CNS Malignancies Clinical Trial
Official title:
A Phase I Trial of RAD001 (Everolimus) and Avastin(R) (Bevacizumab) in Children With Recurrent Solid Tumors
The main goals of this Phase I study are to learn about the side effects that may occur when everolimus and bevacizumab are given to children and young adults and to find the highest doses of these drugs that can be given together without causing severe side effects. Bevacizumab will be given into the vein (IV) over 30-90 minutes every two weeks and everolimus tablets will be given daily by mouth. A cycle of therapy will be four weeks.
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
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT02013336 -
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
|
Phase 1 |