title: A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503).
abstract: 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 γ-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Sahebjam
authors.forename: P L
authors.initials: PL
authors.lastname: Bedard
authors.forename: V
authors.initials: V
authors.lastname: Castonguay
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Reedijk
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: B
authors.initials: B
authors.lastname: Cohen
authors.forename: W-J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Clarke
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: S P
authors.initials: SP
authors.lastname: Ivy
authors.forename: A R A
authors.initials: AR
authors.lastname: Razak
authors.forename: A M
authors.initials: AM
authors.lastname: Oza
authors.forename: E X
authors.initials: EX
authors.lastname: Chen
authors.forename: H W
authors.initials: HW
authors.lastname: Hirte
authors.forename: A
authors.initials: A
authors.lastname: McGarrity
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.forename: S J
authors.initials: SJ
authors.lastname: Hotte
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001552:Benzazepines / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy; D018278:Carcinoma, Neuroendocrine; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D007890:Leiomyosarcoma / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage; D018203:Sarcoma, Endometrial Stromal / Q000188:drug therapy; D013964:Thyroid Neoplasms / Q000188:drug therapy; D016896:Treatment Outcome; D014594:Uterine Neoplasms / Q000188:drug therapy; D055815:Young Adult; D005466:Fluorocarbons; D007211:Indoles
chemical_list: D001552:Benzazepines; D011799:Quinazolines; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons; C500926:cediranib; D007211:Indoles