A Phase II Trial of Tamoxifen and Bortezomib in Patients With Recurrent High-Grade Gliomas
Background:
Tamoxifen (TAM), a member of the selective estrogen receptor modulator (SERM) family, is
widely used in the treatment of estrogen receptor (ER) expressing breast cancer. It has
previously been shown that high-dose TAM has cytotoxic activity against glioma cells, but
whether this effect is drug-specific or represents a general property of SERMs was unknown.
We have now demonstrated that suppression of NF-kB activation markedly enhances SERM-induced
apoptosis, suggesting a role for NF-kB in protecting glioma cells from SERM-induced
cytotoxicity.
Bortezomib is a potent inhibitor of the 26S proteosome and causes significant
anti-proliferative and cytotoxic effects in a number of cell lines through its protean
effects on a variety of cellular signaling pathways, including its ability to potently
inhibit the NF-kB pathway. We have recently demonstrated that bortezomib has significant
anti-glioma activity in vitro and a ongoing clinical trial has demonstrated some possible
activity in patients with recurrent gliomas. We have now also generated preclinical data
demonstrating that bortezomib in combination with Tamoxifen has synergistic cytotoxic
effects on glioma cells.
Thus, given the minimal to modest activity of both drugs in patients with recurrent gliomas,
given their spectrum of non-overlapping toxicities, and given the marked synergistic glioma
cell killing of the combination of drugs in our preclinical screens, we are now proposing a
phase II trial of bortezomib in combination with Tamoxifen in patients with recurrent
gliomas not taking EIAEDs.
Objectives:
The primary statistical endpoint will be response (defined as either stable disease or
objective response as is standard in neuro-oncology clinical trials) after 6 weeks of
treatment.
Eligibility:
Patients with histologically proven high-grade gliomas or patients with a clinical and
radiographic diagnosis of brainstem glioma will be eligible for this protocol.
Design:
The phase II study will be stratified by the type of high grade glioma (AA or GBM) and a
two-stage min-max design with a maximum of 41 patients in the GBM stratum and 36 patients in
the AA stratum.
Interventional
Masking: Open Label, Primary Purpose: Treatment
Response, defined as stable disease or objective (partial or complete) response.
No
Teri N Kreisl, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
050137
NCT00108069
April 2005
March 2013
Name | Location |
---|---|
National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |