TY - JOUR
T1 - Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents
AU - Moreno, Lucas
AU - Dubois, Steven G.
AU - Glade Bender, Julia
AU - Mauguen, Audrey
AU - Bird, Nick
AU - Buenger, Vickie
AU - Casanova, Michela
AU - Doz, François
AU - Fox, Elizabeth
AU - Gore, Lia
AU - Hawkins, Douglas S.
AU - Izraeli, Shai
AU - Jones, David T.W.
AU - Kearns, Pamela R.
AU - Molenaar, Jan J.
AU - Nysom, Karsten
AU - Pfister, Stefan
AU - Reaman, Gregory
AU - Smith, Malcolm
AU - Weigel, Brenda
AU - Vassal, Gilles
AU - Zwaan, Christian Michel
AU - Paoletti, Xavier
AU - Iasonos, Alexia
AU - Pearson, Andrew D.J.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/6/20
Y1 - 2023/6/20
N2 - PURPOSEThere 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.METHODSAfter a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved.RESULTSCombinations 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.CONCLUSIONAn 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.
AB - PURPOSEThere 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.METHODSAfter a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved.RESULTSCombinations 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.CONCLUSIONAn 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.
UR - http://www.scopus.com/inward/record.url?scp=85163903242&partnerID=8YFLogxK
U2 - 10.1200/JCO.22.02430
DO - 10.1200/JCO.22.02430
M3 - Article
C2 - 37015036
AN - SCOPUS:85163903242
SN - 0732-183X
VL - 41
SP - 3408
EP - 3422
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 18
ER -