title: Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.
abstract: OBJECTIVE
  Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner.
  
  
  METHODS
  We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated.
  
  
  RESULTS
  Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders.
  
  
  CONCLUSIONS
  Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Rathkopf
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
authors.forename: Darren R
authors.initials: DR
authors.lastname: Feldman
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Nian
authors.initials: N
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Lefkowitz
authors.forename: Mithat
authors.initials: M
authors.lastname: Gonen
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Cane
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dials
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Winkelmann
authors.forename: George J
authors.initials: GJ
authors.lastname: Bosl
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage*; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D010880:Piperidines / Q000008:administration & dosage*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D005419:Flavonoids; D009944:Organoplatinum Compounds; D010880:Piperidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; C077990:alvocidib; D018844:Cyclin-Dependent Kinases; D002955:Leucovorin; D005472:Fluorouracil