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

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 110 mg/m(2) twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m(2) 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/m(2). Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m(2) 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 = 0.019).

Conclusion: The recommended phase II doses are sorafenib, 90 mg/m(2) twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m(2) once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.

Figure 1

Change in signal intensity from pre-contrast baseline to initial post-contrast peak (ΔSI, in decibels) through therapy in 4 patients who underwent contrast-enhanced ultrasound (CEUS) of target lesions. Patient 1 and 2 showed substantial decreases in ΔSI on days 3 and 7 and at the end of course 1, and both had long times to progression. The maximum decline in ΔSI in these two patients was 12.6 and 26.8 decibels, respectively. In contrast, patient 3 and 4 showing minimal decrease or an increase in ΔSI at the same early time points both had progressive disease by the end of course 1. The maximum decline in ΔSI in these two patients was 1.1 and 2.9 decibels, respectively.

Figure 2

Waterfall plot of percent change in the sum of the longest diameter of all target lesions from baseline in 17 patients with evaluable for tumor response by RECIST. Abbreviations: RH, rhabdoid tumor; MB, medulloblastoma; RMS, rhabdomyosarcoma; SS, synovial sarcoma; NB, neuroblastoma; WT, Wilms tumor; MPNST, malignant peripheral nerve sheath tumor; EP, epithelioid sarcoma; ACC, adrenocortical carcinoma.