Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors.

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.