Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours

摘要: Abstract 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 leucovorin (LV5FU2). Patients methods In this open-label study, 38 patients advanced solid tumours received 2, 4, 5, or 6 mg/kg on day 1, then irinotecan LV5FU2 days 1 2 every 2 weeks. Results Two grade 3/4 aflibercept-associated DLTs occurred 4 mg/kg: proteinuria lasting >2 weeks acute nephrotic syndrome thrombotic microangiopathy. 5 mg/kg (grade 3 stomatitis oesophagitis reflux) three (febrile neutropenia, abdominal pain) were considered related to concurrent chemotherapy underlying disease. The most common adverse events hypertension diarrhoea. Nine had partial responses, five 4 mg/kg. Twenty-two stable disease (five 4 mg/kg), >3 months in 17 patients. No anti-aflibercept antibodies detected. Free was excess bound Conclusion Based pharmacokinetics, acceptable safety encouraging activity, 4 mg/kg selected as the RPTD