Phase I and Clinical Pharmacology Study of Bevacizumab, Sorafenib, and Low-dose Cyclophosphamide in Children and Young Adults with Refractory/Recurrent Solid Tumors
Mené sur 19 jeunes patients atteints d'une tumeur solide récidivante ou réfractaire (âge médian : 9,2 ans), cet essai de phase I évalue la toxicité et des paramètres pharmacologiques d'un traitement combinant sorafenib, bevacizumab et cyclophosphamide
Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. Patients and Methods Sorafenib dose was escalated from 90 mg/m2 to 110 mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was 21 days. PK and PD studies were performed during the first course. Results Nineteen patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1 to 23). DLTs during course 1 included grade 3 rash (2), increased lipase (1), anorexia (1), and thrombus (1). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (9), lymphopenia (9), and rashes (4). Five of 17 evaluable patients had partial tumor responses, and 5 had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 ml/min/m2 at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGFR2 was inversely correlated with sorafenib steady-state concentrations (p=0.019). Conclusion The recommended phase II doses are sorafenib, 90 mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.