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Methods and Applications of Statistics in Clinical Trials, Volume 2: Planning, Analysis, and Inferential Methods by N. Balakrishnan

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Chapter 29

Optimal Biological Dose for Molecularly Targeted Therapies

Chul Ahn, Seung-Ho Kang and Yang Xie

29.1 Introduction

The main purpose of a phase I clinical trial of a cytotoxic chemotherapeutic agent is ordinarily to find the highest dose with an acceptable rate of toxicity, often referred to as the maximum tolerated dose (MTD) of the new agent, which will be used as a recommended dose for experimentation in phase II efficacy studies. This recommended phase II dose is determined under the assumption that the higher the dose, the greater the antitumor activity. Thus, it is assumed that the intensity of the dose-toxicity curve is predictive of the therapeutic effect. Over the past decade, a considerable number of studies have been conducted to investigate the statistical properties of phase I clinical trials of cytotoxic anticancer drugs [1–15].

The emergence of a growing number of molecularly targeted therapies as anticancer agents challenges the traditional phase I clinical trial paradigm in a variety of ways. The clinical development of cytotoxic agents is based on the assumption that the agents will shrink tumors and the shrinkage of tumors will prolong the progression-free survival and overall survival of cancer patients. However, cytotoxic agents that shrink tumors may kill normal cells in addition to cancer cells, so cytotoxic agents may lead to other organ damage and may eventually lead to shorter overall survival of cancer patients. In contrast, molecularly targeted ...

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