The aim of the study is to determine the safety of Cilengitide in combination with radiation therapy.
The prognosis of children and young adults with a malignant glioma in the brain stem or a recurrent malignant glioma (in whatever site) is very poor. Over the last few decades, many therapeutic trials have been performed but have failed to significantly improve survival in these patients. There is thus a need to test new drugs in these indications. There is a strong biological rationale for the use of anti-angiogenic drugs in high-grade glioma. Cilengitide (EMD121974; Merck KgaA, Darmstadt, Germany), a cyclic pentapeptide containing the sequence RGD (cyclo-\[Arg-Gly-Asp-Dphe-(NmeVal)\]) is a selective antagonist of integrins αvβ3 and αvβ5, which are strongly involved in tumour angiogenesis. Positive results with Cilengitide in preclinical models of glioblastoma, its particularly attractive safety profile and its encouraging efficacy in phase I and II studies in adults and children make it a potentially effective molecule for the treatment of malignant glioma in children. Furthermore, its combination with radiotherapy to be appears synergistic, without any apparent increase in toxicity. In this study, Cilengitide will be evaluated when concurrently administered with radiotherapy as a first-line treatment and then as a maintenance monotherapy in children and young adults with malignant brain stem glioma. The main objective will be to determine the maximum tolerated dose (MTD) of Cilengitide when administered twice weekly as a 60-minute intra-venous infusion.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
32
Cilengitide will be administered intravenously over 60 minutes, twice a week, at a given dose. The Cilengitide dose (mg/m²/infusion)levels are as follows : * 240 * 480 * 720 * 1200 * 1800
Patients will be treated at the recommended dose in order to confirm the recommended cilengitide dose and to carry out the exploratory investigations
1.8 Gy per fraction for a total of 54 Gy over 6 weeks, from monday to friday of the first cycle. The radiation will imperatively begin between 3 and 7hours after the end of Cilengitide infusion.
Hôpital des Enfants, Groupe Hospitalier
Bordeaux, France
Centre Oscar Lambret
Lille, France
Centre Léon Bérard
Lyon, France
CHU, Hôpital d'Enfants de la Timone
Marseille, France
Determination of the Maximal Tolerated Dose of Cilengitide
A DLT is defined below: Hematological toxicity: * grade 4 neutropenia for more than 5 days * grade 3 or 4 neutropenia with documented infection * grade 3 or 4 thrombopenia for more than 5 days * requirement of platelet transfusion support for more than 5 days Non-hematological toxicity: Any grade 3 or 4 non-hematological toxicity of whatever duration with the exception of (i) nausea/vomiting without appropriate treatment, and (ii)isolated, transient fever occurring outside an episode of neutropenia), with the exclusion of toxicities related to any other well-identified cause.
Time frame: After 6 weeks of treatment
Safety profile of the Cilengitide
toxicities (NCI-CTCAE v4.0)
Time frame: During all the study
study of the pharmacoKinetic profile of Cilengitide
Blood samples of 2 mL will be collected at each time point : before Cilengitide infusion, at the end of infusion, 30 mn after the end of infusion, 60 mn, 90 mn, 2 hrs, 4 hrs, 6 hrs, 24 hrs after the end of infusion
Time frame: Day 1 and 2 of first cycle
estimate efficacy in terms of response according to histopathology
WHO criteria
Time frame: Every 3 cycles
Progression-free and overall survival
6-month-PFS overall survival
Time frame: During all the study
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A pharmacokinetic assessment for Cilengitide will be carried for all patients. The pharmacokinetic (PK) samples will be drawn during day 1 and day 2 of the first cycle of treatment.
For every patient 1 blood sample will be taken before study treatment. These blood samples can be made at any hour of the day, and does not require to be taken on an empty stomach. DNA will be extracted in the Laboratory of Pharmacology.Constitutional polymorphisms of genes will be measured before the treatment initiation.
Evaluate the metabolic impact of the treatment with dynamic MRI (diffusion, perfusion, spectro), and with FDG-PETand sestamibi SPECT.
Centre Hospitalier Universitaire de Nantes
Nantes, France
Institut Curie
Paris, France
Hôpitaux Universitaires de Strasbourg
Strasbourg, France
CHU
Toulouse, France
Institut Gustave-Roussy
Villejuif, France