Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Periodic Report Summary 2 - 03K (Oral Off-patent Oncology Drugs for Kids)

Project Context and Objectives:

The goal of the Oral, Off-patent, Oncology drugs for Kids (O3K) project is to develop child-appropriate liquid formulations of cyclophosphamide and temozolomide, using this new technology. Temozolomide (TMZ) and cyclophosphamide (CPM) are widely used for the treatment of paediatric cancer and both drugs are included in the list of paediatric needs established by the EMEA.

Two liquid formulations of Cyclophosphamide and Temozolomide for daily oral administration in children will be developed with the goal to further submit a Paediatric Use Marketing Authorisation (PUMA) for both compounds. This will allow the administration of the exact dose along with a good bioavailability and improved compliance at all ages.

The O3K objectives are:

1. To secure the feasibility of developing the new oral formulations in terms of pharmaceutical aspects and to perform this work under the good manufacturing practices
2. To perform the non clinical, clinical and pharmacological development of a drinkable suspension of temozolomide for the purpose of a submission for a Paediatric Use Marketing Authorisation in the EU
3. To perform the non clinical, clinical and pharmacological development of a drinkable solution of cyclophosphamide for the purpose of a submission for a Paediatric Use Marketing Authorisation in the EU

Project Results:

Initially, pharmaceutical development started using a new drug delivery technology named “Oralance Technology”. The NODS technology solubilises drugs in a mixture lipid. However, the consortium faced technological bottlenecks in using this technology with two anticancer cytotoxic drugs, namely cyclophosphamide and temozolomide. Indeed, incorporation of the active principles into the NODS was quantitatively satisfactory but the drugs were released from the NODS rapidly inducing pharmaceutical concerns (no overtime stability, no guarantee to deliver the right dose to the childe) and safety hazard by releasing cytotoxic drugs in the environment.

Thus, for pharmaceutical and safety reasons, it was decided to stop developing the NODS technology in the O3K project. It was decided to develop alternative formulation of both drugs to propose a liquid oral formulation that will fit the paediatric needs. This was the major goal of the project.

 For Cyclophosphamide, two orientations have been chosen: Cyclophosphamide Aqueous solution and dispersible tablets.

The cyclophosphamide aqueous solution has not been selected due to the difficulty to obtain a good stability of cyclophosphamide in aqueous solution.

The formulation plan was then focused on the development of a dispersible tablet which could be dissolved in a glass of water prior to administration: the dispersible tablet. In the initial formulation it has been decided to use Cellulose as one of the excipents. The first stability studies with only one Packaging Blisters PVC/PVDC/Aluminium showed a non acceptable increase of monochloro impurity (>2%). New stability studies have been launched in different more protective packaging. The growth of the monochloro impurity was observed during stability studies at T1 month (>1%). The origin of the degradation of Cyclophosphamide has been identified because of the presence of one excipient: Cellulose microcrystalline.

After the choice of appropriate excipients (Mannitol, sodium croscaramellose, magnesium stearate), the trials of compressibility of the new tablets prototypes showing good compressibility, several analytical determinations were performed among with compared uniformity and monochloro impurity. Based on these analyses, the best formulation candidate is selected. This formulation is based on mannitol as main component. Uniformity results of this formulation are conform according to pharmacopoeia

Regulatory stability batches with the three dosages strengths will be then manufactured in order to have 3 months stability results by the end of 2011. A new IMPD, including these new results will be submitted mid December for starting the clinical program in March 2012.

As agreed with the EU paediatric medicine regulation, a Paediatric investigation plan (PIP) has been designed, submitted to and discussed by the Paediatric Committee of the European Medicine Agency EMA (in advanced evaluation by the PDCO (>day 60 report))

 For Temozolomide, the formulation work was undertaken according to 2 different approaches:

- Suspension formulation
- Dispersible tablets

It has not been possible to develop a Temozolomide suspension which can be safe and stable after dispersion in water over a long period of time.

In order to warrant safety of handling during preparation of the suspension until administration, the strategy is to perform a protective coating in direct contact with Temozolomide drug substance before formulating it in the dosage form.

In conclusion, due to all pharmaceutical issues, the project was delayed and the clinical trial could not be started before the end of the project that was not prolonged.

Potential Impact:

O3K will have important strategic impacts on economy, European competitiveness, and societal problems.

Thanks to the European Regulation for Paediatric use of Medicinal products, paediatric drug development becomes an economically attractive domain.

The ultimate goal of the O3K project, to be taken forward upon completion of the project, is to commercialise and to distribute two new medicinal products for children with cancer in Europe. In addition, by establishing the proof-of-concept of the use of drinkable suspension to develop age appropriate formulations of anticancer drugs, other compounds, including those of the EMEA list, may be developed. Moreover, this technology could be used to develop age-appropriate formulations for innovative targeted compounds developed by Big Pharmaceutical companies. Indeed, the specific paediatric needs for these innovative compounds will have to be addressed according to the EU Regulation on the Paediatric use of Medicinal Products. Altogether, this will adequately answer the needs for old products, as well as new products, and potentially create a healthy economic activity in the field of orphan drugs.

Thus, O3K will reinforce European competitiveness on several points:

By bringing together a network of paediatric oncology clinical investigating centres, (4 institutions committed to sponsor and develop clinical research in paediatric oncology, 2 pharmacology research laboratories with internationally recognised expertise in the field of paediatric oncology), 3 SMEs dedicated to drug development and 1 Parents Organisation, the O3K project will synergize research & development initiatives and create a critical mass of expertise and skills in the field of paediatric oncology and pharmacology research at the European level. The O3K project is a well-focussed project and is likely to generate in the mid term innovative and economically healthy activities.

The consequences are, first, a better working collaboration, financial and technical compatibilities and thereby a harmonisation of European research. By using new technologies and a significant level of oncology expertise, the O3K will advance the European role in drug development in children and strengthen a new R&D domain, namely drug research for children.

Concerning the solving of societal problems, more than 16000 children develop cancer each year in Europe. Despite improved survival rates with currently used multimodality treatments, cancer remains a life-threatening disease in children and represents the primary cause of death by disease in children over 1 year of age with more than 4 000 children dying of cancer each year in Europe. This is a major human health issue for the paediatric population. Safe and efficacious drugs are needed, as outlined by the EU regulation, to improve further cure and quality of life of children with cancer. The O3K project will contribute to the success of the EU Paediatric Medicines Regulation by providing child-appropriate formulations for two off-patent drugs.

The major impact will be for children and parents. The new child-appropriate formulations in oncology will improve safety, quality of life of children and their family and security of the environment. Development of ambulatory treatment with well-studied oral chemotherapy will be feasible and will help to improve quality of life of children, parents and family.

Long term impacts: The two drugs will be marketed and distributed. It is expected that an economically healthy activity will be generated from the O3K project.

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