A Phase I Clinical Trial of the Sequential Combination of Irinotecan Followed by Flavopiridol
| Autor: | Baruch Brenner, Gary K. Schwartz, Marija Drobnjak, Mithat Gonen, Monica Motwani, David P. Kelsen, Sandy Yi, Carlos Cordon-Cardo, Jeremy S. Kortmansky, William P. Tong, Leonard B. Saltz, Manish A. Shah, Amanda R. Weyerbacher, Eileen M. O'Reilly, Robert A. Lefkowitz |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Adult
Cyclin-Dependent Kinase Inhibitor p21 Male Cancer Research Maximum Tolerated Dose Combination therapy Colorectal cancer Phases of clinical research Cell Cycle Proteins Pharmacology Neutropenia Irinotecan Drug Administration Schedule Piperidines Pharmacokinetics Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Drug Interactions Aged Flavonoids biology business.industry Topoisomerase Intracellular Signaling Peptides and Proteins Bilirubin Middle Aged medicine.disease Treatment Outcome Oncology Toxicity biology.protein Camptothecin Female Tumor Suppressor Protein p53 business medicine.drug |
| Zdroj: | Clinical Cancer Research. 11:3836-3845 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-04-2651 |
| Popis: | 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/m2) followed 7 hours later by escalating flavopiridol (10-70 mg/m2) 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/m2, dose-limiting diarrhea and myelosuppression were observed with flavopiridol 70 mg/m2. At irinotecan 125 mg/m2, we observed dose-limiting hyperbilirubinemia, fatigue, and myelosuppression at flavopiridol 60 mg/m2. Peak flavopiridol concentrations of ≥2 μmol/L were achieved above flavopiridol 50 mg/m2. 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/m2 is flavopiridol 60 mg/m2 and with irinotecan 125 mg/m2 is flavopiridol 50 mg/m2. 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. |
| Databáze: | OpenAIRE |
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