Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma

Study Overview
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Brief Summary
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The aim of the study is to determine the safety of Cilengitide in combination with radiation therapy.

Detailed Description
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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.

Official Title
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Cilengitide (EMD121974) in Combination With Irradiation in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma: Phase I Study

Conditions
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Diffuse Intrinsic Pontine Glioma

Intervention / Treatment
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* Drug: Cilengitide dose escalation
* Drug: Cilengitide
* Radiation: Concomitant radiotherapy
* Biological: Pharmacokinetic
* Biological: Pharmacogenetic
* Biological: Exploratory investigation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diffuse intrinsic pontine glioma Metastatic disease allowed MRI measurable disease according to the WHO criteria and for extension cohort Patient is able to undergo functional MRI (diffusion, perfusion, spectro) Patient is able to undergo FDG-PET and sestamibi SPECT Life expectancy > 8 weeks after the start of study treatment. No prior chemotherapy for the present cancer; no treatment for any other cancer during the last 5 years. No prior cerebral radiation therapy Age > 6 months and < 21 years Lansky Play Scale > 50 or ECOG Performance Status < 2; NB: Children and young adults with a worse performance status due to glioma-related motor paresis can be included. Absolute neutrophils count > 1.5 x 109/l, Platelets > 100 x 109/l Total bilirubin < 1,5 x ULN, AST and ALT< 2,5 x ULN Serum creatinine ≤ 1,5 X ULN for age. If serum creatinine > 1,5 ULN, creatinine clearance must be > 70 ml/min/1.73 m² (EDTA radioisotope GFR or 24 hours urines collection) Normal coagulation tests : prothrombin rate (prothrombin time = PT), TCA (PTT), fibrinogen No current organ toxicity > grade 2 according to the NCICTCAE version 4.0, especially cardiovascular or renal disease (nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment). In case of known or possible cardiac disease, a cardiological advice will be required prior to the inclusion in the study If anticonvulsants are currently administered, the dosing regimen must be stable within 1 week prior to the first dose of Cilengitide If corticosteroids are administered, the dosing regimen must be stable ≥ 5 days prior to the first dose of Cilengitide. Effective contraception for patients (male and female) of reproductive potential during their entire participation in the study and during 6 months after the last administration of Cilengitide. Negative pregnancy test (serum beta-HCG) within 1 week prior to start of study treatment in females of reproductive potential Patient covered by government health insurance Written informed consent given by patient and/or parents/ guardians prior to the study participation Exclusion Criteria: Inclusion criteria failure History of coagulation disorder associated with bleeding or recurrent thrombotic events. Prior anti-angiogenic therapy Any other concomitant anti-cancer treatment not foreseen by this protocol. Concomitant inclusion in another therapeutic clinical trial; participation in another therapeutic clinical trial during the last 30 days. Pregnancy or breast feeding woman Uncontrolled intercurrent illness or active infection Unable for medical follow-up (geographic, social or mental reasons)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>In the first part of the trial, a dose-ranging study in ca. 18-21 patients will be done. A standard dose escalation strategy will be used including 3 to 6 patients at each dose level, the first cohort of patients being treated at dose level one Interventions : Cilengitide dose escalation ; Concomitant radiotherapy ; Pharmacokinetic ; Pharmacogenetic | Drug: Cilengitide dose escalation<br>* 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<br>* Other names: Cilengitidine;Radiation: Concomitant radiotherapy<br>* 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.<br>Biological: Pharmacokinetic<br>* 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.<br>Biological: Pharmacogenetic<br>* 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.<br>|
| Experimental: Cohort extension<br>An additional 20 patients will be treated at the recommended dose in order to confirm the recommended cilengitide dose and to carry out the exploratory investigations Interventions : Cilengitide ; Concomitant radiotherapy ; Pharmacokinetic ; Pharmacogenetic | Drug: Cilengitide<br>* Patients will be treated at the recommended dose in order to confirm the recommended cilengitide dose and to carry out the exploratory investigations<br>* Other names: cilengitidine;Radiation: Concomitant radiotherapy<br>* 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.<br>Biological: Pharmacokinetic<br>* 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.<br>Biological: Pharmacogenetic<br>* 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.<br>Biological: Exploratory investigation<br>* Evaluate the metabolic impact of the treatment with dynamic MRI (diffusion, perfusion, spectro), and with FDG-PETand sestamibi SPECT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | After 6 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of the Cilengitide | toxicities (NCI-CTCAE v4.0) | 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 | Day 1 and 2 of first cycle | 
| estimate efficacy in terms of response according to histopathology | WHO criteria | Every 3 cycles | 
| Progression-free and overall survival | 6-month-PFS overall survival | During all the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paediatric oncology, Cilengitide, Glioma