search
Back to results

Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma (CILENT-0902)

Primary Purpose

Diffuse Intrinsic Pontine Glioma

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Cilengitide dose escalation
Cilengitide
Concomitant radiotherapy
Pharmacokinetic
Pharmacogenetic
Exploratory investigation
Sponsored by
Centre Oscar Lambret
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Intrinsic Pontine Glioma focused on measuring Paediatric oncology, Cilengitide, Glioma

Eligibility Criteria

6 Months - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Hôpital des Enfants, Groupe Hospitalier
  • Centre Oscar Lambret
  • Centre Léon Bérard
  • CHU, Hôpital d'Enfants de la Timone
  • Centre Hospitalier Universitaire de Nantes
  • Institut Curie
  • Hôpitaux Universitaires de Strasbourg
  • CHU
  • Institut Gustave-Roussy

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Dose escalation

Cohort extension

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Safety profile of the Cilengitide
toxicities (NCI-CTCAE v4.0)
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
estimate efficacy in terms of response according to histopathology
WHO criteria
Progression-free and overall survival
6-month-PFS overall survival

Full Information

First Posted
July 16, 2010
Last Updated
February 15, 2016
Sponsor
Centre Oscar Lambret
search

1. Study Identification

Unique Protocol Identification Number
NCT01165333
Brief Title
Cilengitide in Combination With Irradiation in Children With Diffuse Intrinsic Pontine Glioma
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
August 2010 (undefined)
Primary Completion Date
January 2014 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Oscar Lambret

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Intrinsic Pontine Glioma
Keywords
Paediatric oncology, Cilengitide, Glioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
32 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose escalation
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort extension
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Cilengitide dose escalation
Other Intervention Name(s)
Cilengitidine
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Cilengitide
Other Intervention Name(s)
cilengitidine
Intervention Description
Patients will be treated at the recommended dose in order to confirm the recommended cilengitide dose and to carry out the exploratory investigations
Intervention Type
Radiation
Intervention Name(s)
Concomitant radiotherapy
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Pharmacokinetic
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Pharmacogenetic
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Exploratory investigation
Intervention Description
Evaluate the metabolic impact of the treatment with dynamic MRI (diffusion, perfusion, spectro), and with FDG-PETand sestamibi SPECT.
Primary Outcome Measure Information:
Title
Determination of the Maximal Tolerated Dose of Cilengitide
Description
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
Secondary Outcome Measure Information:
Title
Safety profile of the Cilengitide
Description
toxicities (NCI-CTCAE v4.0)
Time Frame
During all the study
Title
study of the pharmacoKinetic profile of Cilengitide
Description
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
Title
estimate efficacy in terms of response according to histopathology
Description
WHO criteria
Time Frame
Every 3 cycles
Title
Progression-free and overall survival
Description
6-month-PFS overall survival
Time Frame
During all the study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pierre LEBLOND, MD
Organizational Affiliation
Centre Oscar Lambret
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital des Enfants, Groupe Hospitalier
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
Centre Oscar Lambret
City
Lille
ZIP/Postal Code
59020
Country
France
Facility Name
Centre Léon Bérard
City
Lyon
ZIP/Postal Code
69373
Country
France
Facility Name
CHU, Hôpital d'Enfants de la Timone
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
Centre Hospitalier Universitaire de Nantes
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Institut Curie
City
Paris
ZIP/Postal Code
75231
Country
France
Facility Name
Hôpitaux Universitaires de Strasbourg
City
Strasbourg
ZIP/Postal Code
67091
Country
France
Facility Name
CHU
City
Toulouse
ZIP/Postal Code
33059
Country
France
Facility Name
Institut Gustave-Roussy
City
Villejuif
ZIP/Postal Code
94805
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs