Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium

Pasqualini, Claudia; Rubino, Jonathan; Brard, Caroline; Cassard, Lydie; André, Nicolás; Rondof, Windy; Scoazec, Jean‐Yves; Marchais, Antonin; Nebchi, Souad; Boselli, Lisa; Grivel, Jonathan; Aerts, Isabelle; Thébaud, Estelle; Paolettí, Xavier; Minard‐Colin, Véronique; Vassal, Gilles; Geoerger, Birgit

doi:10.1016/j.ejca.2021.03.032

Cited by 44 publications

(34 citation statements)

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“…In children, immunotherapy relying on immune checkpoint inhibitors with antiPD1/PDL1 alone or in combination has not led to the clinical success observed in adults [ 73 , 74 , 75 ]. The development and progression of medulloblastoma are facilitated by a variety of immune-evading mechanisms including the secretion of immunosuppressive molecules, activation of immunosuppressive cells, inhibition of immune checkpoint molecules, impairment of adhesive molecules, downregulation of the MHC molecules, protection against apoptosis, and of course, the activation of immunosuppressive pathways.…”

Section: Relapse Management and Introduction Of Novel Therapiesmentioning

confidence: 99%

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Bailey

André

Gandola

et al. 2022

Cancers

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Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.

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Section: Relapse Management and Introduction Of Novel Therapiesmentioning

confidence: 99%

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Bailey

André

Gandola

et al. 2022

Cancers

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“…Thirteen patients were treated. Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity, and metronomic cyclophosphamide did not modulate systemic immune response [99].…”

Section: Clinical Trials: Incorporating Combination Strategiesmentioning

confidence: 96%

“…Basket trials are designed to enroll biomarker-selected patients with many different cancer types who are assigned to one of the biology-matched subprotocols [97]. Examples of ongoing pediatric basket trials are AcSé-ESMART (NCT02813135) [53,99], INFORM2 (NCT03838042) [100], and Pediatric MATCH (NCT03155620) [101].…”

Section: Clinical Trial Development: Innovative Global Collaborationmentioning

confidence: 99%

“…Future trial designs will include biologically driven combinations of molecularly targeted therapies as well as targeted treatments combined with chemotherapy or immunotherapy, as initiated by AcSé-ESMART (NCT02813135) [54,99] as well as INFORM2 (NCT03838042) [100]. As an example, AcSé-ESMART Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide with or without irradiation, as per the physician's choice.…”

Section: Clinical Trials: Incorporating Combination Strategiesmentioning

confidence: 99%

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The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Langenberg

Looze

Molenaar

2021

Cancers

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Over the last years, various precision medicine programs have been developed for pediatric patients with high-risk, relapsed, or refractory malignancies, selecting patients for targeted treatment through comprehensive molecular profiling. In this review, we describe characteristics of these initiatives, demonstrating the feasibility and potential of molecular-driven precision medicine. Actionable events are identified in a significant subset of patients, although comparing results is complicated due to the lack of a standardized definition of actionable alterations and the different molecular profiling strategies used. The first biomarker-driven trials for childhood cancer have been initiated, but until now the effect of precision medicine on clinical outcome has only been reported for a small number of patients, demonstrating clinical benefit in some. Future perspectives include the incorporation of novel approaches such as liquid biopsies and immune monitoring as well as innovative collaborative trial design including combination strategies, and the development of agents specifically targeting aberrations in childhood malignancies.

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“…One group combined nivolumab with nab-sirolimus, an mTOR inhibitor, in nine adult patients with advanced sarcomas and observed no dose-limiting toxicities (DLTs); on the third dose level, the median progression-free survival had not yet been reached at the time of the conference report, though the follow-up time was not specified [11]. A European multicenter group tested 13 children aged 5-19 years with relapsed/refractory tumors with a basket trial, one arm of which assessed nivolumab with metronomic cyclophosphamide plus or minus radiation in 13 patients and found it well tolerated with an unconfirmed PR in a patient with desmoplastic small round cell tumor (DSRCT) (1/3 or 33%) and a patient with ependymoma (1/1) [12]. A different arm is currently open and assessing nivolumab plus lirilumab, an anti-Killer Ig-like receptor (KIR) antibody designed to upregulate NK cell activation (ClinicalTrials.gov identifier: NCT02813135).…”

Section: Immune Checkpoint Inhibitors (Pd-1 Pd-l1 Ctla-4)mentioning

confidence: 99%

Immunotherapies for Pediatric Solid Tumors: A Targeted Update

Gupta

Cripe

2021

Pediatr Drugs

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There are encouraging signs in our collective progress to leverage the immune system to treat pediatric cancers. Here, we summarize interim successes in cancer immunotherapy and opportunities to translate from the adult world to pediatrics, and highlight challenges that could benefit from additional development, focusing on solid tumors. Just a decade ago, other than antibodies targeting disialoganglioside (GD2) in neuroblastoma, pediatric cancer immunotherapy was mostly relegated to obscure preclinical studies in a few academic labs. Today there are numerous clinical trials of a variety of antibody, cellular, gene, and viral therapies and vaccines designed to either promote antitumor immunity or specifically attack validated immunotherapy targets. Understanding those targets and their pediatric relevance is paramount. While much work is underway to evaluate the utility of numerous immunologic targets, the lack of regulatory approvals is emblematic of the challenges that remain. Herein we focus our review on the most promising targeted immunotherapies in clinical trials for children. Key PointsTreatment of pediatric solid tumors is starting to benefit from a variety of cell-surface targets and new approaches to attack those targets.The most promising of these targets include: immune checkpoints, GD2, B7-H3, HER2, and CD47. Future directions will likely include combinations of therapies, biomarkers to assess success, the creation of more antibody-drug conjugates, and further breakdown of regulatory barriers.

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Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium

Cited by 44 publications

References 44 publications

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

Immunotherapies for Pediatric Solid Tumors: A Targeted Update

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