Yuval Shaked

Phase I Trial and Pharmacokinetic Study of Bevacizumab in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study

PURPOSE We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)-neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer. PATIENTS AND METHODS BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors. RESULTS Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data. CONCLUSION BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

Combining Antiangiogenic Drugs with Vascular Disrupting Agents Rationale and Mechanisms of Action

A highly reproducible characteristic of vascular disrupting agent (VDA)-mediated anti-tumor therapy is the retention of a rim of viable tumor tissue surrounding a much larger central mass of necrotic tissue within days of therapy. Repopulation from the viable rim subsequently compromises much of the striking initial anti-tumor effect frequently caused by the VDA treatment. The repopulation process is driven in part by robust tumor angiogenesis, which therefore constitutes a compelling rationale for combining VDA therapy with an antiangiogenic drug. In this regard, we have found that tumor angiogenesis in the viable rim after VDA therapy can be driven, at least in part, by a rapid systemic host response caused by the VDA treatment itself, namely, induction within hours of the mobilization of bone marrow-derived cells (BMDCs) including circulating endothelial progenitor cells (CEPs). These cells migrate to the drug treated tumor and heavily colonize the remaining viable tumor rim. This systemic host response appears to be driven, at least in part, by rapid induction of high levels of circulating growth factors, including G-CSF and SDF-1. The mobilization and tumor homing of CEPs can be blunted by prior or concurrent administration of an antiangiogenic drug such as anti-VEGF receptor 2 antibodies – which results in enhanced overall anti-tumor activity, e.g. greater levels of tumor necrosis, a much smaller viable tumor rim and increased survival times. In addition to this systemic effect, a more potent ‘local’ effect may also be obtained by adding an antiangiogenic drug to a VDA as a result of greater levels of apoptosis of endothelial cells in the tumor associated vasculature. Preliminary clinical trial results suggest combination VDA – antiangiogenic drug therapy has promising activity without significant increases in toxicity, and moreover, indicate that some of the preclinical findings, such as rapid VDA-induced elevations of circulating G-CSF and VEGF, are observed in patients as well.