title: Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors.
abstract: OBJECTIVE
  Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib.
  
  
  METHODS
  Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m(2) on days 1 and 8), cisplatin (70 mg/m(2)), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12, and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules.
  
  
  RESULTS
  Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1-5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment.
  
  
  CONCLUSIONS
  Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY, 10029, USA, matthew.galsky@mssm.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.forename: Marshall
authors.initials: M
authors.lastname: Posner
authors.forename: Randall F
authors.initials: RF
authors.lastname: Holcombe
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lee
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Misiukiewicz
authors.forename: Che-Kai
authors.initials: CK
authors.lastname: Tsao
authors.forename: James
authors.initials: J
authors.lastname: Godbold
authors.forename: Rothschild
authors.initials: R
authors.lastname: Soto
authors.forename: Kiev
authors.initials: K
authors.lastname: Gimpel-Tetra
authors.forename: Nancy
authors.initials: N
authors.lastname: Lowe
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D013923:Thromboembolism / Q000139:chemically induced; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; D015363:Quinolones; D003841:Deoxycytidine; D016190:Carboplatin; D002945:Cisplatin; D000093542:Gemcitabine