A pilot study to assess the tolerability and efficacy of RAD-001 (everolimus) with gefitinib in patients with recurrent glioblastoma multiforme (GBM)

Abstract

1507 Background: The majority of GBMs overexpress EGFR and have PTEN loss leading to activation of AKT signaling. mTOR is a downstream target which is blocked by RAD-001. The addition of an mTOR inhibitor to EGFR blockade by gefitinib may augment downregulation of AKT. Methods: Nineteen patients with GBM were enrolled in a phase I/II protocol open to patients with either hormone refractory prostate cancer or recurrent GBM. Patients on enzyme inducing anti-epileptic drugs (EIAEDs) were excluded, but prior treatment with an EGFR inhibitor was allowed. All patients received gefitinib 250 mg daily. Two patients enrolled in a dose escalation arm received RAD-001 30 mg or 50 mg weekly; 17 patients received the maximum tolerated dose of RAD-001 70 mg weekly. Baseline and follow-up MRIs were reviewed by a neuro-radiologist. Primary endpoints were radiographic response and progression-free survival (PFS). Results: There were 11 men and 8 women with a median age of 53 years (range 22–72) and median KPS of 80 (range 70–100). Seventeen patients (89%) were treated at their second or greater recurrence. The most frequent grade 1 and 2 toxicities were thrombocytopenia, elevated ALT, rash, anemia, leukopenia, and diarrhea. Grade 3 lymphopenia occurred in 8 patients (42%); two patients (11%) had grade 4 seizures unrelated to the study drugs. Five patients (26%) had a partial radiographic response, including one treated at 3rd recurrence, 2 treated at 4th recurrence, and one who had progressed through prior gefitinib therapy. Two additional patients (11%) had disease stabilization for greater than 4 months. Median PFS was 2.6 months. Median overall survival has not been reached, with a median follow up of 5.4 months for surviving patients. Conclusions: The combination of RAD-001 and gefitinib demonstrated activity in 37% of patients with GBM (26% responded, 11% achieved stable disease). Most subjects were heavily pre-treated and expected to have resistant disease. Because disease control was not durable, alternate dosing, or treatment earlier in the course of disease should be considered in further studying this promising combination. [Table: see text]

Pediatric multifocal glioblastoma multiforme with fulminant course

“…[ 11 ] High grade gliomas are included in ongoing phase II cancer chemotherapy trials at various centers. [ 12 ] In patients with genetic predisposition where there is expression / deletion of certain genes like PTEN, P53 and others, there are phase I and II trials being conducted for such specific subpopulation[ 13 ] In such rare entities, there are not many ongoing phase III trials. Hence, such rare tumors can be referred for ongoing phase I or phase II trials.…”

Updates in the Management of Recurrent Glioblastoma Multiforme

“…[67][68][69] Gefitinib was given with everolimus in a phase I/II trial but PFS (2.6 months) was similar to that achieved with monotherapy. 70 Sirolimus was added with erlotinib in a pilot study and with carboplatin in a phase II trial in rGBM patients and showed a PFS-6 of 25 and 14%, respectively. 71,72 The European Organisation for research and treatment of Cancer (EORTC) trial compared the efficacy of erlotinib with TMZ or carmustine in 110 rGBM patients.…”