title: Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms.
abstract: OBJECTIVE
  We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks.
  
  
  METHODS
  Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling.
  
  
  RESULTS
  Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred.
  
  
  CONCLUSIONS
  The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.
authors.affiliation: Developmental Therapeutics Program Clinical Trials Unit, Medicine Branch, Biostatistics and Data Management Section, National Cancer Institute, Bethesda, MD 20892, USA. sendero@helix.nih.gov
authors.forename: A M
authors.initials: AM
authors.lastname: Senderowicz
authors.forename: D
authors.initials: D
authors.lastname: Headlee
authors.forename: S F
authors.initials: SF
authors.lastname: Stinson
authors.forename: R M
authors.initials: RM
authors.lastname: Lush
authors.forename: N
authors.initials: N
authors.lastname: Kalil
authors.forename: L
authors.initials: L
authors.lastname: Villalba
authors.forename: K
authors.initials: K
authors.lastname: Hill
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: A
authors.initials: A
authors.lastname: Tompkins
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases