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Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572
Author(s) -
Schiff David,
Jaeckle Kurt A.,
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.
Publication year - 2018
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31219
Subject(s) - medicine , temsirolimus , sorafenib , glioblastoma , oncology , cancer , alliance , discovery and development of mtor inhibitors , cancer research , hepatocellular carcinoma , pi3k/akt/mtor pathway , biochemistry , chemistry , apoptosis , political science , law
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 . © 2018 American Cancer Society .