title: Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies.
abstract: OBJECTIVE
  Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl(+) malignancies.
  
  
  METHODS
  In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.
  
  
  RESULTS
  A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.
  
  
  CONCLUSIONS
  This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.forename: Edward B
authors.initials: EB
authors.lastname: Perkins
authors.forename: Connie
authors.initials: C
authors.lastname: Honeycut
authors.forename: Martha D
authors.initials: MD
authors.lastname: Wellons
authors.forename: Tammy
authors.initials: T
authors.lastname: Stefan
authors.forename: James W
authors.initials: JW
authors.lastname: Jacobberger
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Kontopodis
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Chiyo K
authors.initials: CK
authors.lastname: Imamura
authors.forename: W
authors.initials: W
authors.lastname: Douglas Figg
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Omer N
authors.initials: ON
authors.lastname: Koc
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Cooper
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.forename: John D
authors.initials: JD
authors.lastname: Roberts
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D005419:Flavonoids; D010879:Piperazines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C077990:alvocidib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D018844:Cyclin-Dependent Kinases