A Robust Paradigm of Finding the Maximum Tolerated Dose in Phase I Cancer Clinical Trials

• Activity Number: 659 - Clinical Trial Research
• Type: Contributed
• Date/Time: Thursday, August 3, 2017 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Tina Young* and Dirk Moore and Yong Lin and Weichung Joe Shih
• Companies: Bristol-Myers Squibb and Rutgers School of Public Health and Rutgers and Rutgers School of Public Health
• Keywords: Maximum Tolerated Dose ; Dose Escalation Designs ; Simultaneous Conduct ; Multiple Designs

Abstract

In Phase I oncology trials, the main objective is typically to determine the maximum tolerated dose (MTD), the highest dose of a drug that does not cause unacceptable side effects. The MTD is determined by testing increasing doses on patient cohorts until the highest dose with acceptable side effects is found. To determine the MTD, many different dose escalation designs have been developed, such as the CRM, BLRM, mTPI-2, and BOIN, each of which has improved statistical properties over the traditional A+B class of designs. Yet most published Phase I trials still use a traditional 3+3 design. We propose a new paradigm of conducting Phase I cancer clinical trials that involves simultaneously running multiple designs to obtain a robust MTD. This paradigm will provide more confidence to clinicians and regulators in the selection of the dose for further drug development. We will explain how we implement this paradigm with a realistic example.