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

Jann N. Sarkaria, Evanthia Galanis, Wenting Wu, Patrick J. Peller, Caterina Giannini, Paul D. Brown, Joon H. Uhm, Steven McGraw, Kurt Jaeckle, Jan C. Buckner

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)468-475
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume81
Issue number2
DOIs
StatePublished - Oct 1 2011

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temozolomide
Glioblastoma
radiation therapy
Radiotherapy
cancer
grade
toxicity
dosage
therapy
Neoplasms
Radiation
Therapeutics
Chemoradiotherapy
Sirolimus
radiation
Positron-Emission Tomography
metabolic diseases
positrons
tomography
Everolimus

All Science Journal Classification (ASJC) codes

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Sarkaria, Jann N. ; Galanis, Evanthia ; Wu, Wenting ; Peller, Patrick J. ; Giannini, Caterina ; Brown, Paul D. ; Uhm, Joon H. ; McGraw, Steven ; Jaeckle, Kurt ; Buckner, Jan C. / 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. In: International Journal of Radiation Oncology Biology Physics. 2011 ; Vol. 81, No. 2. pp. 468-475.
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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.",
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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. / Sarkaria, Jann N.; Galanis, Evanthia; Wu, Wenting; Peller, Patrick J.; Giannini, Caterina; Brown, Paul D.; Uhm, Joon H.; McGraw, Steven; Jaeckle, Kurt; Buckner, Jan C.

In: International Journal of Radiation Oncology Biology Physics, Vol. 81, No. 2, 01.10.2011, p. 468-475.

Research output: Contribution to journalArticle

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T1 - 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

AU - Sarkaria, Jann N.

AU - Galanis, Evanthia

AU - Wu, Wenting

AU - Peller, Patrick J.

AU - Giannini, Caterina

AU - Brown, Paul D.

AU - Uhm, Joon H.

AU - McGraw, Steven

AU - Jaeckle, Kurt

AU - Buckner, Jan C.

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