Originally published as JCO Early Release 10.1200/JCO.2008.21.0807 on July 27 2009

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Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics

From the Pharsight Corporation, Mountain View, CA; Université de Lyon, Lyon; Université de Lyon 1, Lyon; EA3738, Faculté de Medecine Lyon Sud, Oulins, France; The University of Texas M. D. Anderson Cancer Center, Houston, TX; University Hospital Gasthuisberg, Leuven, Belgium; and F. Hoffmann-La Roche, Basel, Switzerland.

Corresponding author: René Bruno, 84 Chemin des Grives, 13013 Marseille, France; e-mail: rbruno{at}pharsight.com.

Purpose We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.

Methods We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.

Results The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, –21 to 110 days) versus 35 days observed was predicted for capecitabine.

Conclusion The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.

Supported by F. Hoffmann-La Roche, Basel, Switzerland.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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