First-in-human dose-escalation safety and PK trial of a novel intravenous humanized monoclonal CovX body inhibiting angiopoietin 2.

Abstract

2524 Background: CVX-060 is a recombinant humanized monoclonal antibody fused to two angiopoietin-2 (Ang2) binding peptides. In preclinical studies, CVX-060 is antiangiogenic and decreases tumor proliferation. Methods: In stage 1, pts with solid tumors received escalating doses of CVX-060 in cohorts of 3-6 pts at the following doses: 0.3, 1, 3, 6, 12, or 15 mg/kg. An additional 13 pts were treated at the 15 mg/kg dose in stage 2. CVX-060 was given once weekly in 4 week cycles as a 90 min IV infusion, decreased to 30 min as tolerated. DLTs were defined as ≥ Gr 3 AEs unrelated to tumor progression in cycle 1. Serum PK was assessed by ELISA. DCE-MRI were conducted pre- dose, Day 4, and Day 28, in pts at 3 mg/kg and higher. Results: Complete data are available on 30 of 34 pts who were enrolled in the study. Among the 30 pts (19F/11M), the median age was 65 years (21-90), ECOG performance status 0-1. Drug exposure in pts ranged from 6-407 days (median 49 days). One pt in the 0.3 mg/kg cohort experienced a DLT (Gr 3 back pain). The most common AE was fatigue (23%).The MTD was not defined. There were 5 (17%) pts with proteinuria (one with Gr 3 and the rest Gr 1-2) and 2 (7%) pts with Gr 1 hemorrhage (vaginal spotting). Cmax and AUC increased linearly with dose, with mean ß t1/2 of 5.5 days. Total serum Ang2 (bound plus free) increased with escalating doses, plateauing at 15 mg/kg. Patients with the highest baseline Ang2 levels had the highest increases in total Ang2 after treatment. There were significant mean decreases in Ktrans by DCE-MRI at Day 4 (p=0.034) and Day 28 (p=0.0025) in 11 pts with data available at all 3 time points. 10/11 patients had decreases in Ktranswith mean decreases of 12.9% (0.94%- 44%) at Day 4 and 25.6% (8-61%) at Day 28. Of the 34 patients enrolled, 24 (71%) remained on study ≥8 weeks and 4 patients continue on treatment (maximum of 17+ months in a patient with refractory cervical cancer). Based on the PK/PD analysis, 15 mg/kg is the recommended phase II dose. Conclusions: CVX-060 is a well-tolerated novel therapy targeting angiogenesis. PK results support once-weekly dosing. There is preliminary evidence of biological activity based on DCE-MRI and prolonged stable disease. A combination trial with sunitinib is underway. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Data Safety Committee for non-oncology compound Pfizer