This talk was presented at the ICCCPO-conference, 2004 in Oslo

Introduction

Within the space of 40 years, childhood cancer has changed from being a fatal disease to being curable in 70% of the cases. Especially, Wilms’ tumours, Hodgkin disease and Acute Lymphoblastic Leukaemia (ALL) show excellent survival rates of 75-95%. For a large part this is due to the introduction of effective (combination) chemotherapy and intensification of treatment. Moreover, improved supportive care, bone marrow transplantation and specific treatment protocols, including radiotherapy and surgery, for each cancer have contributed significantly. Still, nearly one-third of children with cancer dies due to the cancer or to early or late toxic effects of therapy. Therefore, new effective drugs are needed for better survival, less toxic effects of treatment and a better quality of life.

Development of new drugs in paediatric oncology

Nowadays, ~70% of drugs used in children have not been analysed in children. Children are therapeutic orphans. Pharmaceutical industries are not willing to perform drug studies in children from an economic point of view. The market is too small. Furthermore, children need special administrations (suspensions, small tablets).

To address this point, partly due to pressure of parent and patient organisations in the USA, the American Congress has set aside a significant amount of money for the benefit of drug studies in children. Several Research Centres specialised in drug research in children are established in cooperation with University Hospitals. Furthermore in 1998, the National Institute of Health (NIH) issued a policy requiring inclusion of children in “all human subject research conducted or supported by the NIH” unless there are scientific or ethical reasons to exclude them. From 1997 till 2001, the US government attempted to provide financial incentive for pharmaceutical companies for paediatric drug development by introducing the Food and Drug Administration (FDA) Paediatric Exclusivity Provision, which was reauthorised as the Best Pharmaceuticals for Children Act in 2002. This act offered an additional 6-month market exclusivity to existing patents for all formulations of any products that have been examined in children, whether appropriate for paediatric use or not. In addition the FDA Pediatric Rule of 1998 requires evidence from randomised controlled trials before new therapies of indications for existing therapies are approved for use in children. This Rule was challenged in court and struck down on Oct. 17, 2002 on the grounds that it exceeded the FDA’s statutory authority to force pharmaceutical companies to test their drugs in children. The FDA, in response, called for Congressional support. On Nov 19, 2003, the US House of Representatives approved the Pediatric Rule, giving the FDA authority to mandate paediatric studies in specific defined conditions, provided the drug is widely used or is considered a therapeutic advance. As a result of these recent changes in regulations and legislation in the US, more trials have been done on children in the USA in the past five years than in the previous 30 years, with resulting improved safety information as well as dose changes for paediatric describing. There is currently no legislation regarding paediatric licensing in any other country. In December 2000, the European Union Health Council adopted a resolution calling on the European Commission to develop similar incentives in Europe. However, a concrete legislative proposal is still to come from the European Commission.

Methodology of early clinical studies

The methodology of clinical studies describes in the first place laboratory research in which a potential drug is analysed in tumour cell-lines and cultures of tumour cells. The second step is animal experiments. Animals can serve as an in vivo tumour model or as a model for toxicity analysis of the drug. Based on these findings, research in humans can start in several phases. The first phase is finding the maximum tolerable dose (MTD) of a drug. Different cohorts of patients receive an ascending amount of the drug until toxicity is the limiting factor. During these experiments the pharmacodynamics (what the body does to the drug) and pharmacokinetics (what the drug does to the body) are analysed. The MTD of the drug is used in phase II studies. In these studies the response of the tumour, toxicity of the drug and pharmacodynamics and –kinetics are analysed. In the case of a fair tumour response the drug will be (randomised) compared in phase III studies with standard treatment.

Nowadays, new (targeted) drugs are only available for children with cancer when these drugs are already analysed in phase I and II studies in adults with cancer and when phase III adult studies are initiated. This means a delay of at least five to ten years before ‘promising’ drugs are available for phase I/II studies in children. This is not acceptable, all the more because the majority of childhood cancers is unique and is not found in adults.

European New Agent Group

A European collaboration, named EURO-New Agent Group (EURO-NAG), has been established between France, England, the Netherlands, Italy and Germany to facilitate phase I/II studies in children with cancer. Since 1996, physicians from France (Vassal) and England (Morland) have initiated 17 phase I/II trials in children with cancer (solid tumours). One year ago, EURO-NAG also started off a laboratory consortium of nine laboratories well known for their experience with biology studies in childhood malignancies and pre-clinical drug evaluation systems such as animal xenografts and cell-lines. This consortium is called Innovative Treatment for Children with Cancer (ITCC). In this consortium new (targeted) drugs can be developed or analysed and selected in pre-clinical setting. So, new drugs will be available more quickly for treatment of childhood cancer. The ITCC has also contacted pharmaceutical companies to collaborate in finding or analysing promising new drugs.

European Legislation

Drug studies in Europe can only be done according to the European law based on the European Directive (2001/20/EC). Since the first of May 2004, this Directive has to be implemented in the local laws of each European country. The main issue of doing research (drug) studies in human beings (children) is the informed consent. The second important point of this Directive is the restriction of non-therapeutic research in incapacitated persons, such as children.

The history of informed consent for research studies in humans goes back to Germany in 1891. The Prussian Minister of Internal Affairs at that time promulgated a directive for all prisons that certain drugs (tuberculin against tuberculosis) must not be used against the explicit will of patients/ prisoners. Nine years later in 1900, a Prussian Minister of Medical Affairs founded the first legal base for medical research in humans with informed consent, especially non-therapeutic research. Since 1931, during the Nazi period, all legislation, concerning (non-) therapeutic research in humans, was lifted. During the ‘Nuremberg’ law suits, the informed consent procedure became important again (Code of ‘Nuremberg’, 1946). But, despite the Declaration of Helsinki in 1964, it took several years (till 1969-1972) before special Institutional Review Boards (IRB) in the USA were established to judge research protocols before experiments could be done in man.

In the Netherlands, based on the European Directive, non-therapeutic drug studies in children are only allowed when the scientific results can solely be obtained by research on persons belonging to the category concerned (sectional interest or group restriction). Furthermore, when minimal risk criteria are fulfilled, in which this minimal risk is defined as risk to the child experience during normal life and last but not least when the burden of the research is minimal. The burden of the research conducted in children depends on the kind of investigations and duration of research.

Nowadays, phase I/II studies in children with cancer are often developed to determine the optimal biological effect instead of the maximum tolerated dose of a drug. This is based on less toxic effects of the drug because it is a tumour specific (targeted) drug and it is also based on data of pre-clinical screening models of specific childhood cancers.

Examples of targeted drugs in ALL

The overall survival in ALL is ~80% by effective but non-specific therapies. Therefore, more effective, targeted therapies are needed, especially for high risk ALL with dismal prognosis such as Philadelphia chromosome positive (Ph+) ALL and infant ALL (children with ALL < 1 year of age). ALL are characterised by chromosomal aberrations such as translocations and deletions. In case of translocations leukomogenic fusion products can be found. In Ph+ ALL, a translocation between chromosome 9 and 22 occurs causing a fusion between the two genes abl (chromosome 9) and bcr (chromosome 22). This fusion gene encodes a BCR-ABL fusion product, which has enhanced tyrosine kinase activity causing cell survival. A specific inhibitor STI571 (Glivec®, Gleevec®) against this tyrosine kinase has been found causing cancer cell death in a significant amount of patients giving rise to a better prognosis in Ph+ ALL.

Certain types of ALL, such as infant ALL, are characterised by a high expression of specific genes. Infant ALL are associated with a poor prognosis (Event Free Survival of 35%) and known for their in vitro resistance to cytostatic drugs. In infant ALL, flt3 activation as a consequence of flt3 overexpression is found. This flt3, a tyrosine kinase, is known to be oncogenic in acute myeloid leukaemia (AML). PKC412 appeared to be a potent flt3 inhibitor causing cell death in several in vitro models and in phase I en II studies in adult patients with AML. Phase I/II studies are currently under development in infants with ALL.

Conclusion

Although survival has improved in paediatric oncology, still 30% of children eventually die. European legislation allows non-therapeutic paediatric drug studies when these studies fulfil specific criteria. Targeted drugs in paediatric oncology are needed for specific therapies, especially for childhood cancers with a bad prognosis. STI571 and PKC412 are examples of targeted drug therapy against tumour cells with minor toxic effects. It is important for progress in treatment of childhood cancer that phase I/II studies can be done in children with cancer and with the shortest delay as possible.

References

Caldwell PHY, Murphy SB, Butow PN, Craig JC. Clinical trials in children. Lancet 2004;364:803-811