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.

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/m(2) (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.

• Authors: Amita Patnaik, Patricia M LoRusso, Wells A Messersmith, Kyriakos P Papadopoulos, Lia Gore, Muralidhar Beeram, Vanitha Ramakrishnan, Amy H Kim, Joseph C Beyer, L Mason Shih, Walter C Darbonne, Yan Xin, Ron Yu, Hong Xiang, Rainer K Brachmann, Colin D Weekes
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 73 Issue 5 Pg. 951-60 (May 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24633809 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Neuropilin-1
• Bevacizumab
• vesencumab
• Paclitaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Antibodies, Monoclonal (administration & dosage, adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized (adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacokinetics, therapeutic use)
• Bevacizumab
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, metabolism, pathology)
• Neuropilin-1 (administration & dosage, therapeutic use)
• Paclitaxel (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Young Adult