1. Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours
- Author
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Van Cutsem, Eric, Khayat, David, Verslype, Chris, Billemont, Bertrand, Tejpar, Sabine, Meric, Jean-Baptiste, Soussan-Lazard, Karen, Assadourian, Sylvie, Cartot-Cotton, Sylvaine, and Rixe, Olivier
- Subjects
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ANTINEOPLASTIC agents , *COMBINATION drug therapy , *TUMORS , *DESCRIPTIVE statistics - Abstract
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 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. [Copyright &y& Elsevier]
- Published
- 2013
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