title: Phase I combination of sorafenib and erlotinib therapy in solid tumors: safety, pharmacokinetic, and pharmacodynamic evaluation from an expansion cohort.
abstract: The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography-computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib.
authors.affiliation: Princess Margaret Hospital Phase II Consortium, University of Toronto, Ontario, Canada.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintela-Fandino
authors.forename: Christophe
authors.initials: C
authors.lastname: Le Tourneau
authors.forename: Ignacio
authors.initials: I
authors.lastname: Duran
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Tsao
authors.forename: Bizhan
authors.initials: B
authors.lastname: Bandarchi-Chamkhaleh
authors.forename: Nhu-Ann
authors.initials: NA
authors.lastname: Pham
authors.forename: Trevor
authors.initials: T
authors.lastname: Do
authors.forename: Martha
authors.initials: M
authors.lastname: MacLean
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nayyar
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tusche
authors.forename: Ur
authors.initials: U
authors.lastname: Metser
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D054316:Biomarkers, Pharmacological / Q000032:analysis* / Q000378:metabolism; D015331:Cohort Studies; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; D054316:Biomarkers, Pharmacological; D010671:Phenylurea Compounds; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride