Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

David Schiff, Kurt A. Jaeckle, S. Keith Anderson, Evanthia Galanis, Caterina Giannini, Jan Craig Buckner, Phillip Stella, Patrick J. Flynn, Bradley J Erickson, John F. Schwerkoske, Vesna Kaluza, Erin Twohy, Janet Dancey, John Wright, Jann N Sarkaria

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63.

Original languageEnglish (US)
Pages (from-to)1455-1463
Number of pages9
JournalCancer
Volume124
Issue number7
DOIs
StatePublished - Apr 1 2018

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Glioblastoma
Vascular Endothelial Growth Factor A
Neoplasms
Maximum Tolerated Dose
temozolomide
Sirolimus
Therapeutics
Disease-Free Survival
Disease Progression
raf Kinases
Vascular Endothelial Growth Factor Receptor-2
temsirolimus
sorafenib
Mitogen-Activated Protein Kinases
Appointments and Schedules
Radiotherapy
Drug Therapy
Survival

Keywords

  • clinical trial
  • glioblastoma
  • sorafenib
  • targeted therapy
  • temsirolimus

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma : North Central Cancer Treatment Group Study/Alliance N0572. / Schiff, David; Jaeckle, Kurt A.; Anderson, S. Keith; Galanis, Evanthia; Giannini, Caterina; Buckner, Jan Craig; Stella, Phillip; Flynn, Patrick J.; Erickson, Bradley J; Schwerkoske, John F.; Kaluza, Vesna; Twohy, Erin; Dancey, Janet; Wright, John; Sarkaria, Jann N.

In: Cancer, Vol. 124, No. 7, 01.04.2018, p. 1455-1463.

Research output: Contribution to journalArticle

Schiff, David ; Jaeckle, Kurt A. ; Anderson, S. Keith ; Galanis, Evanthia ; Giannini, Caterina ; Buckner, Jan Craig ; Stella, Phillip ; Flynn, Patrick J. ; Erickson, Bradley J ; Schwerkoske, John F. ; Kaluza, Vesna ; Twohy, Erin ; Dancey, Janet ; Wright, John ; Sarkaria, Jann N. / Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma : North Central Cancer Treatment Group Study/Alliance N0572. In: Cancer. 2018 ; Vol. 124, No. 7. pp. 1455-1463.
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title = "Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572",
abstract = "BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1{\%}); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8{\%}), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5{\%} of the VEGFi-naive patients and in 73.9{\%} of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63.",
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T1 - Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma

T2 - North Central Cancer Treatment Group Study/Alliance N0572

AU - Schiff, David

AU - Jaeckle, Kurt A.

AU - Anderson, S. Keith

AU - Galanis, Evanthia

AU - Giannini, Caterina

AU - Buckner, Jan Craig

AU - Stella, Phillip

AU - Flynn, Patrick J.

AU - Erickson, Bradley J

AU - Schwerkoske, John F.

AU - Kaluza, Vesna

AU - Twohy, Erin

AU - Dancey, Janet

AU - Wright, John

AU - Sarkaria, Jann N

PY - 2018/4/1

Y1 - 2018/4/1

N2 - BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63.

AB - BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63.

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