PMID- 23564811
OWN - NLM
STAT- MEDLINE
DCOM- 20130611
LR  - 20151119
IS  - 1791-7530 (Electronic)
IS  - 0250-7005 (Linking)
VI  - 33
IP  - 4
DP  - 2013 Apr
TI  - Phase II study of bevacizumab and temsirolimus combination therapy for recurrent 
      glioblastoma multiforme.
PG  - 1657-60
AB  - BACKGROUND: Bevacizumab combined with chemotherapy has recently shown promising 
      efficacy in recurrent high-grade glioma. Phosphatase and tensin homolog (PTEN) 
      mutation in glioblastoma multiforme (GBM) patients causes abnormally high 
      activity of the pathways of Phosphatidylinositide 3-kinases (PI3K), Protein 
      Kinase B (AKT), and the mammalian target of rapamycin (mTOR) and is associated 
      with unfavorable prognosis. Temsirolimus, an mTOR inhibitor, has been 
      well-tolerated in monotherapy, but with limited effects. The combination of 
      temsirolimus and antibodies to vascular endothelial factor (VEGF) has not yet 
      been investigated, but with the hypothesis that temsirolimus might provide 
      complimentary therapeutic benefit in combination with bevacizumab, we included 
      patients with progressive GBM after bevacizumab in an open phase II study. 
      PATIENTS AND METHODS: Adult patients with GBM recurrence after standard 
      temozolomide chemoradiotherapy and bevacizumab-containing second-line therapy, 
      received temsirolimus (25 mg i.v.) on days 1 and 8 and bevacizumab (10 mg/kg) on 
      day 8, every two weeks. Assessments were performed every eight weeks. Blood 
      samples for biomarkers were collected weekly for the first eight weeks and at 
      progression. The primary end-point was median progression-free survival (PFS) and 
      secondary end-points were radiographic response, overall survival (OS), and 
      safety of the bevacizumab-temsirolimus combination. RESULTS: Thirteen patients 
      were included, whereof three went off-study during the first four weeks and were 
      replaced. The trial was terminated at 13 patients, according to the planned 
      two-stage design, because 0/10 patients obtained partial remission (PR). Two out 
      of 10 patients obtained radiological stable disease (SD). The median PFS survival 
      was eight weeks, and OS was 15 weeks. One patient had an serious adverse event 
      (SAE) with a hypersensitive reaction to temsirolimus; overall, side-effects were 
      mild, and the most common grade III side-effect was hypercholesterolaemia (4/10). 
      Other grade III side-effects included hypertriglyceridaemia (1/10), 
      thrombocytopenia (1/10), infection (1/10), hypertension (1/10), and hyperglycemia 
      (1/10). CONCLUSION: Temsirolimus can be safely administered in combination with 
      bevacizumab. This study failed to detect activity of such a combination in 
      patients with progressive GBM beyond bevacizumab therapy.
FAU - Lassen, Ulrik
AU  - Lassen U
AD  - Department of Oncology, Rigshospitalet, Copenhagen, Denmark. 
      ulrik.lassen@rh.regionh.dk
FAU - Sorensen, Morten
AU  - Sorensen M
FAU - Gaziel, Tine Bernhardtsen
AU  - Gaziel TB
FAU - Hasselbalch, Benedikte
AU  - Hasselbalch B
FAU - Poulsen, Hans Skovgaard
AU  - Poulsen HS
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PL  - Greece
TA  - Anticancer Res
JT  - Anticancer research
JID - 8102988
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 2S9ZZM9Q9V (Bevacizumab)
RN  - 624KN6GM2T (temsirolimus)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal, Humanized/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Bevacizumab
MH  - Brain Neoplasms/*drug therapy/mortality/pathology
MH  - Female
MH  - Follow-Up Studies
MH  - Glioblastoma/*drug therapy/mortality/pathology
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy/mortality/pathology
MH  - Neoplasm Staging
MH  - Prognosis
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - Survival Rate
MH  - Young Adult
EDAT- 2013/04/09 06:00
MHDA- 2013/06/12 06:00
CRDT- 2013/04/09 06:00
PHST- 2013/04/09 06:00 [entrez]
PHST- 2013/04/09 06:00 [pubmed]
PHST- 2013/06/12 06:00 [medline]
AID - 33/4/1657 [pii]
PST - ppublish
SO  - Anticancer Res. 2013 Apr;33(4):1657-60.