A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol Journal Article

Authors: Shah, M. A.; Kortmansky, J.; Motwani, M.; Drobnjak, M.; Gonen, M.; Yi, S.; Weyerbacher, A.; Cordon-Cardo, C.; Lefkowitz, R.; Brenner, B.; O'reilly, E.; Saltz, L.; Tong, W.; Kelsen, D. P.; Schwartz, G. K.
Article Title: A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol
Abstract: Purpose: Flavopiridol potently enhances the effect of irinotecan with cures in colorectal cancer xenografts, and is associated with modulation of several molecular targets, including p21, Differentiation-related gene 1 (Drg1), and p53. We initiated a phase I trial of the sequential combination of irinotecan followed by flavopiridol to determine the maximal tolerated dose of this combination therapy. Patients and Methods: Forty-five patients with advanced solid tumors were enrolled. Irinotecan was administered first (100 or 125 mg/m 2) followed 7 hours later by escalating flavopiridol (10-70 mg/m 2) given weekly over 1 hour for 4 of 6 weeks. At the maximal tolerated dose, the pharmacokinetic analysis was expanded and pre- and posttreatment tumor biopsies were done. Results: At irinotecan 100 mg/m 2, dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m 2. At irinotecan 125 mg/m 2, we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m 2. Peak flavopiridol concentrations of ≥2 μmol/L were achieved above flavopiridol 50 mg/m 2. No significant pharmacokinetic interactions with irinotecan were noted. Baseline serum bilirubin significantly predicted cycle 1 dose-limiting toxicity and neutropenia. We observed partial responses in three patients and prolonged stable disease (i.e., >6 months) in 36% of patients including adrenocortical cancer and hepatocellular cancer. Patients with wild-type p53 and either no change or low posttreatment biopsy p21 and a decrease in Drg1 expression showed stable or responsive disease to the combination therapy. Conclusions: The recommended phase II dose with irinotecan 100 mg/m 2 is flavopiridol 60 mg/m 2 and with irinotecan 125 mg/m 2 is flavopiridol 50 mg/m 2. Toxicity can be predicted by baseline bilirubin. Clinical activity is encouraging and may correlate to changes in p21 and Drg1 levels in patients with wild type p53 tumors following therapy. © 2005 American Association for Cancer Research.
Keywords: adult; clinical article; controlled study; human tissue; protein expression; treatment outcome; aged; middle aged; human cell; clinical trial; drug activity; fatigue; neutropenia; diarrhea; liver cell carcinoma; solid tumor; pancreas cancer; neoplasms; colorectal cancer; cell cycle proteins; controlled clinical trial; breast cancer; anemia; bone marrow suppression; leukopenia; nausea; vomiting; antineoplastic combined chemotherapy protocols; drug administration schedule; 7 ethyl 10 hydroxycamptothecin; camptothecin; tumor biopsy; irinotecan; adrenal cortex carcinoma; fever; neuroendocrine tumor; bilirubin; intracellular signaling peptides and proteins; tumor suppressor protein p53; flavonoids; bile duct carcinoma; flavopiridol; hyperbilirubinemia; piperidines; maximum tolerated dose; phase 1 clinical trial; cyclin-dependent kinase inhibitor p21; drug half life; esophagus cancer; drug dose regimen; protein p21; germ cell tumor; stomach carcinoma; dose calculation; drug interactions; hematologic disease; 7 ethyl 10 hydroxycamptothecin glucuronide
Journal Title: Clinical Cancer Research
Volume: 11
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2005-05-15
Start Page: 3836
End Page: 3845
Language: English
DOI: 10.1158/1078-0432.ccr-04-2651
PUBMED: 15897584
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 66" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. William Ping-Yiu Tong
    119 Tong
  2. Baruch Brenner
    10 Brenner
  3. Leonard B Saltz
    578 Saltz
  4. Gary Schwartz
    357 Schwartz
  5. Mithat Gonen
    701 Gonen
  6. Monica V Motwani
    36 Motwani
  7. Manish Shah
    173 Shah
  8. Eileen O'Reilly
    315 O'Reilly
  9. San S Yi
    12 Yi
  10. David P Kelsen
    332 Kelsen