© Shutterstock by VGstockstudio
© Shutterstock by Sergey Nivens
© Shutterstock by 18percentgrey
© Shutterstock by kittirat roekburi
© Shutterstock by zhu difeng


Paediatric Preclinical Proof Of Concept Platform


Cancer remains the leading cause of disease-related death in children. For the ~25% of children who experience relapses of their malignant solid tumors, usually after very intensive first-line therapy, curative treatment options are scarce. Preclinical drug testing to identify promising treatment options that match the molecular make-up of the tumor is hampered by the fact that

  • i) molecular genetic data on pediatric solid tumors from relapsed patients and thus our understanding of tumor evolution and therapy resistance are very limited to date and
  • ii) for many of the high-risk entities, no appropriate and molecularly well characterized patient-derived models are currently available.

Thus, quality-assured upfront preclinical testing of novel molecularly targeted compounds in a repertoire of well-characterized models will establish the basis to increase therapeutic successes of these drugs in children with solid malignancies. Since these tumors are overall genetically much less complex than their adult counterparts, it is anticipated that it will be easier to identify powerful predictive biomarkers to allow for accurate matching of targets and drugs.

ITCC-P4: a new platform to accelerate drug development for children and adolescents dying of cancer

Innovative Therapies for Children with Cancer Paediatric Preclinical Proof-of-concept Platform (ITCC-P4) is a newly formed public-private partnership supported by the European consortium ‘Innovative Medicines Initiative’ (IMI). The consortium with currently 21 partners from 8 countries aims to establish 400 new patient-derived preclinical models of high-risk pediatric solid tumors which will be fully characterized (molecularly, immunologically, pharmacologically and clinically well-annotated) and to build a sustainable comprehensive platform to use these models for drug testing. It brings together many of Europe`s most distinguished academic and clinical research institutions, well established Small-to-Medium sized Enterprises (SMEs), members of the European Biopharmaceutical Enterprises (EBE) and the members of the European Federation of Pharmaceutical Industries and Associations (EFPIA), thus providing a unique setting to improve patient outcomes by introducing new and effective medicines in standard of care of young people still dying of these rare cancers.

1st January 2017

Start Date

5 Years

Project Duration

€ 16.5 Mio


To address this high but as yet unmet clinical need, the main objectives for this preclinical platform project are the following:

  • To establish a representative collection of 400 patient-derived models of the most common pediatric solid high-risk entities including a significant proportion of models from relapses.
  • To molecularly characterize the models as well as the matching primary tumor samples and germline controls with state-of-the-art molecular diagnostic tools.
  • To enable regulatory filings in the EU through the development of comprehensive preclinical data packages necessary to move drugs into clinical trials for children with solid tumors.
  • To prioritize pediatric drug development using existing collections of molecular data for systematic target reports, followed by drug testing in faithful disease models including pharmacokinetics and pharmacodynamics where necessary (e.g., brain penetration). This will also include at least three standard-of care-drugs for all models as a baseline for comparisons.
  • To identify suitable biomarkers for future clinical stratification of patients across entities.
  • Ultimately, the establishment of ITCC-P4 as a sustainable platform over the long term will overcome a long-standing gap by enabling thorough molecular characterization of high-risk pediatric malignancies coupled with standardized preclinical testing procedures, and will thus greatly expedite the development of more precise and efficacious drugs for this patient group. Developing this platform as a public-private partnership will create a model for collaboration that can hopefully be extended to other types of cancer entities and patient groups.

Work Packages

To facilitate the organization and management, ITCC-P4 is structured as seven work packages (WPs). Each Work Package has specific leaders (academic and pharma) who are responsible for the management and the results of their WP.

By clicking on the different WPs you can find out more about their objectives and tasks!

Work Package 1 Work Package 2 Work Package 3 Work Package 4 Work Package 5 Work Package 6 Work Package 7

Work package leader: Stefan Pfister (DKFZ) and Lou Stancato (Eli Lilly). Co-lead: Hubert Caron(Roche),Gilles Vassal (IGR)

Objectives of the work package: This WP is responsible for the overall management of the consortium

Description of the tasks:
This includes the organization of regular telephone conferences and face-to-face meetings, communication between academic partner sites, SMEs and industry, the monitoring of the adherence to budgets and milestones, the governance of sample and data access, the coordination of reports, the preparation of consortium publications together with the respective participants, the representation of the consortium at conferences, and the embedding in ITCC and other participating networks.

Work package leader: Jan Molenaar (PMC), and Hubert Caron (Roche)

Objectives of the work package: Target actionability in pediatric cancers

Description of the tasks:
In this work package we aim to perform a systematic validation of targeted compounds and corresponding actioIn this nable genes and pathways in the different pediatric solid tumor entities prior to the in vitro and in vivo testing phase using relevant literature and the existing (epi)genomic and transcriptomic datasets of all entities in question. We will also map these with the portfolios of the participating pharma partners to enable a first prioritization of compounds for in vivo testing. With this approach, we should be able to select tumor types that will most likely respond to the targeted interventions; this will result in more efficient use of the PDX systems. The pipeline will encompass a systematic literature review followed by in silico analysis of the actionable events.

  • Definition of minimally-required preclinical proof-of-concept (POC) packages for ‘Target Actionability’.
  • Systematic literature reviews of pediatric ‘target actionability' for >6 drug targets/pathways matching the pipelines of the pharma partners.
  • Target aberration/activation patterns in clinical pediatric tumor series.

Work package leader: Marcel Kool (DKFZ) and David Shields (Pfizer). Co-leaders: Johannes H. Schulte (Charité), Gudrun Schleiermacher (IC), Sara Colombetti (Roche)

Objectives of the work package: Pediatric cancer model development and characterization

Description of the tasks:
Prominent to WP3 is the development of a sustainable infrastructure for generation and use of Patient-Derived Models (PDMs) (Patient-Derived Xenograft (PDX) and organoid models) and Genetically Engineered Mouse Models (GEMMs). Robust genomic characterization of all established models will be conducted, including cross-species human (primary/PDX/organoid) : mouse (GEMM) comparisons. Several specialized academic labs, SMEs (EPO, XenTech) and EFPIA partners (Charles River) will generate up to 400 PDX models, representing the major pediatric solid tumor entities (Neuroblastoma, Rhabdomyosarcoma, Synovial Sarcoma, MPNST, MRT, Ewing Sarcoma, Osteosarcoma, Medulloblastoma, AT/RT, CNS-PNET, ETMR, Ependymoma and High-grade glioma) . A comprehensive molecular characterization of all primary tumor material, matching germline samples, derived models and GEMMs will be performed to enable full interpretation of any preclinical results. The comprehensive molecular characterization will include high-coverage, whole-exome and low-coverage, whole-genome sequencing of all PDMs and their matching primary tumors and germline DNA, as well as RNAseq, Affymetrix gene expression profiling and DNA methylation profiling.

Work package leader: Gilles Vassal (ITCC) and Silvia Chioato (Pfizer) Co-leads: Birgit Geoerger (IGR),Olaf Witt (DKFZ), Richard Vart (Eli Lilly) and Louise Hayes (Roche)

Objectives of the work package: Regulatory consensus on disease models and POC data package for PIP requirements

Description of the tasks:
ITCC-P4 aims to generate a science-based regulatory consensus endorsed by the EMA and PDCO on the biological and preclinical information required to support a pediatric investigation plan for an oncology medicinal product. The ITCC-P4 project and then the platform, will generate biological and preclinical data for oncology medicinal products that are considered for pediatric development. This information along with the evaluation of the therapeutic needs of the young population will contribute to the rationale for a pediatric investigation plan. In addition, the PDX platform might generate comparative preclinical data for compounds targeting the same molecular pathway or share the same or similar mechanism of action. This could facilitate the identification of the potentially best and more relevant oncology medicinal products to be developed in the pediatric population. Data from the platform could be used in multistakeholder pediatric drug development strategy forums to discuss how best to develop innovative compounds for pediatric malignancies.

Work package leader: Dieter Zopf (Bayer) and Jens Hofmann (EPO) Co-leader (for CIT) Sara Colombetti (Roche)

Objectives of the work package: Testing of standard of care drugs and open compounds

Description of the tasks:
Testing of compounds from all consortium members (academic and industrial) in a limited number of approved and validated testing sites by a quality-assured methodology, including single drugs with readouts of ‘biological efficacy’. The main drug testing component on PDX will be performed in a standardized fashion exclusively at the SMEs and at two EFPIA partners (Charles River and PharmaMar) to ensure quality and comparability of the PD data. The proof-of-concept drug testing in organoids will be exclusively done at the PMC (where the organoids also will be established). The five disease entity groups will select a panel of standard of care (SOC) and investigational drugs. Three SOC drugs and five selected targeted therapy (including RAS/MEK/ERK pathway in tumors where pathway activation is indicated) will be evaluated for their anti-tumor activity in vivo. Exploratory combination studies will be performed based on the results of WP 2 and 5. Combinations may include small molecules/targeted therapies/new drugs with each other or with chemotherapy or radiotherapy (e.g. to disrupt the blood-brain-barrier). All data will be rapidly distributed to the consortium and made available on the IT platform. Response evaluation is expected to provide guidance for clinical tumor treatment and drug development, to support the identification of suitable combination partners and to uncover potential resistance mechanism through correlation with molecular data generated in WP3.

Work package leader: Jan Koster (AMC), Louis Stancato (Eli Lilly). Co-lead: Natalie Jäger (DKFZ)

Objectives of the work package: Information technology infrastructure and data analysis

Description of the tasks:
Centralized data repository including results of the project such as precompetitive model characteristics (i.e., all data associated with model molecular and pharmacological characterization using commercially-available agents) and SOC testing data with custom informatics tools to visualize and analyze data. For dissemination of processed genomics and drug-testing data, the consortium proposes to build on the existing IT infrastructure that is available at the AMC (R2; http://r2.amc.nl) and which is used extensively in the pediatric cancer research community.

Overview of R2: Genomics Analysis and Visualization Platform – Left panel: Data storage types within the platform. Right panel: Example data visualization and correlation capabilities for mRNA data.

Work package leader: Gilles Vassal (IGR) with Gustave Roussy Transfer, Lou Stancato (Eli Lilly) and Hubert Caron (Roche)

Objectives of the work package: Establishment and implementation of a sustainability model to ensure that the pediatric testing infrastructure (models, testing scheme, data, etc.) continues post-IMI2

Description of the tasks:
The ultimate goal is to build a post-IMI2 sustainable infrastructure that will provide the biological and preclinical data to identify new oncology drugs to be developed in the pediatric population in order to adequately address the needs of children and adolescents with cancer. During the five years of IMI-2 funding, a comprehensive panel of fully molecularly and pharmacologically well characterized preclinical pediatric cancer models (PDXs and GEMMs, including new models such as organoids) will be set up in order to provide the preclinical information required to contribute to the best choice of innovative compounds to be further developed in children, as single agent and in combination. WP7 will design and implement a sustainable platform to ensure the pediatric testing infrastructure continues after the end of the project. ITCC-P4 partners will, amongst others, discuss the following principles:

  • The platform will run commercial activities for pharmaceutical companies and will be accessible for academic institutions.
  • The platform will not focus on the sale of preclinical models, but rather on the in vivo testing in these models
  • The platform will set up secured access to data and models generated during the project and for continued testing and data generation moving forward through a quality-assured program respecting ethical rules on animal testing