International consensus for preclinical testing: a joint initiative by ITCC-P4

and the PPTCACCELERATE 2019

Louis Stancato, Eli Lilly and Company

IMI2 Grant Agreement No 116064 ITCC-P4

The regulatory environment ischanging…

Target date: August 2019

…and the paediatric communitymust make the most of these changes! A supportive regulatory environment will Spur investment in paediatric research Result in the “right” clinical trials Ultimately save lives

Build preclinical research platforms Harmonize preclinical methods to identify promising drugs Test drugs for paediatric and adult efficacy in parallel Ultimately, prioritize drugs for clinical testing

But how?

ITCC-P4: The platform

• 400 PDX models/5yrs; GEMMs• Standard-of-care and targeted compound testing• POC for immunotherapies in humanized models• POC for organoids

ITCC-P4 Workflow

Initial compound testing begins mid ‘19

What did ITCC-P4 accomplish in 2018?

Target Actionability = Matched Targeted Therapy

Established Target Actionability Review Methodology Model establishment well underway R2 informatics portal enhancements

Test drugs selected; SOPs developed2018 Pediatric Cancer Working Group Special Scientific Session

NCI – Preclinical Pediatric Testing Consortium (leader – M. Smith)

http://www.ncipptc.org/

GoalInternational scientific consensus on the role and place of preclinical evaluation of paediatric tumor models to improve prioritization and

effectiveness of drug development for children and adolescents with cancer

OutputPeer-reviewed ‘white paper’ serving as a basis for a guidance to be

submitted to competent authorities for qualification

Who was there?• ITCC-P4 & PPTC

leadership• Leaders from academia

(33/18) & industry (19/11), FDA, advocacy (4/3)

• Concerned citizens

Topics - Current state of preclinical research• Models• Evaluation of brain tumors • Evaluation of IO drugs • Methodology• Data and reporting standards

Minimal / Optimal preclinical package

• Accelerating and improving the development of new drugs for children with cancer

• Prioritizing drugs in adult development to encourage the development of drugs targeting alterations specific to paediatrics

• Relevant preclinical data to support science-driven decisions

• An international, multi stakeholder consensus for preclinical testing

Findings: Defining the need

• ‘Catch-as-catch-can” – haphazard preclinical evaluation; not systematic

• Scarcity of models

• mainly academic• few in pharma; lacks access• no quality process for regulatory use

• The most comprehensive program over the past ten years = The Preclinical Pediatric Testing Program many lessons to be learned

Findings: Current state of preclinical paediatric drug research

• Patient derived xenografts preferred

• Metastatic models should be used for drugs with an anti-metastatic MOA very few metastatic pediatric tumor models

• Paediatric organoids improve in vitro screening (replacing 2D)? Prelude to in vivo for drugs targeting tumors?

• Other models (e.g., drosophila, zebrafish) of lesser value?

Findings: what are the “best”preclinical paediatric models?

Inherent in all of our findings is a critical role in harmonizing methodology, data and reporting standards

Streamlining the preclinical process – an example from PPTCSubtitle: making it affordable

Question: Are large (& expensive)preclinical mouse model studies necessary?

Answer: No

Why this matters• Capacity limitations• Simple economics

Example four-arm study savings• ~ 23 000 €/study (n=8 vs n=1)• Across single ITCC-P4

disease entity = 920 000 € (40 PDX/entity)

Murphy et al, Cancer Res, 2016

Comparison of objective response rates of studies w/ n=8-10 vs n = 1(2106 studies)

Thank you Pete Houghton!

• Orthotopic preferred

• Subcutaneous models as a screening tool prior to orthotopic evaluation?

• Defining efficacy: survival vs imaging approaches comparison studies needed

Findings: Brain tumors require different approaches

• Reminder: children with cancer are not little adults with cancer;even “truer” for IO

• Extremely limited availability of relevant in vivo paediatric tumor models for IO compound testing

• Critical need for humanized mouse models of paediatric cancer

• Sharing expression databases & establishing a paediatric tumor immune atlas will shed light on relevance of antigens and targets

Findings: The next frontier –preclinical immuno oncology research

• Maintain patient need as the driver of all activities

• Bridge b/w all stakeholders

• Insist on the avoidance of any unjustified delays

• Vigilance

Findings: Let’s not forget the importance of patient advocacy

What next?

• Submit white paper• Regulatory interaction

– EMA – submit a document for qualification process later this year– Contacts w/EMA delayed due to Business

Continuity Plan (i.e., BREXIT)– FDA – no qualification process. « The

published article will be used » Greg Reaman, 09/2018

Thanks to ALL Workshopparticipants