5007

Optimizing chemotherapeutic dose-schedule (CDS) by Norton-Simon Modeling: Capecitabine (Xeloda^®= X)

Tuesday, Apr 19, 2005, 1:00 PM - 5:00 PM

Board #22

Larry Norton, Ute Dugan, David Young, Colm Farrell, Yutaka Tanaka, Maria Theodoulou, Tiffany Traina, Clifford Hudis. Memorial Sloan-Kettering Cancer Center, New York, NY, Roche Laboratories Inc, Nutley, NJ, Globomax/ICON, Hanover, MD, Chugai Pharmaceutical Co Ltd, Kamakura, Japan

INTRODUCTION: CDS is usually determined by time-consuming, costly laboratory and clinical experiments. Optimizing CDS more efficiently could maximize the benefit/toxicity ratio and speed drug development. Hence, we studied X, an oral tumor-activated fluoropyrimidine carbamate active against metastatic breast and colorectal carcinoma, now used alone or in combination twice daily for 14 consecutive days every 3 weeks.
METHODS: Mice bearing MX-1 or MAXF401 human breast cancer xenografts received 6 weeks of X on one of 4 CDSs (days on/off): 14/7, 5/2, 2/5, 7/7. Each CDS evaluated 4 dose levels plus control, and all were effective at an appropriate dose (Yanagisawa, Proc. AACR #3086, 2004). We analyzed the data for the approved (14/7) CDS by measuring at each time point after the initiation of therapy the ratio of the (data-derived) expected Gompertzian growth rate in the unperturbed (control) state compared with that observed in the treated state. Curve-fitting was by non-linear mixed-effect population modeling using NONMEM software.
RESULTS and CONCLUSION: The time point of maximum impact of treatment is when the absolute value of the ratio of growth rates (perturbed/control) is greatest as determined by methods of calculus. For all dose levels analyzed this point averaged from 8.3-10.1 days into therapy, with the impact of treatment decreasing thereafter despite administration for 14 days. Schedules shorter than 14 days in length can deliver higher dose levels safely. Hence administering one week of treatment as often as clinically feasible (dose density) should provide optimal benefit vs. toxicity. This will be examined in a phase I-II clinical trial.