Summary
The human monoclonal antibody MNRP1685A targets the VEGF binding domain of neuropilin-1 (NRP1), a multi-domain receptor necessary for neural development and blood vessel maturation. In nonclinical studies, MNRP1685A prevents vascular maturation by keeping blood vessels in an immature, highly VEGF-dependent state. We explored the safety and tolerability of MNRP1685A in patients with advanced solid tumors. Patients were treated with MNRP1685A given intravenously every 3 weeks using a 3 + 3 dose-escalation design with 7 dose-escalation cohorts. Twenty-four of 35 patients (69 %) experienced drug-related adverse events (AEs) of infusion-related reaction on the day of MNRP1685A administration. With premedication including dexamethasone, infusions were well-tolerated with main symptoms of pruritus and rash. Outside the day of infusion, most common (≥ 2 patients) related AEs were fatigue (17 %), pruritus (9 %), myalgia and thrombocytopenia (both 6 %) (all were Grade 1–2). MNRP1685A-related Grade ≥ 3 AEs consisted of one dose-limiting toxicity of Grade 3 upper gastrointestinal bleeding and one related Grade 3 thrombocytopenia, coinciding with unrelated Grade 3 fungemia and duodenal obstruction. MNRP1685A showed nonlinear PK with more-than-dose proportional increases in exposure, consistent with broad target expression. Transient platelet count reductions (≥ 30 % from predose) were observed in 56 % of evaluable patients. Nine patients were on study for ≥ 4 cycles, one colorectal cancer patient for one year. MNRP1685A was generally well-tolerated. The primary MNRP1685A-related AE was infusion-related reaction, which were attenuated by premedication including dexamethasone. Transient platelet count reductions were frequent but did not impact MNRP1685A dosing.
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Acknowledgement
We thank the patients who participated in the study and their families. Medical writing assistance provided by Genentech, Inc.
Research support
This study was sponsored by Genentech, Inc.
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CDW: advisor to and research support from Genentech, Inc.
MB: research support from Genentech, Inc.
AWT: advisor to and research support from Genentech, Inc.
KP: nothing to disclose
LG: nothing to disclose
PH, YX, RY, LMS, HX, and RKB: employees of Genentech, Inc., and shareholders of F. Hoffmann La Roche, Ltd.
AP: advisor to and research support from Genentech, Inc.
Author contributions
CDW: conception and design, collection and assembly of data, data analysis and interpretation, provision of study patients
MB: collection and assembly of data
AWT: collection and assembly of data, provision of study patients
KP: collection and assembly of data
LG: data analysis and provision of study patients
PH: conception and design, data analysis and interpretation
YX: data analysis and interpretation
RY: data analysis and interpretation
LMS: data analysis and interpretation
HX: conception and design, data analysis and interpretation
RKB: conception and design, collection and assembly of data, data analysis and interpretation
AP: conception and design, collection and assembly of data, data analysis and interpretation, provision of study patients
All authors participated in manuscript writing, and approved the final version of the manuscript.
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Weekes, C.D., Beeram, M., Tolcher, A.W. et al. A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors. Invest New Drugs 32, 653–660 (2014). https://doi.org/10.1007/s10637-014-0071-z
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DOI: https://doi.org/10.1007/s10637-014-0071-z