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International Neuroblastoma Research Initiative 2018

Solving Kids’ Cancer is leading an international competitive funding call commencing with a Request for Applications (RFA) issued in April 2018. Researchers are invited to submit applications for funding up to a specified maximum grant award value of $1,000,000. The actual RFA itself can be found here.

The RFA is to conduct a novel international pilot study for newly diagnosed high-risk neuroblastoma, seeking to improve survival outcomes with less toxicity using innovative therapeutic approaches. Proposals must include recruiting centres in the United Kingdom, Europe, and North America as a minimum. Letters of Interest (LOIs) are due in September 2018, and a maximum of 3 will be selected and awarded Feasibility Grants to complete and submit Full Proposals. LOIs will be selected based upon novel and feasible approaches to improvements and reduced toxicity in all phases of treatment of high-risk neuroblastoma including induction, consolidation, residual disease, and maintenance. Proposals must be discussed with cooperative groups and evidence that there is a potential route through which a successful pilot study can be taken forward and incorporated into frontline clinical trial strategies. Full Proposals may include the use of biomarker-driven patient selection techniques to identify particular sub-groups who could benefit from new innovative therapeutic approaches. Full Proposals may further include rationale and planning for innovative approaches for children with a poor prognosis, pending a consensus being formed on prospective identification of such groups of patients.

Project partners: Solving Kids’ Cancer (US); Band of Parents; Wade’s Army; Arms Wide Open Childhood Cancer Foundation

Total project award: $1.000,000

Our project grant: $200,000

Date of award: Spring 2019

Timeline

Background

It is approaching a decade since the pivotal Children’s Oncology Group ANBL0032 study heralded the promise of improvements in outcomes for children diagnosed with high-risk neuroblastoma through the addition of passive immunotherapy targeting GD2 following peripheral blood stem cell transplant, seemingly signalling an end to intensification of frontline therapy.

Fast forward to 2018 and whilst anti-GD2 therapy has pushed survival curves up slightly and out slightly, those early results have not led to similarly dramatic improvements in long-term survival. Gains have once again proven to be incremental and at the expense of additional (acutely) toxic therapy.

The next multi-institutional Phase 3 studies currently in planning or setup phase in both Europe and America will see treatment intensified yet again. Factoring in the VERITAS trial for poor responders soon to open across Europe, there is a broad equivalence between the approaches being taken by SIOPEN and COG respectively.

The goal to cure more children with high-risk neuroblastoma through further intensification of therapy.

However, intensification of therapy does not come at zero cost. In any tandem transplant randomisation, for instance, half the children on trial will be exposed to additional toxicity – some of whom would be cured of their disease in any case. If results confer a survival advantage for the tandem arm and it becomes standard of care, all children will subsequently be exposed to additional toxicity – more of whom would be cured of their disease in any case.

This ‘trade-off’ of survival vs. toxicity is poorly understood, articulated, or studied. Survival advantage using EFS as a proxy for OS is a relatively near-term assessment, cost of cure a long-term one. Survivors are generally not followed up long-term in a systematic way as to make either a qualitative or quantitative judgement on impact of therapy intensification possible.

To compound difficulties around the impact of cost of cure, parents of children who survive neuroblastoma are naturally less inclined to speak up as loudly or persistently as those bereaved. Whilst their children’s challenges and deficits may be daily and profound, there is always that element of it could have been worse; and almost every parent of a child who is cured of their disease will have other parents, some of whom they consider friends, who were not, using survival as a binary measure at least, as fortunate.

Taking an over-arching view, we must at some point reach the end of a ‘more is better approach’ leading to further incremental gains in high-risk neuroblastoma survival. Delving more into the details there also remain sub-groups of patients for whom outcomes are significantly worse. As yet there is no consensus as to how these can be identified prospectively, and this is a challenge Solving Kids’ Cancer are keen to prioritise. If such children could indeed be identified, the question would then turn to how to treat them differently in the hope of improving their chances of survival.

Challenge

A collaborative charity-led funding call to foster international/transatlantic collaborative clinical research.

The value of the award will be $1,000,000.

To undertake a novel clinical trial or pilot studies, within the context of frontline treatment for high-risk neuroblastoma, seeking to improve survival outcomes using innovative therapeutic approaches.

A path-forward plan for continued development must be included, to be actioned if there are positive results. Such a plan might involve expanded access, a larger validation cohort study, or assessing effectiveness in particular groups of children for whom standard therapy was known (to a certain level of confidence) to be ineffective.

Any proposal must include recruiting centres in the United Kingdom, Europe, and United States as a minimum.

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Tel: 020 7284 0800

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