May 30, 2015

Paediatrics cancers
Targeted therapies evaluated in phase I: promising results

Dr Birgit Geoerger of the Gustave Roussy Department of Childhood and Adolescent Oncology (Villejuif) delivered two oral communications in the session devoted to paediatric oncology on the 30th May at the 51st ASCO Conference. Both communications reported beneficial effects of targeted therapy in phase I paediatric clinical trials. These agents had already been shown to be useful in adults with different conditions. The first trial assessed dabrafenib, a tyrosine kinase inhibitor, in children with various solid tumours expressing the BRAF V600E mutation. Notably, this targeted therapy was found to be effective in high grade glioma. This is a world first.

The second study demonstrated the efficacy of ceritinib, an inhibitor of the ALK pathway, in children with a variety of tumour types, all displaying damage to the ALK gene.
Both trials show that it is important to adjust an anti-cancer treatment to the abnormal molecular characteristics of the patient’s tumour, illustrating the principle of “precision medicine”, a project launched in paediatrics at Gustave Roussy in 2012.

Promising phase 1 results for dabafrenib in children

Dabrafenib is an agent which up till now has been used in adults with non-resectable or metastatic melanoma bearing the BRAF V600E mutation.This phase I clinical trial was designed to determine the dose to recommend for children with solid tumours, which are refractory to treatment or in relapse (low and high grade glioma, Langerhans cell histiocytosis and other solid tumours), and which have the same mutation.

27 patients with a median age of 9 years participated in this study. Dabrafenib was taken twice daily. The drug was well tolerated with an acceptable level of toxicity. The recommended dose in patients aged less than 12 years was 4.5 mg/kg/day and for those aged 12 years and over it was 5.25 mg/kg/day.

A high proportion of the group responded to treatment with a reduction in size of the tumour on imaging. This applied to various types of cancer. 21 children are still taking the medication. In the 8 patients with high grade glioma, there were 3 complete responses and 2 durable partial ones (63% objective response). Both patients with Langerhans cell histiocytosis had a complete response.

These results demonstrate that this treatment should be instituted once a diagnosis of malignant glioma with a BRAF V600 mutation has been made.

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Efficacy of ceritinib in phase I

Ceritinib has been shown to be effective in adults with non-small cell lung cancer expressing abnormalities of the ALK gene. All the children recruited for this phase I international paediatric clinical trial had the same gene affected. The principal conditions seen were anaplastic large cell lymphoma, myofibroblastic tumours, inflammatory myofibroblastic tumours, rhabdomyosarcoma and neuroblastoma.

The median age of the 22 participating patients was 10 years. They came from 22 centres in 10 countries. They received doses of ceritinib ranging from 300 to 560 mg/m2/day and the drug was administered in the fasting state. The study has been proceeding for 18 months. It is still ongoing and the dose that should be administered with food is being assessed. The side effect profile is similar to that observed for this agent in the adult. The main adverse effects are gastrointestinal. The recommended dose in the fasting state is 510 mg/m2/day.

Ceritinib has been shown to be very effective in children with anaplastic large cell lymphoma and in inflammatory myofibroblastic tumours, both conditions being associated with the presence of a fusion protein which activates ALK.

> Read abstract

Paediatrics at Gustave Roussy

In 1950 Gustave Roussy established the first Paediatric Oncology Department in France. It has developed innovative treatments which have become standard therapy throughout the world. It has engaged in research to reduce the unwanted consequences of treatment and conducted early trials of new drugs. It argued for a law to oblige the pharmaceutical industry to provide drugs which are effective in adults in forms suitable for children.

Dr Dominique Valteau-Couanet is Head of the Department of Childhood and Adolescent Oncology, which specialises in the diagnosis of solid tumours and lymphomas. Since 2012 the department has been responsible for an innovative project in which former patients, now adults and cured of their childhood cancer, are followed in the long term.

Each year Gustave Roussy sees more than 410 new patients aged less than 18 years with a diagnosis of cancer. The medical team consists of 16 doctors and 80 other care staff (nurses, psychologists, nursing assistants, etc.)

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