PMID- 29313954
OWN - NLM
STAT- MEDLINE
DCOM- 20190826
LR  - 20220408
IS  - 1097-0142 (Electronic)
IS  - 0008-543X (Print)
IS  - 0008-543X (Linking)
VI  - 124
IP  - 7
DP  - 2018 Apr 1
TI  - Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with 
      recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance 
      N0572.
PG  - 1455-1463
LID - 10.1002/cncr.31219 [doi]
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. (c) 2018 American 
      Cancer Society.
CI  - (c) 2018 American Cancer Society.
FAU - Schiff, David
AU  - Schiff D
AUID- ORCID: 0000-0002-1896-2502
AD  - Division of Neuro-Oncology, Neuro-Oncology Center, University of Virginia Health 
      System, Charlottesville, Virginia.
FAU - Jaeckle, Kurt A
AU  - Jaeckle KA
AD  - Atlantic Health System, Summit, New Jersey.
FAU - Anderson, S Keith
AU  - Anderson SK
AD  - Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
FAU - Galanis, Evanthia
AU  - Galanis E
AD  - Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
FAU - Giannini, Caterina
AU  - Giannini C
AD  - Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
FAU - Buckner, Jan C
AU  - Buckner JC
AD  - Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
FAU - Stella, Phillip
AU  - Stella P
AD  - Medical Oncology Program, St. Joseph Mercy Health System, Ann Arbor, Michigan.
FAU - Flynn, Patrick J
AU  - Flynn PJ
AD  - Metro Minnesota Community Clinical Oncology Program, St. Louis Park, Minnesota.
FAU - Erickson, Bradley J
AU  - Erickson BJ
AD  - Department of Radiology, Mayo Clinic, Rochester, Minnesota.
FAU - Schwerkoske, John F
AU  - Schwerkoske JF
AD  - Minnesota Oncology, Woodbury, Minnesota.
FAU - Kaluza, Vesna
AU  - Kaluza V
AD  - Medical Oncology Program, St. Joseph Mercy Health System, Ann Arbor, Michigan.
FAU - Twohy, Erin
AU  - Twohy E
AD  - Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
FAU - Dancey, Janet
AU  - Dancey J
AD  - Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, 
      National Cancer Institute, Rockville, Maryland.
FAU - Wright, John
AU  - Wright J
AD  - Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, 
      National Cancer Institute, Rockville, Maryland.
FAU - Sarkaria, Jann N
AU  - Sarkaria JN
AD  - Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
LA  - eng
GR  - U10 CA025224/CA/NCI NIH HHS/United States
GR  - U10 CA180821/CA/NCI NIH HHS/United States
GR  - U10 CA180882/CA/NCI NIH HHS/United States
GR  - UG1 CA189863/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
DEP - 20180103
PL  - United States
TA  - Cancer
JT  - Cancer
JID - 0374236
RN  - 624KN6GM2T (temsirolimus)
RN  - 9ZOQ3TZI87 (Sorafenib)
RN  - W36ZG6FT64 (Sirolimus)
MH  - Adult
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Brain Neoplasms/*drug therapy/pathology
MH  - Female
MH  - Follow-Up Studies
MH  - Glioblastoma/*drug therapy/pathology
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy/pathology
MH  - Prognosis
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - Sorafenib/administration & dosage
MH  - Survival Rate
PMC - PMC5867230
MID - NIHMS930688
OTO - NOTNLM
OT  - clinical trial
OT  - glioblastoma
OT  - sorafenib
OT  - targeted therapy
OT  - temsirolimus
COIS- Conflict of Interest: David Schiff served on Bayer advisory boards during study 
      accrual.
EDAT- 2018/01/10 06:00
MHDA- 2019/08/27 06:00
PMCR- 2019/04/01
CRDT- 2018/01/10 06:00
PHST- 2017/09/05 00:00 [received]
PHST- 2017/10/17 00:00 [revised]
PHST- 2017/11/10 00:00 [accepted]
PHST- 2018/01/10 06:00 [pubmed]
PHST- 2019/08/27 06:00 [medline]
PHST- 2018/01/10 06:00 [entrez]
PHST- 2019/04/01 00:00 [pmc-release]
AID - 10.1002/cncr.31219 [doi]
PST - ppublish
SO  - Cancer. 2018 Apr 1;124(7):1455-1463. doi: 10.1002/cncr.31219. Epub 2018 Jan 3.