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Phase I Trial of Sorafenib in Combination With 5‐Fluorouracil/Leucovorin in Advanced Solid Tumors
Author(s) -
ShachamShmueli Einat,
Geva Ravit,
Figer Arie,
Bulocinic Sarah,
Nalbandyan Karen,
Shpigel Shulim,
Atsmon Jacob,
Brendel Erich
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011404027
Subject(s) - sorafenib , medicine , tolerability , concomitant , pharmacokinetics , fluorouracil , gastroenterology , regimen , adverse effect , dosing , pancreatic cancer , response evaluation criteria in solid tumors , pharmacology , oncology , phases of clinical research , cancer , chemotherapy , hepatocellular carcinoma
This dose escalation, uncontrolled phase I study evaluated the tolerability, pharmacokinetics (PK), and antitumor activity of oral sorafenib 100, 200, or 400 mg twice daily (bid, continuous regimen) in combination with 5‐fluorouracil/leucovorin (5‐FU/LCV, intravenous infusion or bolus) in patients with advanced, solid tumors. A total of 47 patients (median age 57 years; colon cancer, 55%; pancreatic cancer, 21%; prior systemic therapy, 96%) received treatment; 24 were included in the PK analyses, and 38 were evaluable for tumor response. Treatment‐emergent adverse events were observed in 98% of patients (≥grade 3, 55%); the most frequently reported were fatigue (51%), stomatitis/pharyngitis (47%), and hand‐foot skin reaction (45%). Concomitant 5‐FU/LCV resulted in no clinically relevant changes in the area under the plasma concentration‐time curve in the dosing interval (AUC 0–12 ) and maximum plasma concentration (C max ) of sorafenib (100–400 mg bid) at steady state. Although the start of infusion until the last quantifiable plasma concentration (AUC 0‐tn ) and C max of 5‐FU were increased by concomitant sorafenib 100 to 200 mg, no consistent effect was observed with 400 mg sorafenib. Two (5%) patients with colon cancer achieved partial response; 16 (42%) patients (the majority with colon and pancreatic cancer) had stable disease. Sorafenib plus 5‐FU/LCV was generally well tolerated with encouraging antitumor activity and no clinically relevant drug‐drug interactions in patients with advanced solid tumors.

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