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Clinical Trial Summary

Diffuse Intrinsic Pontine Gliomas (DIPG) appear almost exclusively in children and adolescents, representing 15 to 20% of posterior fossa tumours. Even if it is one of the most common malignant brain tumours, there are only 30 to 40 new cases per year in France. Their clinical presentation is stereotyped with a short clinical history and a unique MRI appearance that was usually considered as sufficient to establish the diagnosis. The prognosis of DIPG is always unfavourable; median overall survival is 9 to 10 months in general and most patients will die within two years after diagnosis (Kaplan 1996,Hargrave 2006). Malignant gliomas infiltrating the brainstem represent the greatest challenge of paediatric oncology; despite numerous collaborative studies performed, patients' survival has not significantly increased in thirty years (Hargrave 2009). There is no validated prognostic factor. There is currently no validated treatment except radiotherapy.

Several targeted agents have been tested in DIPG (Pollack 2007 Haas-Kogan 2008, Geoerger, 2011), without knowing whether the target was present in the tumour. A critical review of the paradigms of these trials tells us that there are long term survivors in these studies that is to say patients who may have benefited from the tested therapy, but they are few. So far, the new therapies that have been tried were evaluated one after the other in search of a treatment that would be effective for all patients, measuring the treatment effect on median survival. They were all rejected as ineffective. However the investigators can challenge the endpoint to evaluate efficacy in these trials as the existence of long term survivors (> 18 months, for example) and their number should not been ignored, especially if targeted therapies are considered. The investigators propose a paradigm shift in the choice of treatment; the issue raised would be to give to each patient the treatment associated with the highest likelihood of efficacy based on the specific biological tumour profile.

The development of targeted therapies for malignant gliomas infiltrating the brainstem has been hampered by the absence of biological data. It is therefore crucial to better understand the biology of these tumours. Despite the safety of the biopsy in brainstem tumours, most teams of paediatric neurosurgery limit the use of stereotactic biopsy only for clinically or radiologically unusual forms. Until recently, there has been no systematic genetic study at diagnosis to date and the few available data were confounded by the inclusion of autopsies or clinically and radiologically unusual cases (Louis, 1993; Gilbertson 2003; Okada, 2008; Zarghooni 2010; Broniscer, 2010; Wu, 2012 and Schwartzentruber, 2012).

French teams gathered in the French Society of Paediatric Oncology and the European consortium "Innovative Therapies in Children with Cancer (ITCC)" decided a few years ago to perform biopsies of these tumours for diagnostic confirmation and to ensure the presence of certain therapeutic targets prior to a possible inclusion in a trial evaluating a targeted therapy (Geoerger, 2009; Geoerger, 2010). Part of this experiment was reported by the team of the Necker Hospital in Paris, confirming the low rate of complications of stereotactic biopsy procedure (Roujeau, 2007). The biopsy specimen analysis allowed practicing immunohistochemical, genomic (CGHarray), gene expression (transcriptome) and direct sequencing of candidate genes studies.

In this study, the majority of patients will receive a treatment assumed to specifically target a biological abnormality identified on the biopsy. More importantly, patients will not receive a drug for which the identified target is absent.

In this first step of the protocol, the patients will thus be allocated to one of the three treatment groups as follows:

- If the tumor overexpresses EGFR without PTEN loss of expression, patients may receive erlotinib or dasatinib allocated by randomization (R1 randomisation).

- If the tumor shows loss of PTEN expression without EGFR overexpression, patients may receive everolimus or dasatinib allocated by randomisation (R2 randomisation).

- If the tumor shows both EGFR overexpression and loss of PTEN expression, patients may receive erlotinib, everolimus or dasatinib by randomisation (R3 randomisation).

- If the tumor shows neither EGFR overexpression nor loss of PTEN expression (a very rare situation in our experience), patients will receive dasatinib (no randomisation).

- If the biopsy assessment is not contributive, the treatment will be allocated by randomisation between erlotinib, everolimus and dasatinib (R3 randomisation).


Clinical Trial Description

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Study Design


Related Conditions & MeSH terms


NCT number NCT02233049
Study type Interventional
Source Gustave Roussy, Cancer Campus, Grand Paris
Contact Jacques GRILL, MD, PhD
Phone 0142116209
Email jacques.grill@gustaveroussy.fr
Status Recruiting
Phase Phase 2
Start date October 2014
Completion date October 2018

See also
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