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000275251 1001_ $$00000-0002-0708-1670$$aMoreno, Lucas$$b0
000275251 245__ $$aCombination Early-Phase Trials of Anticancer Agents in Children and Adolescents.
000275251 260__ $$aAlexandria, Va.$$bAmerican Society of Clinical Oncology$$c2023
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000275251 520__ $$aThere 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.After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved.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.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.
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000275251 7001_ $$00000-0003-0882-738X$$aDuBois, Steven G$$b1
000275251 7001_ $$00000-0001-5316-6440$$aGlade Bender, Julia$$b2
000275251 7001_ $$00000-0003-3236-6093$$aMauguen, Audrey$$b3
000275251 7001_ $$00000-0003-1808-8584$$aBird, Nick$$b4
000275251 7001_ $$00000-0001-9241-6668$$aBuenger, Vickie$$b5
000275251 7001_ $$00000-0003-0368-7883$$aCasanova, Michela$$b6
000275251 7001_ $$00000-0001-9286-4831$$aDoz, François$$b7
000275251 7001_ $$00000-0002-9998-5326$$aFox, Elizabeth$$b8
000275251 7001_ $$00000-0002-2546-4616$$aGore, Lia$$b9
000275251 7001_ $$00000-0003-3602-1375$$aHawkins, Douglas S$$b10
000275251 7001_ $$aIzraeli, Shai$$b11
000275251 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b12$$udkfz
000275251 7001_ $$00000-0003-2756-5813$$aKearns, Pamela R$$b13
000275251 7001_ $$00000-0002-2007-0431$$aMolenaar, Jan J$$b14
000275251 7001_ $$00000-0003-2935-0058$$aNysom, Karsten$$b15
000275251 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b16$$udkfz
000275251 7001_ $$00000-0002-6698-4503$$aReaman, Gregory$$b17
000275251 7001_ $$00000-0001-9880-9876$$aSmith, Malcolm$$b18
000275251 7001_ $$00000-0003-1080-1402$$aWeigel, Brenda$$b19
000275251 7001_ $$00000-0003-1780-8869$$aVassal, Gilles$$b20
000275251 7001_ $$00000-0001-6892-8268$$aZwaan, Christian Michel$$b21
000275251 7001_ $$00000-0002-1250-0040$$aPaoletti, Xavier$$b22
000275251 7001_ $$00000-0003-0471-8477$$aIasonos, Alexia$$b23
000275251 7001_ $$00000-0002-8738-5913$$aPearson, Andrew D J$$b24
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