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 00:00:00 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]

---

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, Vol. 81, Issue 2; Other Information: DOI: 10.1016/j.ijrobp.2010.05.064; PII: S0360-3016(10)00815-1; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

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