title: Developing safety criteria for introducing new agents into neoadjuvant trials.
abstract: New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. Angela.demichele@uphs.upenn.edu
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.forename: Donald A
authors.initials: DA
authors.lastname: Berry
authors.forename: JoAnne
authors.initials: J
authors.lastname: Zujewski
authors.forename: Sally
authors.initials: S
authors.lastname: Hunsberger
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Gary
authors.initials: G
authors.lastname: Kelloff
authors.forename: Jane
authors.initials: J
authors.lastname: Perlmutter
authors.forename: Meredith
authors.initials: M
authors.lastname: Buxton
authors.forename: Julia
authors.initials: J
authors.lastname: Lyandres
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Chris
authors.initials: C
authors.lastname: Benz
authors.forename: A Jo
authors.initials: AJ
authors.lastname: Chien
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.forename: Minetta C
authors.initials: MC
authors.lastname: Liu
authors.forename: Pamela
authors.initials: P
authors.lastname: Munster
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Olopade
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Parker
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Debu
authors.initials: D
authors.lastname: Tripathy
authors.forename: Hope
authors.initials: H
authors.lastname: Rugo
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
authors.forename: Laura
authors.initials: L
authors.lastname: Esserman
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D054316:Biomarkers, Pharmacological; D002986:Clinical Trials as Topic / Q000592:standards; D004347:Drug Interactions; D006801:Humans; D020360:Neoadjuvant Therapy / Q000009:adverse effects* / Q000592:standards*; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological