PDCT-04. Phase 1 Trial of Wee1 Kinase Inhibitor Azd1775 Combined With Radiation Therapy for Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report From the Children’s Oncology Group Phase 1 Pilot Consortium (Advl1217)

Mueller, Sabine; Yang, Xiaodong; Pal, Sharmistha; Ermoian, Ralph; Gajjar, Amar; Liu, Xiaowei; Prem, Komal; Minard, Charles G.; Mugundu, Ganesh; Reid, Joel M.; Haas‐Kogan, Daphne A.; Fox, Elizabeth; Weigel, Brenda

doi:10.1093/neuonc/noy148.834

Cited by 3 publications

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“…Concurrent chemo/radiotherapy and WEE1 inhibition in newly diagnosed patients was also recently explored in a phase I study of adavosertib in combination with up front radiotherapy in newly diagnosed DIPG (NCT01922076). Interim evaluations have demonstrated safety of this combination, with ongoing analyses pending ( 44 ).…”

Section: Targeted Therapies and Radiationmentioning

confidence: 99%

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

2021

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Pediatric brain tumors are the most common solid tumors in children and represent a heterogenous group of diagnoses. While some are treatable with current standard of care, relapsed/refractory disease is common and some high-risk diagnoses remain incurable. A growing number of therapy options are under development for treatment of CNS tumors, including targeted therapies that disrupt key tumor promoting processes and immunotherapies that promote anti-tumor immune function. While these therapies hold promise, it is likely that single agent treatments will not be sufficient for most high-risk patients and combination strategies will be necessary. Given the central role for radiotherapy for many pediatric CNS tumors, we review current strategies that combine radiation with targeted therapies or immunotherapies. To promote the ongoing development of rational combination treatments, we highlight 1) mechanistic connections between molecular drivers of tumorigenesis and radiation response, 2) ways in which molecular alterations in tumor cells shape the immune microenvironment, and 3) how radiotherapy affects the host immune system. In addition to discussing strategies to maximize efficacy, we review principles that inform safety of combination therapies.

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Section: Targeted Therapies and Radiationmentioning

confidence: 99%

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

2021

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“…This has led to the preclinical identification of many potentially suitable agents and targets for the treatment of this disease. Despite these advances, only a few effective single-agents for the treatment of DMG have been identified in a preclinical setting, such as the MELK inhibitor OTSSP167, the HDAC inhibitor Panobinostat, and the WEE1 inhibitor AZD1775 ( Meel et al., 2018a , 2020 ; Mueller et al., 2018 ). However, monotherapy often results in recurrent growth from resistant DMG subclones, which has rendered all drugs tested in clinical trials to this day ineffective.…”

Section: Introductionmentioning

confidence: 99%