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 mumol/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.
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 mumol/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 p53tumors following therapy.
Authors: Richard Gorlick; E Anders Kolb; Peter J Houghton; Christopher L Morton; Geoffrey Neale; Stephen T Keir; Hernan Carol; Richard Lock; Doris Phelps; Min H Kang; C Patrick Reynolds; John M Maris; Catherine Billups; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2012-02-07 Impact factor: 3.167
Authors: Bin Jia; Edwin Choy; Gregory Cote; David Harmon; Shunan Ye; Quancheng Kan; Henry Mankin; Francis Hornicek; Zhenfeng Duan Journal: Cancer Lett Date: 2013-09-02 Impact factor: 8.679
Authors: Jason J Luke; David R D'Adamo; Mark A Dickson; Mary Louise Keohan; Richard D Carvajal; Robert G Maki; Elisa de Stanchina; Elgilda Musi; Samuel Singer; Gary K Schwartz Journal: Clin Cancer Res Date: 2012-02-28 Impact factor: 12.531
Authors: Tobias Else; Alex C Kim; Aaron Sabolch; Victoria M Raymond; Asha Kandathil; Elaine M Caoili; Shruti Jolly; Barbra S Miller; Thomas J Giordano; Gary D Hammer Journal: Endocr Rev Date: 2013-12-20 Impact factor: 19.871
Authors: N Nitta; A Sonoda; A Seko; S Ohta; Y Nagatani; K Tsuchiya; H Otani; T Tanaka; S Kanasaki; M Takahashi; K Murata Journal: Br J Radiol Date: 2009-12-17 Impact factor: 3.039
Authors: Laura A Lambert; Na Qiao; Kelly K Hunt; Donald H Lambert; Gordon B Mills; Laurent Meijer; Khandan Keyomarsi Journal: Cancer Res Date: 2008-10-01 Impact factor: 12.701
Authors: Dana Rathkopf; Mark A Dickson; Darren R Feldman; Richard D Carvajal; Manish A Shah; Nian Wu; Robert Lefkowitz; Mithat Gonen; Lauren M Cane; Heather J Dials; Jennifer L Winkelmann; George J Bosl; Gary K Schwartz Journal: Clin Cancer Res Date: 2009-11-24 Impact factor: 12.531