Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. METHODS: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. RESULTS: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. CONCLUSIONS: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.

Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors.

PURPOSE: Antiangiogenic agents show significant antitumor activity against various tumor types. In a study evaluating the combination of sorafenib, bevacizumab, and low-dose cyclophosphamide in children with solid tumors, an unexpectedly high incidence of pneumothorax was observed. We evaluated patient characteristics and risk factors for the development of pneumothorax in patients receiving this therapy. PATIENTS AND METHODS: Demographics, clinical course, and radiographic data of 44 patients treated with sorafenib, bevacizumab and cyclophosphamide were reviewed. Risk factors associated with the development of pneumothorax were analyzed. RESULTS: Pneumothorax likely related to study therapy developed in 11 of 44 (25%) patients of whom 33 had pulmonary abnormalities. Median age of patients was 14.7 years (range, 1.08-24.5). Histologies associated with pneumothorax included rhabdoid tumor, synovial sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, and renal cell carcinoma. Cavitation of pulmonary nodules in response to therapy was associated with pneumothorax development (P<0.001). Median time from start of therapy to development of pneumothorax was 5.7 weeks (range, 2.4-31). CONCLUSION: The development of cavitary pulmonary nodules in response to therapy is a risk factor for pneumothorax. As pneumothorax is a potentially life-threatening complication of antiangiogenic therapy in children with solid tumors, its risk needs to be evaluated when considering this therapy.

Comparable efficacy with varying dosages of glucarpidase in pediatric oncology patients.

BACKGROUND: Glucarpidase rapidly reduces methotrexate plasma concentrations in patients experiencing methotrexate-induced renal dysfunction. Debate exists regarding the role of glucarpidase in therapy given its high cost. The use of reduced-dose glucarpidase has been reported, and may allow more institutions to supply this drug to their patients. This report explores the relationship between glucarpidase dosage and patient outcomes in pediatric oncology patients. METHODS: The authors evaluated data from 26 patients who received glucarpidase after high-dose methotrexate. Decrease in plasma methotrexate concentrations and time to renal recovery were evaluated for an association with glucarpidase dosage, which ranged from 13 to 90 units/kg. RESULTS: No significant relationship was found between glucarpidase dosage (units/kg) and percent decrease in methotrexate plasma concentrations measured by TDx (P > 0.1) or HPLC (P > 0.5). Patients who received glucarpidase dosages <50 units/kg had a median percent reduction in methotrexate plasma concentration of 99.4% (range, 98-100) measured by HPLC compared to a median percent reduction of 99.4% (range, 77.2-100) in patients who received ≥50 units/kg. Time to SCr recovery was not related to glucarpidase dosage (P > 0.8). CONCLUSIONS: The efficacy of glucarpidase in the treatment of HDMTX-induced kidney injury was not dosage-dependent in this retrospective analysis of pediatric oncology patients.

Phase I and clinical pharmacology study of bevacizumab, sorafenib, and low-dose cyclophosphamide in children 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. 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.