title: A phase I-II, dose-escalating trial of ZD9331 in combination with irinotecan (CPT11) in previously pretreated metastatic colorectal cancer patients.
abstract: BACKGROUND
  To establish the recommended dose (RD) of the thymidylate-synthase inhibitor ZD9331 administered with irinotecan (CPT-11) in patients with pretreated metastatic colorectal cancer, and to assess toxicity profile, pharmacokinetics (PK), and anti-tumor activity in a phase I/II open, multicenter, intrapatient chemotherapy dose escalating trial.
  
  
  METHODS
  Twenty-one patients who failed first-line therapy (5-fluorouracil/leucovorin +/- oxaliplatin) received every 2 weeks CPT-11 180 mg/m2 D1, followed by ZD9331 30-minute infusion D2 at three dose levels: 90, 120 and 150 mg/m2.
  
  
  RESULTS
  RD of ZD9331 was established at 90 mg/m2 for the first two cycles, with possibility to escalate at 120 mg/m2 according to safety evaluation. Grade 3-4 toxicities were neutropenia (67% of patients), grade 3 vomiting (14%), grade 3 nausea (10%) and grade 3 diarrhea (5%). ZD9331 dose level does not affect the PK of CPT-11 or SN-38. Tumor growth control (PR + SD) was achieved for 14 (66.7%) patients. Median time to progression was 6 months, and median survival was 8.4 months.
  
  
  CONCLUSIONS
  ZD9331 90 mg/m2 combined with CPT-11 180 mg/m2 may be a viable option for treatment of metastatic colorectal cancer, with possible escalation to 120 mg/m2 of ZD9331 according to safety evaluation.
authors.affiliation: Service d'oncologie, Hôpital Saint-Antoine, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Louvet
authors.forename: T
authors.initials: T
authors.lastname: André
authors.forename: E
authors.initials: E
authors.lastname: Gamelin
authors.forename: M-L
authors.initials: ML
authors.lastname: Garcia
authors.forename: A
authors.initials: A
authors.lastname: Saavedra
authors.forename: G
authors.initials: G
authors.lastname: Lenaers
authors.forename: A
authors.initials: A
authors.lastname: de Gramont
authors.forename: D
authors.initials: D
authors.lastname: Méry-Mignard
authors.forename: S
authors.initials: S
authors.lastname: Kalla
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D012004:Rectal Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D011799:Quinazolines; C094299:ZD 9331; D000077146:Irinotecan; D002166:Camptothecin