Abstract
Purpose
MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined.
Methods
Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m2 (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A.
Results
Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in >20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed.
Conclusions
The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.
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Acknowledgments
We thank the patients who participated in the study and their families. This study was sponsored by Genentech, Inc. Medical writing assistance was provided by Genentech, Inc.
Conflict of interest
AP: advisor to and research support from Genentech, Inc., PML: advisor to and research support from Genentech, Inc., WAM: research support from Genentech, Inc., KP: nothing to disclose, LG: nothing to disclose, MB: research support from Genentech, Inc., VR, AHK, JCB, LMS, WD, YX, RY, HX, RKB: employees of Genentech, Inc., and shareholders of F. Hoffmann La. Roche, Ltd., and CDW: advisor to and research support from Genentech, Inc. All authors had full control of all primary data and agree to allow the journal to review the data if requested.
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Patnaik, A., LoRusso, P.M., Messersmith, W.A. et al. A Phase Ib study evaluating MNRP1685A, a fully human anti-NRP1 monoclonal antibody, in combination with bevacizumab and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 73, 951–960 (2014). https://doi.org/10.1007/s00280-014-2426-8
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DOI: https://doi.org/10.1007/s00280-014-2426-8