Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors Journal Article

Authors: Schwartz, G. K.; O'reilly, E.; Ilson, D.; Saltz, L.; Sharma, S.; Tong, W.; Maslak, P.; Stoltz, M.; Eden, L.; Perkins, P.; Endres, S.; Barazzoul, J.; Spriggs, D.; Kelsen, D.
Article Title: Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors
Abstract: Purpose: 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. Patients and 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/m2 and flavopiridol doses of 10 and 20 mg/m2, respectively. With 3-hour paclitaxel at 100 mg/m2, flavopiridol could be escalated to 70 mg/m2 without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m2, dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m2. This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m2, dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m2. Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. Conclusion: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m2 on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m2 on day 2. Flavopiridol dose escalations to 80 mg/m2 are possible. At these doses, toxicities are manageable and clinical activity is promising. © 2002 by American Society of Clinical Oncology.
Keywords: adult; clinical article; aged; middle aged; clinical trial; neutropenia; advanced cancer; cancer combination chemotherapy; drug efficacy; solid tumor; paclitaxel; neoplasms; lung toxicity; antineoplastic combined chemotherapy protocols; lung cancer; antineoplastic activity; drug effect; prostate cancer; drug infusion; flavonoids; flavopiridol; piperidines; phase 1 clinical trial; esophagus cancer; cyclin-dependent kinases; cyclin dependent kinase inhibitor; humans; human; male; female; priority journal; article
Journal Title: Journal of Clinical Oncology
Volume: 20
Issue: 8
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2002-04-15
Start Page: 2157
End Page: 2170
Language: English
DOI: 10.1200/jco.2002.08.080
PUBMED: 11956278
PROVIDER: scopus
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. William Ping-Yiu Tong
    122 Tong
  2. Leonard B Saltz
    580 Saltz
  3. Gary Schwartz
    358 Schwartz
  4. Sunil Sharma
    26 Sharma
  5. Sandra Endres
    7 Endres
  6. Peter Maslak
    166 Maslak
  7. David H Ilson
    269 Ilson
  8. David R Spriggs
    312 Spriggs
  9. Eileen O'Reilly
    316 O'Reilly
  10. David P Kelsen
    332 Kelsen