Clinical trial NCT01165333: Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma
Official title: Cilengitide (EMD121974) in Combination With Irradiation in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma: Phase I Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diffuse Intrinsic Pontine Glioma
Keywords: Paediatric oncology
Cilengitide
Glioma
Lead sponsor: Centre Oscar Lambret
Sponsor class: OTHER
First posted: 2010-07-19
Enrollment: 32
Sex: ALL
Minimum age (years): 6
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of the study is to determine the safety of Cilengitide in combination with radiation therapy.

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Determination of the Maximal Tolerated Dose of Cilengitide
timeFrame: After 6 weeks of treatment
Secondary outcomes:
measure: Safety profile of the Cilengitide
timeFrame: During all the study
measure: study of the pharmacoKinetic profile of Cilengitide
timeFrame: Day 1 and 2 of first cycle
measure: estimate efficacy in terms of response according to histopathology
timeFrame: Every 3 cycles
measure: Progression-free and overall survival
timeFrame: During all the study
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Hôpital des Enfants, Groupe Hospitalier
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: CHU, Hôpital d'Enfants de la Timone
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Paris
country: France
facility: Institut Curie
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg
city: Toulouse
country: France
facility: CHU
city: Villejuif
country: France
facility: Institut Gustave-Roussy
Study officials:
affiliation: Centre Oscar Lambret
name: Pierre LEBLOND, MD
role: PRINCIPAL_INVESTIGATOR
References: