Chapter 3 - The Evolution of Phase I Trials, Past, Present, and Future: A Biostatistical Perspective

Abstract

Phase I trial design for anticancer drug development have historically focused on identifying the maximum-tolerated dose (MTD), based on the assumption that higher doses lead to greater efficacy. Recent examples of immunotherapies do not adhere to the MTD paradigm, suggesting that alternative approaches to dose finding in the era of novel agents should be utilized and developed. Optimal dose-finding approaches should consider both efficacy and toxicity and perhaps endpoints should be redefined to incorporate late occurring toxicities, and to address pseudo-progression and delayed responses. Large Phase I trials with expansion cohorts are feasible to implement, but should be developed with sound statistical designs, and rigorous monitoring of safety outcomes.