BACKGROUND: Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4 mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4 mg/kg) on day 1 then irinotecan-LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan-LV5FU2 every 2 weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS:Twenty-seven patients were treated; 14 receivedplacebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4 mg/kg upfront. The median number of aflibercept cycles was 16 (range 1-44), 12 patients received ≥20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3 months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept. CONCLUSION:Aflibercept 4 mg/kg plus irinotecan-LV5FU2 every 2 weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity.
RCT Entities:
BACKGROUND: Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4 mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4 mg/kg) on day 1 then irinotecan-LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan-LV5FU2 every 2 weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients were treated; 14 received placebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4 mg/kg upfront. The median number of aflibercept cycles was 16 (range 1-44), 12 patients received ≥20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3 months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept. CONCLUSION: Aflibercept 4 mg/kg plus irinotecan-LV5FU2 every 2 weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity.