Establishing surrogate markers of angiogenesis in pediatric oncology phase I and II clinical trials: A Children’s Oncology Group study

Background
70% of children with cancer are cured with standard chemotherapy treatment however 30% will recur and eventually die of their disease. Therefore, there is a need to develop new drugs and this is an endeavour of the Children’s Oncology Group (COG) phase I consortium – a North American network of pediatric oncology institutions that conducts phase I/II clinical research. \

Project Goal
The objective of this proposal is to conduct correlative biological studies on angiogenesis surrogate markers in pediatric oncology phase I/II clinical trials. Establishing and validating these surrogate markers will help to define the biologically active dose of new anti-angiogenic agents used pediatric phase I/II clinical trials.

Candidate biomarkers include plasma VEGF and its receptors, endoglin, vascular cell adhesion molecule (VCAM-1), circulating endothelial cells (CECs) and progenitors (CEPs) and expression of angiogenic genes in peripheral blood mononuclear cells. We plan to establish the dose-effect on these biomarkers in a phase I COG anti-angiogenic clinical trial using sunitinib.

In a parallel phase II COG study of bevacizumab, we will correlate these biomarkers with clinical response and progression free survival. Dynamic contrast enhanced magnetic resonance imaging (DEMRI) parameters will be described and correlated with the biomarkers in these phase I/II clinical trials.

The studies proposed will facilitate the development process of these new agents for childhood malignancies. Validating anti-angiogenic biological and imaging markers has implications beyond this proposal as they will be useful in non-malignant vascular tumors and will prevent valid and relevant treatment options from being discarded due to apparent lack of clinical response. Such endpoints are of paramount importance for the development of future molecularly targeted therapy.