2008 - Marseille - France

PAGE 2008: Applications
Laurent Claret

A modeling framework to simulate Xeloda dose intensity and survival in colorectal cancer

L. Claret(1), F. Schaedeli Stark(2), F. Sirzen(2), R. Gieschke(2), R. Bruno(1)

(1) Pharsight Corp., Mountain View, USA, (2) F. Hoffmann-La Roche Ltd., Basel, Switzerland

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].

[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.

Reference: PAGE 17 (2008) Abstr 1312 [www.page-meeting.org/?abstract=1312]
Oral Presentation: Applications
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