3050^ Background: Neuropilin-1 (NRP1) is involved in remodeling and maturation of blood vessels. MNRP1685A is a human monoclonal antibody that blocks binding of ligands, including VEGF, VEGF-B and PlGF, to NRP1 thereby maintaining vessel immaturity and VEGF-dependency. This study sought to determine whether MNRP1685A can be safely combined with bevacizumab with or without paclitaxel.
METHODS
Patients received escalating doses of MNRP1685A with 15 mg/kg bevacizumab (every 3 weeks) in Arm A, or with 10 mg/kg bevacizumab (every two weeks) and 90 mg/m2 paclitaxel (weekly, 3 of 4 weeks) in Arm B. Objectives were to determine safety, pharmacokinetics (PK), pharmacodynamics (PD), and the maximum tolerated dose of MNRP1685A in both arms.
RESULTS
14 patients were enrolled into dose-escalation cohorts (3+3 design) of 7.5, 15, 24 and 36 mg/kg in Arm A, and 10 patients into cohorts of 12 and 16 mg/kg in Arm B. As in phase Ia, grade 1 or 2 acute infusion reactions (AIRs, mainly rash and pruritus, premedication included dexamethasone) and transient platelet reductions within 2-8 days following MNRP1685A infusion were observed. Treatment-related grade 3-5 adverse events (AEs; cut-off date 11/23/10) included 1 sudden death, unknown etiology, at Day 7 in Arm A (36 mg/kg), neutropenia (n=4, all Arm B), proteinuria (n=3), thrombocytopenia (n=2), hypertension (n=2), and one each of fatigue, keratorhexis, and peripheral edema. AEs occurring in ≥25% included AIRs (67%), neutropenia (60%, Arm B), hypertension (29%), fatigue (29%), epistaxis, nausea and proteinuria (25% each). 5 of 5 patients treated beyond 5 cycles developed grade ≥2 proteinuria. MNRP1685A PK was similar to phase Ia, but increases in PD biomarker placental growth factor were higher and sustained longer.
CONCLUSIONS
The safety profile of MNRP1685A when combined with bevacizumab with or without paclitaxel was evaluated in this Phase Ib study. AIRs were frequent but tolerable with premedication. Platelet reductions were frequent, transient and recoverable. A higher than expected rate of clinically significant proteinuria, resulting in hold or discontinuation of drugs, was observed.