title: A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol.
abstract: OBJECTIVE
  Flavopiridol potently enhances the effect of irinotecan with cures in colorectal cancer xenografts, and is associated with modulation of several molecular targets, including p21, Differentiation-related gene 1 (Drg1), and p53. We initiated a phase I trial of the sequential combination of irinotecan followed by flavopiridol to determine the maximal tolerated dose of this combination therapy.
  
  
  METHODS
  Forty-five patients with advanced solid tumors were enrolled. Irinotecan was administered first (100 or 125 mg/m(2)) followed 7 hours later by escalating flavopiridol (10-70 mg/m(2)) given weekly over 1 hour for 4 of 6 weeks. At the maximal tolerated dose, the pharmacokinetic analysis was expanded and pre- and posttreatment tumor biopsies were done.
  
  
  RESULTS
  At irinotecan 100 mg/m(2), dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m(2). At irinotecan 125 mg/m(2), we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m(2). Peak flavopiridol concentrations of >/=2 mumol/L were achieved above flavopiridol 50 mg/m(2). No significant pharmacokinetic interactions with irinotecan were noted. Baseline serum bilirubin significantly predicted cycle 1 dose-limiting toxicity and neutropenia. We observed partial responses in three patients and prolonged stable disease (i.e., >6 months) in 36% of patients including adrenocortical cancer and hepatocellular cancer. Patients with wild-type p53 and either no change or low posttreatment biopsy p21 and a decrease in Drg1 expression showed stable or responsive disease to the combination therapy.
  
  
  CONCLUSIONS
  The recommended phase II dose with irinotecan 100 mg/m(2) is flavopiridol 60 mg/m(2) and with irinotecan 125 mg/m(2) is flavopiridol 50 mg/m(2). Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy.
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kortmansky
authors.forename: Monica
authors.initials: M
authors.lastname: Motwani
authors.forename: Marija
authors.initials: M
authors.lastname: Drobnjak
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Sandy
authors.initials: S
authors.lastname: Yi
authors.forename: Amanda
authors.initials: A
authors.lastname: Weyerbacher
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Robert
authors.initials: R
authors.lastname: Lefkowitz
authors.forename: Baruch
authors.initials: B
authors.lastname: Brenner
authors.forename: Eileen
authors.initials: E
authors.lastname: O'Reilly
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001663:Bilirubin / Q000032:analysis; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D001663:Bilirubin; D002166:Camptothecin; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D000077146:Irinotecan; D010880:Piperidines; D016159:Tumor Suppressor Protein p53; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C493956:CDKN1A protein, human; C077990:alvocidib