Background: Angiogenesis is necessary for tumor growth, metastasis, and survival. Endothelial cells and pericytes, key cellular components of blood vessels, are primarily regulated by VEGF and PDGF signaling. We therefore performed a phase I trial to determine the feasibility and toxicity profile of agents combined to inhibit angiogenesis by targeting PDGFR-β and VEGFR2 with sorafenib, VEGF with bevacizumab, and endothelial cells with continuous low-dose CYC. Methods: Cohorts of 3-6 eligible patients with recurrent solid tumors received CYC and escalating dosages of sorafenib and then of bevacizumab (see table). Each course of therapy was 21 days. We used standard physical exams and laboratory tests to assess toxicities. Results: 19 patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1-23). The table summarizes dose levels explored and dose-limiting toxicities (DLTs) in course 1. With additional 71 courses of therapy, the most common nonhematologic toxicities ≥ grade 3 included rashes (5) and febrile neutropenia (2). Predominant hematologic toxicities were neutropenia and lymphopenia. Five of 17 evaluable patients had partial tumor responses (2 rhabdoid, 1 rhabdomyosarcoma, 1 medulloblastoma, 1 synovial sarcoma), and 9 had disease stabilization. First-dose pharmacokinetics results from 14 patients follow. The median (range) apparent CYC clearance was 2.03 L/hr/m² (1.8-2.1 L/hr/m²), and the absorption rate constant was 0.12 hr^-1 (0.08-0.23 hr^-1). Sorafenib at 90 and 110 mg/m² yielded the following respective median (range) values: C_max, 1.1 (0.37-2.4) and 1.6 (0.91-2.4) mg/L; T_max, 8.5 (3.9-17.5) and 10.7 (8.2-14.1) h; AUC (0-12h), 10.4 (2.6-23.0) and 13.6 (8.0-20.4) mg*h/L. Conclusions: The recommended phase II doses are sorafenib, 90 mg/m²/dose BID; bevacizumab, 15 mg/kg q3 weeks; and CYC, 50 mg/m² once daily. This regimen is feasible with promising evidence of anti-tumor activity that warrants further investigation.

*All received CYC (50 mg/m²) PO once daily.