Phase I study of gefitinib and rapamycin in adult patients with recurrent glioblastoma multiforme (GBM)

B92

Purpose: To evaluate the safety and toxicity of gefitinib and rapamycin, while secondarily determining time to tumor progression, overall survival and quality of life in recurrent GBM. 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 because a possible mechanism of EGFR TKI resistance may be targeted by mTOR antagonists. Patients and Methods: Patients aged 18 years or older with recurrent progressive GBM treated previously with surgery, radiation, chemotherapy with or without immunotherapy and KPS > 40% are eligible. Gefitinib is dosed at 500 mg/day for patients, who are not taking enzyme inducing anti-epileptic drugs (-EIAED) and patients with enzyme inducing anti-epileptic drugs (EIAED) the dose is escalated to 1000 mg/day. Rapamycin is dosed at 2 mg/day and adjusted to levels of 4-12 nanograms/ml. Neurological examination, KPS, laboratory parameters and NCI CTC are initially obtained every 2 weeks and then monthly. MRI 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. Only 5 patients received vaccine immunotherapy in addition to surgery, radiotherapy and chemotherapy. There were 3 patients with grade 3/4 non -hematological toxicities with rash, diarrhea, renal failure, hypotension, dyspnea, coagulopathy, and elevated LFT. One patient developed wound infection and it 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%. Conclusion: Oral daily co-administration of gefitinib and rapamycin is safe, tolerable in this heavily treated group of patients. The median progressive free survival time and time to tumor progression is to be determined.