Pathway for the Development of ATR Inhibitors in Pediatric Malignancies: An ACCELERATE Multistakeholder Analysis.

Abstract

High levels of DNA replication stress and defects in the DNA damage response (DDR) pathways are vulnerabilities of many poor prognosis childhood malignancies. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of these pathways and constitutes an attractive target, especially in combination. However, the malignancies where ATR inhibitors have maximum benefit and synergistic combinations differ between adults and children. ACCELERATE convened a multistakeholder meeting and conducted review and analysis to propose the optimal pathway for the development of ATR inhibitors in pediatric malignancies. Considering the lack of identified biomarkers, the initial evaluation of ATR inhibitors should focus on Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma in view of their high levels of DNA replication stress and defects in DDR pathways. Early phase trials of ATR inhibitors should be iterative, based on a clear hypothesis with responders and nonresponders undergoing detailed molecular analysis and a revised new hypothesis generated. Trial designs should restrict monotherapy evaluation to a brief exposure in a small number of patients and progress rapidly to combinations. Highlighted combination partners are poly(ADP-ribose) polymerase inhibitors and antibody drug conjugates with topoisomerase I inhibitor payloads. Combinations with ALK inhibitors (in <i>ALK</i>/<i>MYCN</i>-aberrant neuroblastoma) and aurora A kinase (in <i>MYCN</i>-amplified) are supported by robust mechanisms of action and preclinical data. Early interactions with regulators are crucial, and early phase clinical trials should be conducted in regulatory-approved, academic-sponsored, industry-supported, platform trials. ATR inhibitors are a prototype for the development of medicinal products in a limited pediatric population. For the substantial potential of ATR inhibitors in children with malignancy to be realized, strategic planning between academia, industry, regulators, and patient advocates is vital.