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

Diffuse Intrinsic Pontine Glioma Clinical Trial

— CILENT-0902  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01165333
• Other study ID #: CILENT-0902
• Status: Completed
• Phase: Phase 1
• First received: July 16, 2010
• Last updated: February 15, 2016
• Start date: August 2010
• Est. completion date: March 2015

Study information

• Verified date: February 2016
• Source: Centre Oscar Lambret
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: March 2015
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 6 Months to 21 Years

Eligibility

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)

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Glioma

Intervention

Drug:
• Cilengitide dose escalation
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
• Cilengitide
Patients will be treated at the recommended dose in order to confirm the recommended cilengitide dose and to carry out the exploratory investigations

Radiation:
• Concomitant radiotherapy
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.

Biological:
• Pharmacokinetic
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.
• Pharmacogenetic
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.
• Exploratory investigation
Evaluate the metabolic impact of the treatment with dynamic MRI (diffusion, perfusion, spectro), and with FDG-PETand sestamibi SPECT.

Locations

Country	Name	City	State
France	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	Centre Hospitalier Universitaire de Nantes	Nantes
France	Institut Curie	Paris
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
France	CHU	Toulouse
France	Institut Gustave-Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Centre Oscar Lambret

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Safety profile of the Cilengitide	toxicities (NCI-CTCAE v4.0)	During all the study	Yes
Secondary	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	No
Secondary	estimate efficacy in terms of response according to histopathology	WHO criteria	Every 3 cycles	No
Secondary	Progression-free and overall survival	6-month-PFS overall survival	During all the study	No