Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

Pearson, Andrew D.J.; Federico, Sara; Gatz, Susanne A.; Ortiz, Michael; Lesa, Giovanni; Scobie, Nicole; Gounaris, Ioannis; Weiner, Susan L.; Weigel, Brenda; Unger, T.J.; Stewart, Elizabeth; Smith, Malcolm; Slotkin, Emily K.; Reaman, Gregory; Pappo, Alberto; Nysom, Karsten; Norga, Koen; McDonough, Joe; Marshall, Lynley V.; Ludwinski, Donna; Ligas, Franca; Karres, Dominik; Kool, Marcel; Horner, Thierry J.; Henssen, Anton; Heenen, Delphine; Hawkins, Douglas S.; Gore, Lia; Bender, Julia Glade; Galluzzo, Sara; Fox, Elizabeth; de Rojas, Teresa; Davies, Barry R.; Chakrabarti, Jayeta; Carmichael, Juliet; Bradford, Diana; Blanc, Patricia; Bernardi, Ronald; Benchetrit, Sylvie; Akindele, Korede; Vassal, Gilles

doi:10.1016/j.ejca.2023.112950

Cited by 9 publications

(7 citation statements)

References 119 publications

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“…To optimize the design of pediatric trials, eligibility based on the mutational status of key genes, rather than histology, may be a better approach, as molecular profiling efforts have revealed that specific gene mutations are often found across multiple histologies. The evidence to date suggests that the biomarkers in pediatrics for DDR responsiveness greatly differ from those in adult malignancies, highlighting the need for further identification of relevant pediatric biomarkers [182]. Such potential biomarkers include measurements of replication stress (e.g., R-loops), chromosome 11q loss in NB, and aberrant transcription factor gene fusions, among others [182].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy

Zhao,

Prior,

Heske

et al. 2024

Cancers

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DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy

Zhao,

Prior,

Heske

et al. 2024

Cancers

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“…The continued evaluation of targeted strategies requires an expert and experienced network of collaborating pediatric institutions joined with the COG that aspire to conduct global trials to better study the growing number of rare molecular subsets. Effective development of new precision medicine approaches for children with relapsed AML and other acute leukemias will also be further facilitated by efforts of the ACCELERATE Pediatric Strategy Forum 6 and the recently created international consortium created by the Leukemia & Lymphoma Society to facilitate international collaborations involving the COG 80 . This innovative international cooperative infrastructure has successfully engaged academic pediatric oncologists, federal regulatory agencies, and pharmaceutical companies to (1) standardize relapse definitions, response criteria, and outcomes reporting, (2) hasten pediatric‐specific drug development and clinical investigation, and (3) increase enrollment efficiency of rare HR subtypes of childhood acute leukemias within specific trials.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

“…5,6 Patients with nucleophosmin 1 (NPM1) mutations, 7,8 CCAAT enhancer-binding protein alpha (CEBPA) biallelic mutations, 9 and corebinding factor (CBF) leukemias (RUNX1::RUNXT1 or CBFB::MYH11 rearrangements) have more favorable outcomes. 1,5,6,10 This is in stark contrast to outcomes for children with high-risk (HR) cytomolecular (CM) alterations who continue to have unacceptably poor survival despite maximally intensive initial and relapse therapy. 3,4 The refractory nature of AML combined with challenges to conduct relapsed trials have limited or ability to identify new active agents for children.…”

Section: Current Outcomes In Pediatric Amlmentioning

confidence: 99%

“…Progress has focused on the dose and schedule intensification of conventional therapy, improved identification of patients with higher risk of relapse, advances in hematopoietic stem cell transplant (HSCT), and enhanced supportive care. Major recent advances in elucidation of predictive biomarkers of treatment response and survival have led to further therapy refinements 5,6 …”

Section: Introductionmentioning

confidence: 99%

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Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms

Cooper

Alonzo

Tasian

et al. 2023

Pediatric Blood & Cancer

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During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5‐year event‐free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high‐risk disease, who have 5‐year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A‐rearranged AML and/or FLT3 internal tandem duplication (FLT3‐ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti‐CD33 antibody–drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3‐ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data‐driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard‐of‐care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.

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“…The 10th Forum, on DNA damage response pathway inhibitors, concluded that combinations of poly-ADP ribose polymerase (PARP) inhibitors with ataxia telangiectasia and Rad3-related (ATR) inhibitors, antibody drug conjugates with DNA topoisomerase I inhibitor related warheads, or targeted radiotherapy warrant evaluation ( 17 ). Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended, and a further meeting on relevant biomarkers and a prioritization meeting on ATR inhibitors were held.…”

Section: Paediatric Strategy Forum Modelmentioning

confidence: 99%

Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development

Pearson,

de Rojas,

Karres

et al. 2023

JNCI: Journal of the National Cancer Institute

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In a landscape of an increasing number of products and histology and age agnostic trials for rare patient cancer, prioritisation of products is required. Paediatric Strategy Forums, organised by ACCELERATE and the European Medicines Agency with participation of the US Food and Drug Administration, are multi-stakeholder meetings that share information to best inform paediatric drug development strategies and subsequent clinical trial decisions. Academia, industry, regulators and patient advocates are equal members with patient advocates highlighting unmet needs of children and adolescents with cancer. The eleven Paediatric Strategy Forums since 2017 have made specific and general conclusions to accelerate drug development. Conclusions on product prioritisation meetings, as well as global master protocols, have been outputs of these meetings. Forums have provided information for regulatory discussions and decisions by industry to facilitate development of high priority products; for example, 62% high-priority assets (agreed at a Forum) in contrast to 5% of those assets not considered high priority have been the subject of a Paediatric Investigational Plan or Written Request. Where there are multiple products of the same class, Forums have recommended a focused and sequential approach. Class prioritisation resulted in an increase in waivers for non-prioritised B cell products (44% to 75%) and a decrease in monotherapy trials, proposed in PIP submissions of checkpoint inhibitors from 53% to 19%. Strategy Forums could play a role in defining unmet medical needs. Multi-stakeholder forums, such as the Paediatric Strategy Forum, serve as a model to improve collaboration in the oncology drug development paradigm.

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Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

Cited by 9 publications

References 119 publications

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy

Therapeutic Targeting of DNA Repair Pathways in Pediatric Extracranial Solid Tumors: Current State and Implications for Immunotherapy

Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms

Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development

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