Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents

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

doi:10.1200/JCO.22.02430

Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents

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 WeigelGilles Vassal, Christian Michel Zwaan, Xavier Paoletti, Alexia Iasonos, Andrew D J Pearson^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Journal	Journal of Clinical Oncology
Early online date	4 Apr 2023
DOIs	https://doi.org/10.1200/JCO.22.02430
Publication status	E-pub ahead of print - 4 Apr 2023

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10.1200/JCO.22.02430Licence: Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

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Moreno, L., DuBois, S. G., Glade Bender, J., Mauguen, A., Bird, N., Buenger, V., Casanova, M., Doz, F., Fox, E., Gore, L., Hawkins, D. S., Izraeli, S., Jones, D. T. W., Kearns, P. R., Molenaar, J. J., Nysom, K., Pfister, S., Reaman, G., Smith, M., ... Pearson, A. D. J. (2023). Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents. Journal of Clinical Oncology . Advance online publication. https://doi.org/10.1200/JCO.22.02430

@article{2357850aa4fd4c56aff828fe6ab88de8,

title = "Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents",

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.",

author = "Lucas Moreno and DuBois, {Steven G} and {Glade Bender}, Julia and Audrey Mauguen and Nick Bird and Vickie Buenger and Michela Casanova and Fran{\c c}ois Doz and Elizabeth Fox and Lia Gore and Hawkins, {Douglas S} and Shai Izraeli and Jones, {David T W} and Kearns, {Pamela R} and Molenaar, {Jan J} and Karsten Nysom and Stefan Pfister and Gregory Reaman and Malcolm Smith and Brenda Weigel and Gilles Vassal and Zwaan, {Christian Michel} and Xavier Paoletti and Alexia Iasonos and Pearson, {Andrew D J}",

year = "2023",

month = apr,

day = "4",

doi = "10.1200/JCO.22.02430",

language = "English",

journal = "Journal of Clinical Oncology ",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

}

Moreno, L, DuBois, SG, Glade Bender, J, Mauguen, A, Bird, N, Buenger, V, Casanova, M, Doz, F, Fox, E, Gore, L, Hawkins, DS, Izraeli, S, Jones, DTW, Kearns, PR, Molenaar, JJ, Nysom, K, Pfister, S, Reaman, G, Smith, M, Weigel, B, Vassal, G, Zwaan, CM, Paoletti, X, Iasonos, A & Pearson, ADJ 2023, 'Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents', Journal of Clinical Oncology . https://doi.org/10.1200/JCO.22.02430

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

PY - 2023/4/4

Y1 - 2023/4/4

N2 - 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.

AB - 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.

U2 - 10.1200/JCO.22.02430

DO - 10.1200/JCO.22.02430

M3 - Article

C2 - 37015036

SN - 0732-183X

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

ER -

Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents

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