Our programs
ITCC Clinical Evaluation program
Early clinical evaluation of new anticancer compounds will be performed through the :- Conduct of Phase I and II trials of novel agents
- Development of translational research within the clinical trials, including new imaging techniques, to better address endpoints and surrogate biomarkers of activity
- Improvement of paediatric drug development plans using innovative designs and methodology, in order to accelerate the evaluation process.
- Has developed its clinical network by identifying and accrediting clinical centres with expertise in phase I and phase II trials, in order to provide a critical mass of expertise with a capacity to complete high quality clinical trials in a timely fashion (e.g. to complete a phase II trial in a “frequent” paediatric cancer in less than 18 months).
- Has set up the administrative facilities and processes to facilitate the initiation of clinical trials in keeping with the implementation of the new European Clinical Trials Directive
- Is reinforcing compliance with Good Clinical Practice and Ethics requirements
- Has developed the facilities to run clinical trials sponsored by Academia if required.
- Will set up workshops, committees and communication facilities to improve the dissemination of information on clinical trials, and within clinical trials. Moreover, the accessibility of patients to early clinical trials will be increased by improving the information available to parents and patients who may participate in early clinical trials.
Early development in children
Any new anticancer compound for children first enters clinical evaluation in phase I trials in adults. When compounds targeting biological targets that are specific and unique in paediatric malignancies are available, the first use will have to be in children.
By the time phase II trials are underway in adults, the data on toxicity, pharmacokinetics and pharmacodynamics, and preliminary suggestions concerning efficacy are already available and thus provide the prerequisites initiating paediatric drug development.
Two points should be appropriately addressed concerning the future of paediatric drug development :
- The optimal time to start the paediatric evaluation of a new compound under development in adults
- A new design and methodology to accelerate early drug development in children through better use of information available in adults.
ITCC aims to develop partnerships with pharmaceutical companies and regulatory bodies in order to appropriately address the rationale and design of Paediatric Investigation Plans for anticancer compounds that will meet the needs of children with cancer. In addition, ITCC will conduct methodological research to speed up the drug development design in children, in particular when new types of compounds with new mechanisms of action and new endpoints are considered.
Current activities
ITCC is currently running 5 clinical trials:- Phase I trial of Tarceva, a EGFR receptor inhibitor, in partnership with Roche
- Phase I trial of Aplidin, a marine cytotoxic compound, sponsored by PharmaMar
- Phase II trial of Gemcitabine and Oxaliplatin combination, in partnership with Lilly and Sanofi-Aventis
- Phase I/II trial of Dasatinib, a BCR/ABL, Kit and Src inhibitor, sponsored by BMS
- Phase II trial of Temozolomide and Irinotecan combination, sponsored by Pfizer
And is preparing 5 new clinical trials
In 2005, the audit process of clinical centres was initiated with institutions currently participating in ITCC. This auditing process will be applied to all potential new partners.
A committee composed of parent representatives from the 5 member states of ITCC was set up :
- to review protocols, information documents and provide recommendations
- to identify the needs and means for training parents to review protocols
- to understand cultural differences in between member states with regard to clinical research and evaluation of new drugs
ITCC Biology & Preclinical Evaluation
The two aims are :To select and prioritise anti-cancer compounds being developed in adults by :
- Identifying targets in paediatric primary tumours and relevant tumour models,
- Determining the target-dependency on paediatric tumour models,
- Testing new (targeted and non-targeted compounds) in pre-clinical in vitro and in vivo models.
The pre-clinical stepwise evaluation of drugs in ITCC consists of :
- Target presence screening
- In vitro efficacy testing
- Target validation (tumour dependency)
- In vivo proof of principle testing
- Exploring the role of kinases through functional knockout and mutation analysis
- Validating selected kinases in vitro and in vivo cell lines and transplantable experimental models
- Developing LNA inhibitors for selected kinases
Prioritisation Strategy
Six aggressive childhood tumours have been selected to be studied and tested in this rational drug evaluation approach. Altogether, these high-risk childhood tumours account for approximately 50% of the childhood deaths from cancer in Europe. Large frozen specimens (80 - 300 per tumour type) of these tumours (neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma, medulloblastoma and acute lymphocytic leukaemia), are available, as well as cell lines and xenograft models.The pre-clinical stepwise evaluation of drugs in ITCC consists of :
- a. target presence screening
- b. in vitro efficacy testing
- c. target validation
- d. in vivo proof of principle testing
Scheme of preclinical drug evaluation for targeted compounds (rights) and compounds with unknown target (left)
Targeted drug evaluation
Target presence was analysed by array (Affymetrix) screening of mRNA in all ITCC cell lines (12-30 cell lines per tumour type, total number of 140 cell lines available), representing the six high-risk paediatric tumours.
In addition, the ITCC has created gene expression profiles of ± 100 samples of each tumour type. The profiles are used to identify the tumour types expressing genes targeted by the novel drugs. The target presence will be confirmed at the protein level by performing tissue arrays on paraffin-embedded tissue.
In vitro efficacy of any new targeted compound is being tested for anti-tumour efficacy by performing in vitro incubation assays on a panel of cell lines of each tumour type demonstrating the presence of a target (and target-negative control cell lines). Furthermore, the ITCC core cell line panel, which consists of 24 cell lines, is being used for in vitro incubation experiments, regardless of target presence (general in vitro screening).
Potentially effective drugs will subsequently be tested in vivo in xenograft models of tumour types demonstrating in vitro sensitivity. The most sensitive cell line of each tumour type will be grown subcutaneously in vivo . Three dose levels will be tested per compound in ± 10 mice per tumour type.
Target validation (tumour dependency). In order to establish drug independent proof of the importance of the drug target for the paediatric malignancy under investigation, ITCC is performing siRNA studies aimed at the gene target for the evaluated drug. For each tumour type in which promising in vitro drug efficacy is observed, the expression of the drug target will be knocked down by siRNA in the most sensitive cell line. Cell viability and functional measurement of gene target activity will serve as readouts for siRNA studies.
Non targeted drug evaluation
The evaluation program of novel non-targeted compounds will consist in general in vitro screening of the ITCC core panel of 24 cell lines. The most sensitive cell line of each tumour type will be grown in vivo (xenograft) in order to confirm the therapeutic effect of the novel compound.
Timeframe for pre-clinical testing
It is estimated that all the above mentioned experiments are feasible in the period of twelve to eighteen months, as specified below, starting from the time that a compound is available for pre-clinical testing at the ITCC labs. The most time-consuming experiments will probably be siRNA (6 - 15 months).
- General in vitro efficacy evaluation (1 lab): 4 months (range 3 – 6 months)
- Tumour type specific labs (6 labs)
- Profiling: available
- In vitro efficacy: 6 months (range 4 -8 months)
- Target validation (siRNA): 9 months (range 6 -15 months)
- In vivo efficacy evaluation (1 lab): 12 months (range 9 -15 months)
Consortium Agreement
The nine labs involved in ITCC Biology have signed a Consortium Agreement (describing all aspects of Intellectual Property Rights and Organisational/Decisional aspects), a Material Transfer Agreement (facilitating the mutual transfer of cell lines and tumour samples), as well as a Mandate/ Confidentiality Disclosure Agreement( facilitating Exploratory meetings with Third parties).