title: A Phase I study of bortezomib plus irinotecan in patients with advanced solid tumors.
abstract: BACKGROUND
  The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients with advanced solid tumors.
  
  
  METHODS
  Patients who had received >/=1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m(2), 1.3 mg/m(2), or 1.5 mg/m(2)) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m(2) to 125 mg/m(2)) on Days 1 and 8 of each 21-day cycle for a maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics.
  
  
  RESULTS
  Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients), gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received >/=1 dose of study drug. Nausea, vomiting, and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m(2) bortezomib and 125 mg/m(2) irinotecan. The most common grade >/=3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n = 4 episodes), and nausea (n = 4 episodes). grade >/=3 bortezomib-related hematologic adverse events included neutropenia (n = 6 episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration.
  
  
  CONCLUSIONS
  The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m(2) on Days 1, 4, 8, and 11 plus irinotecan at a dose of 125 mg/m(2) on Days 1 and 8 every 21 days were the recommended Phase II doses.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA. dpryan@partners.org
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Rocha Lima
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Clark
authors.forename: Phinos
authors.initials: P
authors.lastname: Fidias
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.forename: Oscar
authors.initials: O
authors.lastname: Kashala
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
authors.forename: James C
authors.initials: JC
authors.lastname: Cusack
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D000077146:Irinotecan; D002166:Camptothecin