Phase I trial of sorafenib in combination with 5-fluorouracil/leucovorin in advanced solid tumors.
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.
Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Einat
E
Shacham-Shmueli
Ravit
R
Geva
Arie
A
Figer
Sarah
S
Bulocinic
Karen
K
Nalbandyan
Shulim
S
Shpigel
Jacob
J
Atsmon
Erich
E
Brendel
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007557:Israel; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000008:administration & dosage
D000964:Antimetabolites, Antineoplastic; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014803:Vitamin B Complex; D009536:Niacinamide; D000077157:Sorafenib; D002955:Leucovorin; D005472:Fluorouracil