Year: 2023
Type: article
Abstract: PURPOSE: There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders. METHODS: After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved. RESULTS: Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements. CONCLUSION: An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.
Source: Journal of Clinical Oncology
DOI: 10.1200/jco.22.02430
Authors: Lucas Moreno, Steven G. DuBois, Julia Glade Bender, Audrey Mauguen, Nick Bird, Vickie Buenger, Michela Casanova, François Doz, Elizabeth Fox, Lia Gore, Douglas S. Hawkins, Shai Izraeli, David T.W. Jones, Pamela R. Kearns, Jan J. Molenaar, Karsten Nysom, Stefan Pfister, Gregory Reaman, Malcolm Smith, Brenda Weigel, Gilles Vassal, Christian Michel Zwaan, Xavier Paoletti, Alexia Iasonos, Andrew D.J. Pearson
Institutions: Vall d'Hebron Hospital Universitari, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Memorial Sloan Kettering Cancer Center, Coalition Against Childhood Cancer, Fondazione IRCCS Istituto Nazionale dei Tumori, Université Paris Cité, Institut Curie, St. Jude Children's Research Hospital, Children's Hospital Colorado, University of Colorado Anschutz, Children's Oncology Group, Seattle Children's Hospital, Children's Oncology Group, Tel Aviv University, Schneider Children's Medical Center, Hopp Children's Cancer Center Heidelberg, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Utrecht University, Princess Máxima Center, German Cancer Research Center, Rigshospitalet, Heidelberg University, University Hospital Heidelberg, United States Food and Drug Administration, National Cancer Institute, University of Minnesota, Institut Gustave Roussy, Erasmus MC - Sophia Children’s Hospital
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: hybrid
Funders: Ipsen, National Cancer Institute
Award: Cancer Center Support Grant
OpenAlex ID: W4362546187