A phase I trial of gefitinib and sirolimus in adults with recurrent glioblastoma multiforme (GBM)

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2088 Background: Glioblastoma multiforme (GBM) overexpresses the epidermal growth factor receptor (EGFR) and gefitinib is an EGFR tyrosine kinase inhibitor (TKI). The protein mammalian target of rapamycin (mTOR) also promotes GBM growth and rapamycin blocks the interaction of mTOR with its target proteins. Therefore, the novel therapeutic approach by combination of gefitinib (iressa), and sirolimus (rapamycin) should have a synergistic effect in treating GBM. A possible mechanism of EGFR TKI resistance may be targeted by mTOR antagonists. The primary objective is to evaluate the safety, toxicity of gefitinib and sirolimus with a secondary end point of determining time to tumor progression, overall survival and quality of life in recurrent GBM. Methods: Eligible patients aged 18 years or older with recurrent GBM, who were treated previously with surgery, radiation, chemotherapy with or without immunotherapy (vaccine) and KPS > 40% are eligible. Gefitinib is dosed at 500 mg/day with those receiving dexamethasone or enzyme inducing anti-epileptic drugs (EIAED) escalated to 1,000 mg/day. Sirolimus is dosed at 2 mg/day and adjusted to levels of 4–12 nanograms/ml. They were co-administered on a continuous oral daily dosing. Neurological 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. Results: To date 21 patients have enrolled and 18 are evaluable. There are 13 male and 5 female with a median age of 51.6 years (range 23–72 years), a median KPS of 60% (range 50–80%) and 12 patients were on EIAED. Diarrhea, rash and mucositis were the most common toxicities as expected. There were 3 patients with grade 3/4 non-hematological toxicities with rash, renal failure, hypotension, dyspnea, coagulopathy, and elevated LFT. One patient developed wound infection which was not related to these drugs. There were 2 (11%) minor response and 6 (33%) stable disease (range 1–18 months) with a clinical benefit of 44%. Conclusions: Oral daily co-administration of getifinib and sirolimus is safe, tolerable in this heavy treated group of patients with modest antitumor activity. The median progressive free survival time and time to tumor progression is to be determined. No significant financial relationships to disclose.