title: Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial.
abstract: Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.
authors.affiliation: Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium. ahmad.awada@bordet.be
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Thierry
authors.initials: T
authors.lastname: Gil
authors.forename: Nicolas
authors.initials: N
authors.lastname: Whenham
authors.forename: Julie
authors.initials: J
authors.lastname: Van Hamme
authors.forename: Tatiana
authors.initials: T
authors.lastname: Besse-Hammer
authors.forename: Erich
authors.initials: E
authors.lastname: Brendel
authors.forename: Heinz
authors.initials: H
authors.lastname: Delesen
authors.forename: Miranda C
authors.initials: MC
authors.lastname: Joosten
authors.forename: Chetan D
authors.initials: CD
authors.lastname: Lathia
authors.forename: Bienvenu A
authors.initials: BA
authors.lastname: Loembé
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart-Ghebart
authors.forename: Alain
authors.initials: A
authors.lastname: Hendlisz
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage*; D000069287:Capecitabine; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003967:Diarrhea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D003841:Deoxycytidine; D009536:Niacinamide; D000069287:Capecitabine; D000077157:Sorafenib; D005472:Fluorouracil