PMID- 25503302
OWN - NLM
STAT- MEDLINE
DCOM- 20151027
LR  - 20231104
IS  - 1573-7373 (Electronic)
IS  - 0167-594X (Print)
IS  - 0167-594X (Linking)
VI  - 121
IP  - 3
DP  - 2015 Feb
TI  - Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a 
      phase I and dose expansion cohort study.
PG  - 627-34
LID - 10.1007/s11060-014-1680-2 [doi]
AB  - Targeting specific molecular alterations in glioblastoma (GBM) might more 
      effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal 
      growth factor receptor and vascular endothelial growth factor receptor 2. 
      Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the 
      phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum 
      tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with 
      sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. 
      Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to 
      anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing 
      drugs. Vandetanib and sirolimus were orally administered on a continuous daily 
      dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose 
      escalation phase. Twelve more enrolled at the MTD to explore progression-free 
      survival at 6 months (PFS6) in a single arm, single stage phase II-type design. 
      In total, 19 patients received at least one dose at the MTD, and 15 completed at 
      least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was 
      elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, 
      and hypophosphatemia. For 19 patients who received at least one dose at the MTD, 
      including seven from the phase I group, two had a partial response [10.5 %; 95 % 
      CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and 
      sirolimus can be safely co-administered on a continuous, daily dosing schedule.
FAU - Chheda, Milan G
AU  - Chheda MG
AD  - Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General 
      Hospital, Yawkey 9 East, 55 Fruit Street, Boston, MA, 02114, USA, 
      chhedam@mskcc.org.
FAU - Wen, Patrick Y
AU  - Wen PY
FAU - Hochberg, Fred H
AU  - Hochberg FH
FAU - Chi, Andrew S
AU  - Chi AS
FAU - Drappatz, Jan
AU  - Drappatz J
FAU - Eichler, April F
AU  - Eichler AF
FAU - Yang, Daniel
AU  - Yang D
FAU - Beroukhim, Rameen
AU  - Beroukhim R
FAU - Norden, Andrew D
AU  - Norden AD
FAU - Gerstner, Elizabeth R
AU  - Gerstner ER
FAU - Betensky, Rebecca A
AU  - Betensky RA
FAU - Batchelor, Tracy T
AU  - Batchelor TT
LA  - eng
SI  - ClinicalTrials.gov/NCT00821080
GR  - K08 NS062907/NS/NINDS NIH HHS/United States
GR  - K12 CA090354/CA/NCI NIH HHS/United States
GR  - K24 CA125440/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141213
PL  - United States
TA  - J Neurooncol
JT  - Journal of neuro-oncology
JID - 8309335
RN  - 0 (Piperidines)
RN  - 0 (Quinazolines)
RN  - W36ZG6FT64 (Sirolimus)
RN  - YO460OQ37K (vandetanib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Brain Neoplasms/*drug therapy
MH  - Cohort Studies
MH  - Disease-Free Survival
MH  - Female
MH  - Glioblastoma/*drug therapy
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/*drug therapy
MH  - Piperidines/administration & dosage/adverse effects
MH  - Quinazolines/administration & dosage/adverse effects
MH  - Sirolimus/administration & dosage/adverse effects
PMC - PMC4324090
MID - NIHMS649066
COIS- Conflict of interest All other authors have no conflict of interest.
EDAT- 2014/12/17 06:00
MHDA- 2015/10/28 06:00
PMCR- 2016/02/01
CRDT- 2014/12/16 06:00
PHST- 2014/09/29 00:00 [received]
PHST- 2014/11/21 00:00 [accepted]
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/10/28 06:00 [medline]
PHST- 2016/02/01 00:00 [pmc-release]
AID - 10.1007/s11060-014-1680-2 [doi]
PST - ppublish
SO  - J Neurooncol. 2015 Feb;121(3):627-34. doi: 10.1007/s11060-014-1680-2. Epub 2014 
      Dec 13.