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Phase I study of gefitinib and
rapamycin in patients with recurrent or progressive glioblastoma (Gbm)
A. Das, M.
Badruddoja, D. Tryciecky, J. Yu and K.
Black
Maxine Dunitz Neurosurgical
Institute, Los Angeles, CA
Background. GBMs
overexpress epidermal growth factor receptor (EGFR) and
gefitinib inhibits EGFR tyrosine kinase.
The protein mTOR also promotes GBM growth and rapamycin
blocks the interaction of mTOR with its target
proteins.
Therefore, the combination of gefitinib and rapamycin
should have a synergistic effect in treating GBM.
The primary objectives of this study are to evaluate the
safety and toxicity of gefitinib and rapamycin, while
secondarily determining time to tumor progression, overall survival
and quality of life assessments in progressive or recurrent GBM.
Methods. Patients aged 18
years or older with progressive or recurrent GBM and KPS of
40% or greater are included.
Gefitinib is dosed at 500 mg/day with those receiving
dexamethasone or enzyme inducing anti-epileptic drugs
(EIAED) escalated to 1000 mg/day.
Rapamycin is dosed at 2 mg/day and adjusted to levels of
4–12 nanograms/mL.
Neurologic exam, KPS, laboratory parameters and NCI CTC are
initially obtained every 2 weeks and then monthly.
MRI scans of the brain and FACT-Br are performed every two
months.
Those patients with stable disease, partial or complete
responses continue study medications until tumor progression
or dose-limiting toxicities occur.
Results. To date 10
patients have enrolled and 7 are assessable.
There are 6 men and 1 woman with a median age of 57 years
(range 31 to 72 years) and a median KPS of 60% (range
50–80%).
Previous treatments included surgery, with 4 patients
having undergone 1 craniotomy and 3 patients had 2
craniotomies.
All patients had received radiation and chemotherapy, and 4
participated in a phase I immunotherapy trial.
Six patients were taking steroids and 3 were taking
EIAED.
Toxicities included fatigue, rash, diarrhea and
infection.
Of the 7 patients, 4 were assessable for response with 0
CR, 1 PR, 2 PD, and 1 SD.
The median progression free and median survival times have
yet to be attained.
Conclusions. The
combination of gefitinib and rapamycin is well tolerated in
this heavily pre-treated group.
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