Paediatric Strategy Forum A new concept proposed by ACCELERATE

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1 A new concept proposed by ACCELERATE 1

2 2

3 s Objective - provide a unique opportunity for interaction between all stakeholders (regulators, pharmaceutical companies, clinical and researcher academics and patient representatives) on topics requiring open discussion in drug development in children and adolescents with malignancy - scientific meeting to share information and advance learning which will inform a paediatric drug development strategy and subsequent decisions - introduce innovative treatments into the standard care of very rare children with cancer 3

4 Two types - target and disease centric Content Biology of target Therapeutic needs including epidemiology, clinical features, standard therapy current needs and future therapeutic plans Europe and North America Non-clinical data Data on compounds Output - Brief high level conceptual report from all participants documenting the type of meeting, remit, objective, summary and conclusions 4

5 for ALK Inhibition in Paediatric Malignancies Pilot Forum Co-organised ACCELERATE and EMA 30 & 31 January 2017 ALK important target in paediatric malignancies - Inflammatory myofibroblastic tumour, anaplastic large cell lymphoma, neuroblastoma and rhabdomyosarcoma Biology of genomic aberration differs Population of children with tumours with the target is very small A number of ALK inhibitors in development Challenge develop ALK inhibitors to meet the therapeutic needs of children and adolescents with cancer ALK inhibitor which has the greatest therapeutic benefit may vary according to the different malignancy 5

6 Participants Academia International (European and US) experts in ALK driven malignancies and in paediatric drug development Pharma Ariad Ignyta Novartis Pfizer Roche Genentech Patient representatives -Unite2Cure Regulators - EMA - PDCO and CHMP 6

7 - ALK Inhibition ALK inhibitors Crizotinib (Xalkori) (Pfizer) Ceritinib (LDK378) (Novartis) Lorlatinib (PF ) (Pfizer) Alectinib (AF802) (Roche/Genentech) Entrectinib (Ignyta) - also as a pan-trk-inhibitor Brigatinib (Ariad) Bold Ongoing paediatric development 7

8 Disease Specific Anaplastic large cell lymphoma (ALCL) As ALK inhibitors are active in ALCL - ALK inhibitor should be incorporated in first-line therapy EICNHL only high risk patients ALK inhibitor COG all ALK positive patients are eligible to receive an ALK inhibitor Very high priority EICNHL to open a frontline study ALK inhibitor Results COG open study (ANHL12P1) randomising patients to receive either brentuximab or crizotinib (in addition to an ALCL99 chemotherapy backbone) will be very informative There are many questions about the best use of ALK inhibitors in ALCL 8

9 Disease Specific Inflammatory myofibroblastic tumour (IMT) Surgery mainstay of treatment; non standard medical therapy - unresectable ALK inhibitors are active Optimal approach - international clinical trial of ALK inhibition in IMT in children and adults, with integrated study of tumour biology and re-biopsy at time of progression 9

10 Disease Specific Neuroblastoma Inhibition of mutant ALK is complex and challenging, very different from targeting ALK fusion proteins in ALCL, IMT and lung cancer Frequency and type of ALK genomic aberrations differ between presentation and relapse and therefore therapeutic needs differ Very informative non-clinical research is ongoing to identify most potent inhibitors and combinations COG will soon evaluate crizotinib to improve the outcome for patients with ALK mutations in front-line therapy (ANBL1531) SIOPEN will take forward in a frontline randomised study the most promising drug/combination based on pre-clinical research and then clinical studies 10

11 Disease Specific Rhabdomyosarcoma Not a priority area for evaluation of ALK inhibitors, but the results of existing trials will be informative 11

12 Pre-clinical research Pre-clinical research using cell lines, xenograft models, patient derived xenograft models and genetically engineered murine models (GEMM) (Th-ALK F1174L /MYCN and ALK[F1174L]) is informative and can inform the selection of single drugs or combination to take forward into clinical trials Greatest value is comparable, comparative data Most extensively used in neuroblastoma 12

13 Discussion In view of the number of children available for clinical trials and paediatric studies are open with four ALK inhibitors, some pharma believed that ALK inhibitors should move forward only if pre-clinical data provide clear utility for paediatric tumours compared with other ALK inhibitors Academia should devise clinical trials with intent to file, so that clinical trial data can be used for regulatory proposes Early scientific advice from regulators should be sought Academia sponsored studies of compounds from different pharma was strongly endorsed Global studies should ideally be undertaken in rare populations 13

14 Combination studies Combination studies (for example CRISP and NEPENTHE) with molecular profiling are strongly encouraged; these can lead to enriched trials with predictive biomarkers 14

15 Conclusion First proof-of-concept pilot ALK inhibition - highly successful Representation 5 pharma, European and North American clinical experts, patient representatives from Unite2Cure, PDCO and EMA Comprehensive overview of the biology and therapeutic needs of patients and clinical and pharmacological information of currently available 6 compounds Greatly increased the knowledge of participants - future decisions will be now well informed No regulatory decisions were made Innovative treatments will be introduced into the standard care of very rare children with ALK driven malignancies 15

16 Future The Forums should continue as a joint collaboration between ACCELERATE and the EMA Forums should be implemented earlier in the drug development process One potential topic for the next Forum, which has been suggested and very strongly supported by academia, parent representatives and pharma is B cell malignancies introducing innovative treatments into the standard care of very rare children with B cell malignancies Another is checkpoint inhibitors 16