North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme

Abstract

Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt signaling pathway as a critical modulator of cell survival. On the basis of promising preclinical data, the safety and tolerability of therapy with the mTOR inhibitor RAD001 in combination with radiation (RT) and temozolomide (TMZ) was evaluated in this Phase I study.

Methods and materials: All patients received weekly oral RAD001 in combination with standard chemoradiotherapy, followed by RAD001 in combination with standard adjuvant temozolomide. RAD001 was dose escalated in cohorts of 6 patients. Dose-limiting toxicities were defined during RAD001 combination therapy with TMZ/RT.

Results: Eighteen patients were enrolled, with a median follow-up of 8.4 months. Combined therapy was well tolerated at all dose levels, with 1 patient on each dose level experiencing a dose-limiting toxicity: Grade 3 fatigue, Grade 4 hematologic toxicity, and Grade 4 liver dysfunction. Throughout therapy, there were no Grade 5 events, 3 patients experienced Grade 4 toxicities, and 6 patients had Grade 3 toxicities attributable to treatment. On the basis of these results, the recommended Phase II dosage currently being tested is RAD001 70 mg/week in combination with standard chemoradiotherapy. Fluorodeoxyglucose (FDG) positron emission tomography scans also were obtained at baseline and after the second RAD001 dose before the initiation of TMZ/RT; the change in FDG uptake between scans was calculated for each patient. Fourteen patients had stable metabolic disease, and 4 patients had a partial metabolic response.

Conclusions: RAD001 in combination with RT/TMZ and adjuvant TMZ was reasonably well tolerated. Changes in tumor metabolism can be detected by FDG positron emission tomography in a subset of patients within days of initiating RAD001 therapy.

Conflict of interest statement

Conflicts of Interest Notification. Funding was provided by Novartis in support of this clinical trial.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

The treatment schema for this Phase I trial is shown. RAD001 was given weekly during concomitant radiation (RT) and temozolomide (TMZ) and then during after adjuvant TMZ. FDG PET scans were performed before the 1st dose and after the 2nd dose of RAD001, before RT and TMZ were started.

Figure 2

FDG PET brain scans were obtained before (pre-RAD001) and after the 2nd dose of RAD001 (post-RAD001), and the change in SUVmax was calculated for each patient. A) Representative pre- and post-RAD001 PET scans from a patient with a partial metabolic response (PMR) is shown with a corresponding axial T1 MR image with gadolinium. B) Waterfall plot of change in SUVmax for each patient is shown. Those patients in white are alive without evidence of progression. Those in gray are either dead or alive with progressive disease. The numbers along the X-axis are the days from diagnosis to last follow-up or date of progressive disease, respectively.

Figure 2

FDG PET brain scans were obtained before (pre-RAD001) and after the 2nd dose of RAD001 (post-RAD001), and the change in SUVmax was calculated for each patient. A) Representative pre- and post-RAD001 PET scans from a patient with a partial metabolic response (PMR) is shown with a corresponding axial T1 MR image with gadolinium. B) Waterfall plot of change in SUVmax for each patient is shown. Those patients in white are alive without evidence of progression. Those in gray are either dead or alive with progressive disease. The numbers along the X-axis are the days from diagnosis to last follow-up or date of progressive disease, respectively.

Figure 3

Serum drug levels and change in SUVmax by PET. A) RAD001 serum levels were obtained 24 hours after the first dose of RAD001 and are plotted for individual patients according to dose cohort. The mean serum level for each cohort is shown as a horizontal line. B) RAD001 serum levels are plotted relative to the change in SUVmax for 17 patients treated on this trial.

Figure 3

Serum drug levels and change in SUVmax by PET. A) RAD001 serum levels were obtained 24 hours after the first dose of RAD001 and are plotted for individual patients according to dose cohort. The mean serum level for each cohort is shown as a horizontal line. B) RAD001 serum levels are plotted relative to the change in SUVmax for 17 patients treated on this trial.