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.
PATIENTS AND 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.
CONCLUSION: 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.