title: A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group.
abstract: Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM.
  
  
  
  This open-label multicentre phase II trial [NCT01769547] enrolled fit, consenting adult patients with advanced MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Dovitinib was administered orally at 500mg/day for 5days on, 2days off, in 28-day cycles. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. The primary end-point was the proportion of patients progression-free at 3 months (PF3) using a two-stage design.
  
  
  
  12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). One unconfirmed partial response was observed. PF3 was 50% (95% confidence interval 28.4% to 88.0%); although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population. One of 12 tumour specimens had low amplification of FGFR-1.
  
  
  
  Dovitinib has minimal activity in previously-treated MPM. The role of the FGFR pathway in MPM remains unclear.
authors.affiliation: The Ottawa Hospital Cancer Centre, 501 Smyth Road Ottawa, ON, Canada. Electronic address: slaurie@toh.on.ca.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.affiliation: Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada. Electronic address: desiree.hao@albertahealthservices.ca.
authors.forename: Desiree
authors.initials: D
authors.lastname: Hao
authors.affiliation: Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, Canada. Electronic address: nleighl@uhn.ca.
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
authors.affiliation: Juravinski Cancer Centre, 699 Concession St, Hamilton, ON, Canada. Electronic address: goffinj@hhsc.ca.
authors.forename: John
authors.initials: J
authors.lastname: Goffin
authors.affiliation: The Cancer Centre of NorthEastern Ontario, 41 Ramsey Lake Road, Sudbury, ON, Canada. Electronic address: xopowbiu@gmail.com.
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Khomani
authors.affiliation: The Ottawa Hospital Cancer Centre, 501 Smyth Road Ottawa, ON, Canada. Electronic address: ashgupta@toh.ca.
authors.forename: Ashish
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada. Electronic address: caddison@ohri.ca.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Addison
authors.affiliation: Department of Pathology and Molecular Medicine and Department of Oncology, McMaster University, 699 Concession St, Hamilton, ON, Canada. Electronic address: bane@hhsc.ca.
authors.forename: Anita
authors.initials: A
authors.lastname: Bane
authors.affiliation: The Ottawa Hospital Cancer Centre, 501 Smyth Road Ottawa, ON, Canada. Electronic address: jeseely@toh.ca.
authors.forename: Jean
authors.initials: J
authors.lastname: Seely
authors.affiliation: Ontario Clinical Oncology Group, McMaster University, 711 Concession St, Hamilton, ON, Canada. Electronic address: filion@mcmaster.ca.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Filion
authors.affiliation: Ontario Clinical Oncology Group, McMaster University, 711 Concession St, Hamilton, ON, Canada. Electronic address: gpond@mcmaster.ca.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Pond
authors.affiliation: Ontario Clinical Oncology Group, McMaster University, 711 Concession St, Hamilton, ON, Canada. Electronic address: mlevine@mcmaster.ca.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Levine
mesh_terms: D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009864:Ontario; D010997:Pleural Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000627:therapeutic use
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D017468:Receptors, Fibroblast Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Angiogenesis; Fibroblast growth factor receptor; Mesothelioma; Phase II