An Investigation of Proportion Designs Based on a Molecularly Targeted Endpoint

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An Investigation of Proportion Designs Based on a Molecularly Targeted Endpoint Serng-Ho long Department of Applied Statistics. Yonsei University, Seoul, Korea Sangaee Lee Department of Statistics. Ewha Womans University, Seoul, Korea

Chrl W. Ahn Department of Clinical Sciences. UT Southwestern Medical Center, Dallas, Texas

Key Words Phase 1 trials; Cancer; Exact formula Correspondence Address Seung-Ho Kang. Associate Professor, Department of Applied Statistics. Yonsei University, 134 Sinchondong SeoDaeMun-Ku, Seoul, Korea, 120-749 (email: [email protected]).

Most phase I dinical trials for anticancer agents base dose escalation on taxicity and are employed to find the maximum tdemted dose. Recently, Hunsbergeret al. (statistics in Medicine 2 M ; 24: 217.2-2181) proposed proportion designs that are use@ for mdeculaljr targeted agents, because these new agents do not yield severe taxicity. The aim of the proportion designs is to find a dose to produce a spe-

INTRODUCTION Over the past decade a considerable number of studies have been conducted on statistical properties of phase 1 clinical trials (1-10). Most phase 1 studies for anticancer agents such as the standard 3 + 3 design and the continual reassessment methods base dose escalation on toxicity and are designed to find the maximum tolerated dose. Innovative approaches to drug discovery led to a move from identifying cytotoxic agents to molecularly targeted agents even though current anticancer clinical drug development standards still use historical precedents for cytotoxic agents. Initial clinical trials of these novel molecularly targeted agents have indicated that the steps and endpoint routinely applied for the evaluation of traditional cytotoxic agents are not necessarily appropriate for the evaluation of molecularly targeted agents (11,12).For molecularly targeted agents, it would be expected that the maximum biological effects may occur at doses lower than the maximum tolerated dose, as determined in conventional dose-escalation phase 1 trials. Therefore, it is important to find an optimal biologic dose or dose range without causing dose-limiting toxicity in phase 1 clinical trials. As an example of clinical trials using molecularly targeted agents, see Friedman et al. (U). Hunsberger et al. (14)developed the new designs that are appropriate for these new agents.

cific high response mte. We genemlize the proportion designs and derive the exact fmulas of key statisticalproperties of the genemlized proportion designs. Using the exact fmulas,we compute the expected response mte at the recommended dose and the expected number of patients to finish the trials. Based on the numeric results, we recommend six genemlized proportion designs.

In the designs proposed by Hunsberger et al. the goal is to find a biologically adequate dose, not the optimal dose. They defined an adequate dose as either a dose that produces a specific high response rate or a dose in the plateau and developed two types of designs, proportion designs and slope designs,