title: Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor.
abstract: Bortezomib inhibits nuclear factor-kappaB (NF-kappaB). Cetuximab is a chimeric mouse-human antibody targeted against epidermal growth factor receptor (EGFR). We hypothesised that concomitant blockade of NF-kappaB and EGFR signalling would overcome EGFR-mediated resistance to single-agent bortezomib and induce apoptosis through two molecular pathways. The aim of this phase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumours. The 21-day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.3-2 mg m(-2)). Cetuximab was delivered at a dose of 250 mg m(-2) on days 1, 8 and 15 (400 mg m(-2) day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. No grade > or =3 haematological toxicity was noted. Non-hematological grade > or =3 toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mg m(-2)). Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck. This combination therapy was moderately effective in extensively pretreated patients with non-small cell lung or head and neck cancers and warrants further investigation.
authors.affiliation: Division of Hematology, Department of Medicine, Oncology and Transplantation, Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA. dudek002@umn.edu
authors.forename: A Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: K
authors.initials: K
authors.lastname: Lesniewski-Kmak
authors.forename: N J
authors.initials: NJ
authors.lastname: Shehadeh
authors.forename: O N
authors.initials: ON
authors.lastname: Pandey
authors.forename: M
authors.initials: M
authors.lastname: Franklin
authors.forename: R A
authors.initials: RA
authors.lastname: Kratzke
authors.forename: E W
authors.initials: EW
authors.lastname: Greeno
authors.forename: P
authors.initials: P
authors.lastname: Kumar
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D001897:Boronic Acids / Q000627:therapeutic use / Q000633:toxicity*; D000069286:Bortezomib; D000068818:Cetuximab; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use / Q000633:toxicity*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib; D066246:ErbB Receptors; D000068818:Cetuximab