[6077] Optimizing chemotherapy administration: a phase I study of biweekly capecitabine dose and schedule based on Norton-Simon mathematical modeling.
Traina TA, Theodoulou M, Dugan U, Feigin K, Panageas K, Hodgman E, Norton L, Hudis CA.. Memorial Sloan-Kettering Cancer Center, New York, NY; Roche Laboratories, Inc, Nutley, NJ
BACKGROUND: Chemotherapy dose and schedule (CDS) are typically determined empirically or by time consuming, costly, laboratory and clinical experiments. Optimizing CDS by mathematical methods has recently been described (Norton et al, AACR 2005). Capecitabine (Xeloda
, X) has activity in breast cancer and is currently dosed for 14 days (d), q3 weeks (14/7). However, the predicted optimal dosing schedule for X using this model is 7d followed by a 7d rest (biweekly, 7/7). We are testing this hypothesis in a Phase I/II study described below.
METHODS: Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) <2 and normal organ function. There is no limit on number of prior chemotherapy (CRx) regimens. Pts with prior fluoropyrimidine for MBC are excluded. HER2(+) pts must not be candidates for trastuzumab. Therapy (tx) consists of X in divided daily dose for 7d followed by a 7d rest. The dose escalation scheme is a standard 
3+3
design, using flat dosing which begins at 1,500mg BID and increases by 500mg/dose level. The primary endpoint is the maximum tolerated dose (MTD), defined as the highest dose for which the incidence of dose limiting toxicity (DLT) is <33%.
RESULTS: 14 pts are now accrued; 12 pts have been treated, 2 withdrew prior to receiving X. Medians: Age 46.5 yrs (39-62) and ECOG PS 0 (0-2). Sites of MBC: bone 5, viscera 11, soft tissue 10. ER/PR(+) 8. HER2(+) 1. Prior adjuvant tx: CRx 13, hormone tx 5. Five pts had adjuvant fluoropyrimidine-based tx. Two pts had 1 prior CRx for MBC; 7 pts received 1st-line hormone tx for MBC. Twelve pts had prior anthracycline and taxane. Treatment-related toxicities after a median of 2 cycles (1-10) are shown in the Table. The MTD has not been reached. Pts continue accrual to the 2,000mg/2,500mg dose level.
CONCLUSIONS: As predicted by the mathematical model, biweekly X is well tolerated and allows for safe delivery of higher daily doses than routinely used in practice. A pharmacogenomic correlative study regarding toxicity and response is ongoing. Capecitabine 7/7 warrants further study and will be tested in combination with other targeted agents in Phase II trials.
Sunday, December 17, 2006 7:00 AM
Poster Session VI: Treatment: Chemotherapy – General (7:00 AM-9:00 AM)