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Research to evaluate the relation of toxicity and the relative dose intensity in phase I trials beyond cycle 1 of Molecular Targeted Agents (MTAs)








Research to evaluate the relation of toxicity and the relative dose intensity in phase I trials beyond cycle 1 of Molecular Targeted Agents (MTAs)


Kan Yonemori, MD., PhD


Department of Breast and Medical Oncology
National Cancer Center Hospital, National Cancer Center, Japan


None


None


19 January 2017


Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials, so called the “recommended phase 2 dose (RP2D)”. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. Recently, the emergence of molecularly targeted agents (MTA) and other new biological drugs are rapid. Nonetheless, regardless of drug type (ex. cytotoxic, molecular targeted, immune-modulator) or administration route (ex. oral, iv, im) or schedule (ex. weekly, bi-weekly, daily) or mode of action (ex. Taxanes, VEGFR TKI, PD-1 antibody) or differences of toxicity, the RP2D is generally determined by the same procedure. However, cytotoxic agents and MTAs show different biological activity should be handled differently.
RP2D is generally based on the maximum tolerated dose (MTD) in a phase I trial that is determined based on dose limiting toxicity in the first cycle. MTAs are a newer class of therapeutic agent administered daily with or without short term rest until progression or unacceptable toxicity develops, and treatment duration of MTAs is generally longer than that of cytotoxic drugs. Therefore, some MTAs require dose modification in treatment beyond cycle 1, due to persistent low grade toxicities and as a result, dose intensity is decreased. We hypothesize that on determining the RP2D, the traditional method of using only the cycle one toxicity data is insufficient.
Therefore, the main purpose of our research is to evaluate the relation of toxicity and the relative dose intensity in phase I trials of MTAs using the data of not only the first cycle but also the second and the later courses in the phase I trial. By doing that, we plan to develop a novel method for dose modification in clinical trials and examine the utility of our proposed method for determining the MTD.
With this new method to estimate RP2Ds in MTAs and a dose modification method, we hypothesize that the true RP2D will be calculated and therefore find the ideal dose delivery level, which can be used in a broad range of phase I trials.



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Statistical Analysis Plan


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