Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors

Fariba Navid, Sharyn D. Baker, M. Beth McCarville, Clinton F. Stewart, Catherine A. Billups, Jianrong Wu, Andrew M. Davidoff, Sheri L. Spunt, Wayne L. Furman, Lisa M. McGregor, Shuiying Hu, John C. Panetta, David Turner, Demba Fofana, Wilburn E. Reddick, Wing Leung, Victor M. Santana

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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. Experimental Design: Sorafenib dose was escalated from 90 to 110mg/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 of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course. Results: Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 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/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m2at 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 = 0.019). Conclusion: The recommended phase II doses are sorafenib, 90mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.

Original languageEnglish (US)
Pages (from-to)236-246
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2013

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Navid, F., Baker, S. D., McCarville, M. B., Stewart, C. F., Billups, C. A., Wu, J., Davidoff, A. M., Spunt, S. L., Furman, W. L., McGregor, L. M., Hu, S., Panetta, J. C., Turner, D., Fofana, D., Reddick, W. E., Leung, W., & Santana, V. M. (2013). Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children and young adults with refractory/recurrent solid tumors. Clinical Cancer Research, 19(1), 236-246. https://doi.org/10.1158/1078-0432.CCR-12-1897