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

Journal Article · Sat Oct 01 04:00:00 EDT 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.05.064· OSTI ID:21587731

Galanis, Evanthia; Wenting, Wu; Peller, Patrick J; Giannini, Caterina; Brown, Paul D; Uhm, Joon H ^[1]; McGraw, Steven ^[2]; Jaeckle, Kurt A ^[3]; Buckner, Jan C ^[1]

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1. Mayo Clinic Rochester, Rochester, MN (United States)
2. Sioux Community Cancer Consortium, Sioux Falls, SD (United States)
3. Mayo Clinic Florida, Jacksonville, FL (United States)

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.

• OSTI ID: 21587731
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 2 Vol. 81; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
ANTIMETABOLITES
BODY
COMBINED THERAPY
COMPUTERIZED TOMOGRAPHY
DIAGNOSTIC TECHNIQUES
DIGESTIVE SYSTEM
DISEASES
DOSES
DRUGS
EMISSION COMPUTED TOMOGRAPHY
FLUORODEOXYGLUCOSE
GLANDS
GLIOMAS
LIVER
MEDICINE
METABOLIC DISEASES
METABOLISM
NEOPLASMS
NERVOUS SYSTEM DISEASES
NUCLEAR MEDICINE
ORGANS
POSITRON COMPUTED TOMOGRAPHY
RADIATION DOSES
RADIOLOGY
RADIOTHERAPY
STANDARDS
THERAPY
TOMOGRAPHY
TOXICITY