PMID- 23868004
OWN - NLM
STAT- MEDLINE
DCOM- 20131104
LR  - 20211214
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 109
IP  - 4
DP  - 2013 Aug 20
TI  - A phase I study of the combination of ro4929097 and cediranib in patients with 
      advanced solid tumours (PJC-004/NCI 8503).
PG  - 943-9
LID - 10.1038/bjc.2013.380 [doi]
AB  - BACKGROUND: The Notch signalling pathway has been implicated in tumour 
      initiation, progression, angiogenesis and development of resistance to vascular 
      endothelial growth factor (VEGF) targeting, providing a rationale for the 
      combination of RO4929097, a gamma-secretase inhibitor, and cediranib, a VEGF receptor 
      tyrosine kinase inhibitor. METHODS: Patients received escalating doses of 
      RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib 
      (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 
      weeks followed by the co-administration of both RO4929097 and cediranib starting 
      from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of 
      angiogenesis were measured in plasma samples. Archival tumour specimens were 
      assessed for expression of three different components of Notch signalling pathway 
      and genotyping. RESULTS: In total, 20 patients were treated in three dose levels 
      (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 
      days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent 
      treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and 
      nausea. Eleven patients had a best response of stable disease and one patient 
      achieved partial response. We did not detect any correlation between tested 
      biomarkers of angiogenesis or the Notch pathway and treatment effect. There was 
      no correlation between mutational status and time to treatment failure. 
      CONCLUSION: RO4929097 in combination with cediranib is generally well tolerated 
      at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged 
      disease stabilisation in some patients with progressive malignancies warrants 
      further clinical investigation of this treatment strategy.
FAU - Sahebjam, S
AU  - Sahebjam S
AD  - Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
FAU - Bedard, P L
AU  - Bedard PL
FAU - Castonguay, V
AU  - Castonguay V
FAU - Chen, Z
AU  - Chen Z
FAU - Reedijk, M
AU  - Reedijk M
FAU - Liu, G
AU  - Liu G
FAU - Cohen, B
AU  - Cohen B
FAU - Zhang, W-J
AU  - Zhang WJ
FAU - Clarke, B
AU  - Clarke B
FAU - Zhang, T
AU  - Zhang T
FAU - Kamel-Reid, S
AU  - Kamel-Reid S
FAU - Chen, H
AU  - Chen H
FAU - Ivy, S P
AU  - Ivy SP
FAU - Razak, A R A
AU  - Razak AR
FAU - Oza, A M
AU  - Oza AM
FAU - Chen, E X
AU  - Chen EX
FAU - Hirte, H W
AU  - Hirte HW
FAU - McGarrity, A
AU  - McGarrity A
FAU - Wang, L
AU  - Wang L
FAU - Siu, L L
AU  - Siu LL
FAU - Hotte, S J
AU  - Hotte SJ
LA  - eng
GR  - U01 CA132123/CA/NCI NIH HHS/United States
GR  - U01-CA132123/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
DEP - 20130718
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Benzazepines)
RN  - 0 (Quinazolines)
RN  - KK8645V7LE 
      (2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide)
RN  - NQU9IPY4K9 (cediranib)
RN  - Thyroid cancer, medullary
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/*therapeutic use
MH  - Benzazepines/administration & dosage
MH  - Breast Neoplasms/drug therapy
MH  - Carcinoma, Neuroendocrine
MH  - Carcinoma, Renal Cell/drug therapy
MH  - Colorectal Neoplasms/drug therapy
MH  - Female
MH  - Humans
MH  - Kidney Neoplasms/drug therapy
MH  - Leiomyosarcoma/drug therapy
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy
MH  - Quinazolines/administration & dosage
MH  - Sarcoma, Endometrial Stromal/drug therapy
MH  - Thyroid Neoplasms/drug therapy
MH  - Treatment Outcome
MH  - Uterine Neoplasms/drug therapy
MH  - Young Adult
PMC - PMC3749563
EDAT- 2013/07/23 06:00
MHDA- 2013/11/05 06:00
PMCR- 2013/08/20
CRDT- 2013/07/23 06:00
PHST- 2013/03/13 00:00 [received]
PHST- 2013/05/24 00:00 [revised]
PHST- 2013/06/24 00:00 [accepted]
PHST- 2013/07/23 06:00 [entrez]
PHST- 2013/07/23 06:00 [pubmed]
PHST- 2013/11/05 06:00 [medline]
PHST- 2013/08/20 00:00 [pmc-release]
AID - bjc2013380 [pii]
AID - 10.1038/bjc.2013.380 [doi]
PST - ppublish
SO  - Br J Cancer. 2013 Aug 20;109(4):943-9. doi: 10.1038/bjc.2013.380. Epub 2013 Jul 
      18.