A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K

Daniel J. Ma, Evanthia Galanis, S. Keith Anderson, David Schiff, Timothy J. Kaufmann, Patrick J. Peller, Caterina Giannini, Paul D. Brown, Joon H. Uhm, Steven McGraw, Kurt Jaeckle, Patrick J. Flynn, Keith L. Ligon, Jan C. Buckner, Jann N. Sarkaria

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Abstract

Background. The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy. Methods. Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3′-deoxy-3′-18F-fluorothymidine (18FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis. Results. This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had 18FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that 18FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders. Conclusion. Combining everolimus with conventional chemoradiation had moderate toxicity. 18FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.

Original languageEnglish (US)
Pages (from-to)1261-1269
Number of pages9
JournalNeuro-Oncology
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2015

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temozolomide
Glioblastoma
Radiotherapy
Sirolimus
Phosphatidylinositol 3-Kinase
Survival
Exons
Radiation
Tuberous Sclerosis
Neurofibromatosis 1
Chemoradiotherapy
Disease Progression
Everolimus
Neoplasms
Cell Survival
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Ma, D. J., Galanis, E., Anderson, S. K., Schiff, D., Kaufmann, T. J., Peller, P. J., ... Sarkaria, J. N. (2015). A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro-Oncology, 17(9), 1261-1269. https://doi.org/10.1093/neuonc/nou328
Ma, Daniel J. ; Galanis, Evanthia ; Anderson, S. Keith ; Schiff, David ; Kaufmann, Timothy J. ; Peller, Patrick J. ; Giannini, Caterina ; Brown, Paul D. ; Uhm, Joon H. ; McGraw, Steven ; Jaeckle, Kurt ; Flynn, Patrick J. ; Ligon, Keith L. ; Buckner, Jan C. ; Sarkaria, Jann N. / A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma : NCCTG N057K. In: Neuro-Oncology. 2015 ; Vol. 17, No. 9. pp. 1261-1269.
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abstract = "Background. The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy. Methods. Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3′-deoxy-3′-18F-fluorothymidine (18FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis. Results. This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64{\%} and median time to progression was 6.4 months. Of the patients who had 18FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that 18FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders. Conclusion. Combining everolimus with conventional chemoradiation had moderate toxicity. 18FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.",
author = "Ma, {Daniel J.} and Evanthia Galanis and Anderson, {S. Keith} and David Schiff and Kaufmann, {Timothy J.} and Peller, {Patrick J.} and Caterina Giannini and Brown, {Paul D.} and Uhm, {Joon H.} and Steven McGraw and Kurt Jaeckle and Flynn, {Patrick J.} and Ligon, {Keith L.} and Buckner, {Jan C.} and Sarkaria, {Jann N.}",
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Ma, DJ, Galanis, E, Anderson, SK, Schiff, D, Kaufmann, TJ, Peller, PJ, Giannini, C, Brown, PD, Uhm, JH, McGraw, S, Jaeckle, K, Flynn, PJ, Ligon, KL, Buckner, JC & Sarkaria, JN 2015, 'A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K', Neuro-Oncology, vol. 17, no. 9, pp. 1261-1269. https://doi.org/10.1093/neuonc/nou328

A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma : NCCTG N057K. / Ma, Daniel J.; Galanis, Evanthia; Anderson, S. Keith; Schiff, David; Kaufmann, Timothy J.; Peller, Patrick J.; Giannini, Caterina; Brown, Paul D.; Uhm, Joon H.; McGraw, Steven; Jaeckle, Kurt; Flynn, Patrick J.; Ligon, Keith L.; Buckner, Jan C.; Sarkaria, Jann N.

In: Neuro-Oncology, Vol. 17, No. 9, 01.09.2015, p. 1261-1269.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma

T2 - NCCTG N057K

AU - Ma, Daniel J.

AU - Galanis, Evanthia

AU - Anderson, S. Keith

AU - Schiff, David

AU - Kaufmann, Timothy J.

AU - Peller, Patrick J.

AU - Giannini, Caterina

AU - Brown, Paul D.

AU - Uhm, Joon H.

AU - McGraw, Steven

AU - Jaeckle, Kurt

AU - Flynn, Patrick J.

AU - Ligon, Keith L.

AU - Buckner, Jan C.

AU - Sarkaria, Jann N.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background. The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy. Methods. Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3′-deoxy-3′-18F-fluorothymidine (18FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis. Results. This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had 18FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that 18FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders. Conclusion. Combining everolimus with conventional chemoradiation had moderate toxicity. 18FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.

AB - Background. The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy. Methods. Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3′-deoxy-3′-18F-fluorothymidine (18FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis. Results. This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had 18FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that 18FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders. Conclusion. Combining everolimus with conventional chemoradiation had moderate toxicity. 18FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy.

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U2 - 10.1093/neuonc/nou328

DO - 10.1093/neuonc/nou328

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