in different cancer models (132,133), ABT-165 in mouse xenografts (103) and in clinical studies of navicixizumab (93). Two additional anti-VEGF/DLL4 bispecific IgG1 antibodies exist and have shown promising results in preclinical cancer models -HB105 and HB-32 (134,135).…”

“…This potential risk may be minimized by the use of less effector potent subclasses, such as IgG2 or IgG4 (89). With the exception of the anti-DLL4 IgG1 mAbs MEDI0639 (90) and enoticumab (91), all anti-Notch mAb candidates under investigation to date are based on IgG2 (52,(92)(93)(94). Other options include hybrid mAb scaffolds, engineering of the IgG1 Fc to abolish effector molecule engagement or even excluding the Fc altogether by utilizing only Fab or the fragment variables (Fvs) (95)(96)(97).…”

“…As reviewed elsewhere, other DLL4-specific mAbs (MEDI0639, enoticumab) have undergone similar trials and pause (92). Navicixizumab is however (as ABT-165) moving forward, having demonstrated notable antitumor activity in its first-in-human phase 1a trial of pretreated solid tumors (93).…”

Soluble ligands as drug targets

“…Indeed, as tumour angiogenesis is known to play a crucial role in tumour growth, seven bispecific therapies for oncological applications target either VEGFA plus DLL4 to enhance antitumour effects while limiting VEGFA-induced vascular sprouting 86 or VEGFA plus ANGPT2 for dual inhibition of the VEGFA-VEGFR and ANGPT2-TIE2 signalling pathways.…”

Multi-Faceted Notch in Allergic Airway Inflammation

“…The unique function of DLL4-Notch signaling in angiogenesis has uncovered a novel therapeutic target for various diseases where angiogenesis plays a role in perpetuating the disease pathogenesis. Indeed, in the past decade, clinical trials have been undertaken by utilizing anti-DLL4 Ab alone or in combination with VEGR blockade for better cancer treatment outcomes [126,127,128,129]. In the aspect of allergic airway disease, we are awaiting this novel and promising DLL4 angiogenesis pathway being applied to clinical studies of chronic asthma.…”