title: A phase Ib study of the VEGF receptor tyrosine kinase inhibitor tivozanib and modified FOLFOX-6 in patients with advanced gastrointestinal malignancies.
abstract: BACKGROUND
  Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors.
  
  
  METHODS
  Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6.
  
  
  RESULTS
  Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease.
  
  
  CONCLUSIONS
  Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Corina N
authors.initials: CN
authors.lastname: Oldenhuis
authors.affiliation: Department of Medical Oncology, Erasmus University Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.affiliation: AVEO Oncology, Cambridge, MA.
authors.forename: Brooke
authors.initials: B
authors.lastname: Esteves
authors.affiliation: Department of Medical Oncology, Erasmus University Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Leni
authors.initials: L
authors.lastname: van Doorn
authors.affiliation: AVEO Oncology, Cambridge, MA.
authors.forename: Monette M
authors.initials: MM
authors.lastname: Cotreau
authors.affiliation: AVEO Oncology, Cambridge, MA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Strahs
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Martha W
authors.initials: MW
authors.lastname: den Hollander
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Medical Oncology, Erasmus University Cancer Institute, Rotterdam, The Netherlands. Electronic address: f.eskens@erasmusmc.nl.
authors.forename: Ferry A L M
authors.initials: FA
authors.lastname: Eskens
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil
keywords: Angiogenesis; Clinical study; Pharmacokinetics; Safety; mFOLFOX-6