title: Phase I pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer.
abstract: Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels. Results Eighteen patients were recruited with median age 56.5 years. In the first five patients treated, 2 irinotecan related DLTs were observed. With reduced dose intensity irinotecan, there were no further DLTs. The most common toxicities were diarrhea, nausea/vomiting, fatigue, anorexia and rash. DLTs included neutropenia and thrombocytopenia. Two patients had partial responses (one with a KRAS mutation) and 8 had stable disease (8-36 weeks). The median progression free survival (PFS) and overall survival (OS) were 2.5 and 4.7 months respectively. Pharmacokinetic analyses suggest sorafenib and metabolite exposure correlate with OS and DLTs. Conclusions The recommended phase II dose (RP2D) is irinotecan 100 mg/m(2) i.v. days 1, 8; cetuximab 400 mg/m(2) i.v. days 1 and 250 mg/m(2) i.v. weekly; and sorafenib 400 mg orally twice daily in advanced, pretreated CRC. The combination resulted in a modest response rate.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Bldg, Room 1M52, 1650 Orleans Street, Baltimore, MD 21231-1000, USA.
authors.forename: Nilofer
authors.initials: N
authors.lastname: Azad
authors.forename: Arvind
authors.initials: A
authors.lastname: Dasari
authors.forename: John
authors.initials: J
authors.lastname: Arcaroli
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Taylor
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Laheru
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Martine
authors.initials: M
authors.lastname: McManus
authors.forename: Kevin
authors.initials: K
authors.lastname: Quackenbush
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Ross C
authors.initials: RC
authors.lastname: Donehower
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D000077157:Sorafenib; D014018:Tissue Distribution
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077146:Irinotecan; D000077157:Sorafenib; D000068818:Cetuximab; D002166:Camptothecin