title: The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial.
abstract: OBJECTIVE
  Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas.
  
  
  METHODS
  Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion.
  
  
  RESULTS
  Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m(2) bolus; 50 mg/m(2) bolus + 40 mg/m(2) infusion) both in combination with doxorubicin (60 mg/m(2)). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C(max) with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks.
  
  
  CONCLUSIONS
  The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Luke
authors.forename: David R
authors.initials: DR
authors.lastname: D'Adamo
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
authors.forename: Mary Louise
authors.initials: ML
authors.lastname: Keohan
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Elgilda
authors.initials: E
authors.lastname: Musi
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage; D006801:Humans; D015151:Immunoblotting; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D060787:Neoplasm Grading; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage; D012509:Sarcoma / Q000188:drug therapy*; D014018:Tissue Distribution
chemical_list: D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D004317:Doxorubicin; D018844:Cyclin-Dependent Kinases