A Phase I/II, Dual-Center, Open-Label Trial of the Safety and Efficacy of Tarceva™ (Erlotinib Hydrochloride) Plus Sirolimus in Patients With Recurrent Malignant Glioma Not on P450-Inducing Anti-Epileptics
- Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of
escalating doses of erlotinib hydrochloride in combination with sirolimus in adult
patients with malignant glioma, who are not receiving enzyme-inducing anti-epileptic
drugs (EIAED). (Phase I)
- Evaluate preliminary efficacy (response rate [RR], progression-free survival [PFS], and
overall survival [OS]) of erlotinib hydrochloride and sirolimus combination therapy in
glioblastoma multiforme (GMB)/gliosarcoma (GS) patients who are not undergoing surgery
at the time of recurrence or relapse (dose-expansion arm). (Phase II)
- Evaluate molecular determinants of response to the combination of erlotinib
hydrochloride and sirolimus, especially the roles of the mutation of EGFR (e.g., vIII
mutant, other somatic mutations of vIII, and mutation/deletion of PTEN).
- To characterize the safety and tolerability of erlotinib hydrochloride and sirolimus
combination therapy in these patient populations.
- To characterize the single-dose and repeated-dose pharmacokinetic (PK) profiles of
erlotinib hydrochloride (in serum) and sirolimus (in whole blood) combination therapy
in these patient populations.
- To characterize, in pre- and/or post-treatment tumor samples, when available,
expression levels of total and activated phosphorylated proteins relevant to the EGFR,
VEGFR, and PI3K/mTOR signaling pathways, relevant downstream signaling network
components, EGFR and VEGFR-related ligands, apoptosis (TUNEL), cell cycle control, and
- To assess pre- and/or post-treatment tumor samples, when available, for DNA-based
changes (e.g., EGFR [DNA] amplification, EGFR and EGFRvIII mutations, and
mutations/deletions in the PTEN gene) relevant to the molecular biology in GBM.
OUTLINE: Patients receive oral erlotinib hydrochloride and sirolimus once daily on days
1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable
Patients undergo tumor tissue and blood sample collection periodically for pharmacological
and biological studies. Samples are analyzed for concentrations of erlotinib hydrochloride
and trough serum levels of sirolimus via HPLC, EGFR, EGFRvIII, PTEN and the phospho-specific
antibodies associated with the MAPK and PI3K pathways via IHC, and EGFRvIII and sequencing
of EGFR, PTEN and other critical genes via PCR, gene expression, and SNP analysis. Germline
DNA will also be used to distinguish polymorphisms from somatic mutations in gene sequenced.
After completion of study treatment, patients are followed periodically.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine maximum tolerated dose and dose limiting toxicity of escalating doses of erlotinib in combination with sirolimus
day 28 of cycle 1
Timothy F. Cloughesy, MD
Jonsson Comprehensive Cancer Center
United States: Food and Drug Administration
|Jonsson Comprehensive Cancer Center at UCLA||Los Angeles, California 90095-1781|