European Journal of Cancer vol:49 issue:1 pages:17-24
BACKGROUND: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2weeks. RESULTS: Two grade 3/4 aflibercept-associated DLTs occurred with 4mg/kg: proteinuria lasting >2weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4mg/kg. Twenty-two patients had stable disease (five with 4mg/kg), lasting >3months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4mg/kg. CONCLUSION: Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2weeks.