Objectives: Capecitabine (Xeloda®) is approved for colorectal cancer (“CRC”) as a monotherapy at 1250 mg/m2 BID x 14 days every 3 weeks. A reduced starting dose has frequently been used off-label in clinical practice and will also be recommended for the combination with oxaliplatin (XELOX) and with other chemotherapeutics. A modeling framework has been developed to simulate dose intensity and survival for lower starting doses of Xeloda.
Methods: Models for longitudinal tumor size and for survival were previously developed [1, 2]. In the tumor size model, drug effect simulations were conditioned on observed dose intensity. A new model for the probability of dose modifications as a function of time and dose has been developed based on data from 596 patients with CRC from two phase III monotherapy studies [3, 4]. The full simulation framework was assessed in predicting dose intensity (starting dose of 1250, 1000 and 850 mg/m2), tumor shrinkage at week 6, and survival. The predictive distributions were derived from 500 replicates of 1000 patients and compared to observed values.
Results: The probability of dose modifications increased with time and dose. The simulations showed that reduction of the starting dose from 1250 to 1000 and 850 mg/m2 would result in 1) a nearly proportional reduction of median dose intensity, 2) a reduction in the extent of tumor shrinkage at week 6 from 13.1% to 9.0% and 6.6%, respectively, and 3) a minor change of expected survival from 423 to 400 and 387 days, respectively.
Conclusions: This modeling framework is a useful tool to simulate expected clinical response and support dosing decisions for Xeloda® monotherapy. The minor impact on median survival time supports tailoring Xeloda dose in case of toxicity, older age or impaired performance status to retain a favorable therapeutic ratio in clinical practice. This approach has been proven for dose reduction of Xeloda in combination therapy [5].
References:
[1] Claret L, Girard P, O'Shaughnessy J et al: Model-based predictions of expected anti-tumor response and survival in phase III studies based on phase II data of an investigational agent. Proc. Am Soc Clin Oncol, 24, 307s (abstract 6025), 2006.
[2] Claret L, Girard P, Zuideveld KP, et al: A longitudinal model for tumor size measurements in clinical oncology studies. PAGE 15 (abstract 1004), 2006 [www.page-meeting.org/?abstract=1004].
[3] Van Cutsem E, Twelves C, Cassidy J et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19, 4097−4106, 2001.
[4] Hoff PM, Ansari R, Batist G et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19, 2282-2292, 2001.
[5] Cassidy J, Tabernero J, Twelves C et al: XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22, 2084–2091, 2004.
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