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 Jaeckle, S. Keith Anderson, Evanthia Galanis, Caterina Giannini, Jan C. 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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Schiff, D., Jaeckle, K., Anderson, S. K., Galanis, E., Giannini, C., Buckner, J. C., ... Sarkaria, J. N. (2018). Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572. Cancer, 124(7), 1455-1463. https://doi.org/10.1002/cncr.31219
Schiff, David ; Jaeckle, Kurt ; Anderson, S. Keith ; Galanis, Evanthia ; Giannini, Caterina ; Buckner, Jan C. ; 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.",
author = "David Schiff and Kurt Jaeckle and Anderson, {S. Keith} and Evanthia Galanis and Caterina Giannini and Buckner, {Jan C.} and Phillip Stella and Flynn, {Patrick J.} and Erickson, {Bradley J.} and Schwerkoske, {John F.} and Vesna Kaluza and Erin Twohy and Janet Dancey and John Wright and Sarkaria, {Jann N.}",
year = "2018",
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Schiff, D, Jaeckle, K, Anderson, SK, Galanis, E, Giannini, C, Buckner, JC, Stella, P, Flynn, PJ, Erickson, BJ, Schwerkoske, JF, Kaluza, V, Twohy, E, Dancey, J, Wright, J & Sarkaria, JN 2018, 'Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572', Cancer, vol. 124, no. 7, pp. 1455-1463. https://doi.org/10.1002/cncr.31219

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; Anderson, S. Keith; Galanis, Evanthia; Giannini, Caterina; Buckner, Jan C.; 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

TY - JOUR

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

AU - Anderson, S. Keith

AU - Galanis, Evanthia

AU - Giannini, Caterina

AU - Buckner, Jan C.

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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