A Trial of Everolimus and Bevacizumab in Children With Recurrent Solid Tumors

This is a traditional phase I dose finding study to estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities (DLT) of the combination of bevacizumab, administered every 2 weeks IV and everolimus administered orally daily to children with recurrent or refractory solid tumors including CNS malignancies. Patients will receive bevacizumab every two weeks IV, and everolimus orally daily. Four consecutive weeks will constitute one course and subsequent courses will immediately follow with no break in the administration of either drug. In the absence of disease progression or unacceptable toxicity, treatment can continue for 2 years. The bevacizumab dose will start at 10 mg/kg. Everolimus will start at 4 mg/m2, 80% of the MTD established in our current phase I trial. A traditional 3+3 dose escalation/de-escalation design will be used to determine the joint MTD for these two agents. Doses to be studied are detailed in the table below. Consistent with the traditional design, we will enroll cohorts of 3 patients at each dose level starting with dose level 1 and will escalate to the next higher dose, if none of these 3 experiences a DLT. If one of 3 patients experiences a DLT at a dose level then 3 more patients will be studied at this level. If none of these 3 experiences a DLT then escalation to the next level will occur. Otherwise the current dose will be considered too toxic and de-escalation will occur. Under this setting, MTD will be the dose level at which 0/3 or 1/6 patient would have experienced DLT and the next dose level is determined to be too toxic. Exploratory objectives: 1. To preliminarily define the antitumor activity of the combination of everolimus and bevacizumab within the confines of a phase I study 2. To assess the incidence of PTEN and PI3Kinase pathway activation in recurrent or refractory solid tumors of childhood 3. To assess everolimus pharmacokinetics in children, including the effect of concomitant drug therapy (e.g., dexamethasone). 4. To explore changes in correlative magnetic resonance imaging in children receiving everolimus and bevacizumab 5. To identify additional genes both within and outside of the mTOR pathway that may act as determinants of response to everolimus 6. To explore the pharmacogenetic polymorphisms responsible for everolimus disposition (e.g., metabolism and elimination) 7. To test the ability of everolimus to inhibit mTOR pathway signaling in patients with recurrent solid tumors including CNS malignancies in peripheral blood mononuclear cells 8. To estimate blood levels of VEGF, BFGF, TSP-1, I-CAM, v-CAM and circulating endothelial cells prior to, during therapy and after therapy