Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Academic Article uri icon

Overview

abstract

  • PURPOSE: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent. EXPERIMENTAL DESIGN: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. RESULTS: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 microg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t(1/2) of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year. CONCLUSION: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.

publication date

  • December 22, 2009

Research

keywords

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Neoplasms
  • Recombinant Fusion Proteins

Identity

PubMed Central ID

  • PMC4211604

Scopus Document Identifier

  • 74949101370

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-09-2103

PubMed ID

  • 20028764

Additional Document Info

volume

  • 16

issue

  • 1