title: Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.
abstract: BACKGROUND
  Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and β (PGFRα/β), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors.
  
  
  METHODS
  This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive).
  
  
  RESULTS
  Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients.
  
  
  CONCLUSIONS
  Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.
authors.affiliation: Department of Drug Development, Gustave-Roussy Cancer Campus, Villejuif, France. Electronic address: soria@igr.fr.
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: DeBraud
authors.affiliation: Department of Drug Development, Gustave-Roussy Cancer Campus, Villejuif, France.
authors.forename: R
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Adamo
authors.affiliation: Department of Drug Development, Gustave-Roussy Cancer Campus, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Andre
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain; Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle.
authors.forename: R
authors.initials: R
authors.lastname: Dientsmann
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Delmonte
authors.affiliation: Clovis Oncology, Inc., San Francisco; Clovis Oncology, Inc., Boulder,USA; Clovis Oncology, Inc., Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cereda
authors.affiliation: Clovis Oncology, Inc., San Francisco; Clovis Oncology, Inc., Boulder,USA; Clovis Oncology, Inc., Milan, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Isaacson
authors.affiliation: Clovis Oncology, Inc., San Francisco; Clovis Oncology, Inc., Boulder,USA; Clovis Oncology, Inc., Milan, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Litten
authors.affiliation: Clovis Oncology, Inc., San Francisco; Clovis Oncology, Inc., Boulder,USA; Clovis Oncology, Inc., Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Allen
authors.affiliation: Institut de Recherche International Servier, Suresnes, France.
authors.forename: F
authors.initials: F
authors.lastname: Dubois
authors.affiliation: Institut de Recherche International Servier, Suresnes, France.
authors.forename: C
authors.initials: C
authors.lastname: Saba
authors.affiliation: Institut de Recherche International Servier, Suresnes, France.
authors.forename: R
authors.initials: R
authors.lastname: Robert
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zucchetti
authors.affiliation: Clovis Oncology, Inc., San Francisco; Clovis Oncology, Inc., Boulder,USA; Clovis Oncology, Inc., Milan, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Camboni
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009281:Naphthalenes / Q000032:analysis*; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000032:analysis*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors
chemical_list: C000595232:E-3810; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: FGFR1 amplification; Phase I trial; breast cancer; kinase inhibitor; lung cancer