A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors

• Published in: Investigational new drugs Vol. 32; no. 4; pp. 653 - 660
• Main Authors: Weekes, Colin D., Beeram, Muralidhar, Tolcher, Anthony W., Papadopoulos, Kyriakos P., Gore, Lia, Hegde, Priti, Xin, Yan, Yu, Ron, Shih, L. Mason, Xiang, Hong, Brachmann, Rainer K., Patnaik, Amita
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-08-2014; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Angiogenesis; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Biological and medical sciences; Blood vessels; Cancer; Cancer therapies; Clinical trials; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug dosages; Drug therapy; Female; Humans; Ligands; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - metabolism; Neuropilin-1 - antagonists & inhibitors; Neuropilin-1 - metabolism; Neutropenia; Oncology; Patients; Pharmaceuticals; Pharmacokinetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; Pruritus; Statistical analysis; Thrombocytopenia; Tumors; Vascular endothelial growth factor; United States > US; Neuropilin-1; Clinical trial; VEGF; MNRP1685A; Human; Solid tumor; Membrane protein; Toxicity; Malignant tumor; Monoclonal antibody; Vascular endothelium growth factor; Treatment; Phase I trial; Advanced stage; Pharmacokinetics; Cancer; Neuropilin 1
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0071-z

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.