Novel Radiosensitization Strategies in Uterine Cervix Cancer.

Abstract

The clinical, molecular, and genetic heterogeneity of uterine cervix cancers makes the discovery of effective therapies a challenge. Optimal evaluation of effective radiotherapy-agent combinations requires sophisticated trial strategies from the United States National Cancer Institute and its pharmaceutical collaborators. One strategy involves the phase 0 trial, which falls under the United States Food and Drug Administration Exploratory Investigational New Drug Guidance, or xIND. As currently envisioned for radiotherapy-based trials, the phase 0 trial provides a platform for study of pharmacodynamic effects linked to pharmacokinetic exposures, designed to screen a new experimental agent's dose or schedule, in combination with standard radiotherapy regimens, in a very small number (10-15) of subjects. In the phase 0 trial, radiotherapy-agent combinations are intended to be biologically active, but a new experimental agent's low dose or infrequent schedule is considered nontoxic and nonbeneficial. The phase 0 trial primary endpoint is an individual subject's pharmacodynamic response. Regimens move on from phase 0 trial development if and when a predetermined all-subject pharmacodynamic response rate is crossed. An initial safety experience during and after the radiotherapy-agent combination determines future feasibility. For this article, the clinical example of women with abdominopelvic lymph node-positive uterine cervix cancer is used to elaborate the phase 0 trial approach to the discovery of novel radiosensitizing oncological agents. It is expected that phase 0 radiotherapy-agent trials will become more prevalent in near-term clinical development.