Cancer Therapy: Clinical Phase I and Clinical Pharmacology Study of Bevacizumab, Sorafenib, and Low-DoseCyclophosphamide inChildren and Young Adults with Refractory/Recurrent Solid Tumors

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. ExperimentalDesign: Sorafenib dosewas escalated from90 to110mg/m twice dailywithfixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m daily. Once sorafenib’s MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course. Results:Nineteen patients (11males;median age, 9.2 years) received amedian of four courses (range, 1– 23).DLTsduring course 1 included grade3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m.Median day 1 sorafenib apparent oral clearance was 44 and 39mL/min/m at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P 1⁄4 0.019). Conclusion: The recommendedphase II doses are sorafenib, 90mg/m twice daily; bevacizumab, 15mg/ kgq3weeks; and cyclophosphamide, 50mg/moncedaily. This regimen is feasiblewithpromising evidence of antitumor activity that warrants further investigation. Clin Cancer Res; 19(1); 236–46. 2012 AACR.