title: Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol.
  
  
  METHODS
  Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients.
  
  
  RESULTS
  Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m(2) and flavopiridol doses of 10 and 20 mg/m(2), respectively. With 3-hour paclitaxel at 100 mg/m(2), flavopiridol could be escalated to 70 mg/m(2) without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m(2), dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m(2). This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m(2), dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m(2). Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel.
  
  
  CONCLUSIONS
  The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m(2) on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m(2) on day 2. Flavopiridol dose escalations to 80 mg/m(2) are possible. At these doses, toxicities are manageable and clinical activity is promising.
authors.affiliation: Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Section, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. schwartg@mskcc.org
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: Eileen
authors.initials: E
authors.lastname: O'Reilly
authors.forename: David
authors.initials: D
authors.lastname: Ilson
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Peter
authors.initials: P
authors.lastname: Maslak
authors.forename: Maxine
authors.initials: M
authors.lastname: Stoltz
authors.forename: Larry
authors.initials: L
authors.lastname: Eden
authors.forename: Pam
authors.initials: P
authors.lastname: Perkins
authors.forename: Sandra
authors.initials: S
authors.lastname: Endres
authors.forename: John
authors.initials: J
authors.lastname: Barazzoul
authors.forename: David
authors.initials: D
authors.lastname: Spriggs
authors.forename: David
authors.initials: D
authors.lastname: Kelsen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel