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Evaluation of the Irinotecan/Bevacizumab Association for Naive Unresectable Glioblastoma (TemAvIr)

Primary Purpose

Naive Unresectable Glioblastoma

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Avastin + Campto / radiotherapy + Temodal + Avastin (4 cures)

Temodal/radiotherapy

About this trial

This is an interventional treatment trial for Naive Unresectable Glioblastoma focused on measuring unresectable glioblastoma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

All the eligibility criteria must be met before registration :

delay upper or equal to 14 days from stereotaxic biopsy and 28 days from surgical biopsy
Histopathologically proven diagnosis of glioblastoma (WHO grade IV astrocytoma)
Patient belonging to the RPA V class or associated
only supratentorial glioblastoma
Diagnosis must be obtained by a stereotactic or surgical biopsy
Age between 18 and 70
A contrast-enhanced MRI must be performed within 28 days prior to study registration
Total or partial surgical resection deemed as not possible by a neurosurgeon
Karnofsky Index (KI) performance status over 50
Life expectancy of at least 3 months
A stable dose of corticosteroid for at least 7 days to control intracranial pressure and neurological symptoms
Adequate blood function : absolute neutrophil count > 1.5 x 109/L, platelets count > 100 x 109/L platelets; hemoglobin > 10 g/dl after blood transfusion if required
Adequate liver function: bilirubin < 1.5 ULN (upper limit of normal), ALT and AST < 2.5 ULN, Prothrombin rate > 75 %
Adequate renal function: creatinine < 1.2 ULN; proteinuria test 0 or trace (or urine protein concentration < 1g/24h if proteinuria test is + or ++).
Negative pregnancy test for women of childbearing potential and adequate contraception for men and women.
systolic arterial blood pressure at rest ≤ 170 mmHg
Patient must have been informed and must have signed the specific informed consent form.
holder of a coverage by the health insurance

Exclusion Criteria:

patient belonging to the RPA III or IV
prior malignant tumor in the recent 5 years or concomitant malignancy
prior anti-tumoral chemotherapy or radiotherapy
prior gross resection of the brain tumor
patient receiving gliadel
cardiovascular contra-indications to bevacizumab : prior angina pectoris, prior myocardial infarction, prior brain stroke, even transient, distal severe arteriopathy, uncontrolled high blood pressure
anticomitial drug p450 cytochrome inductors
other substances inducing p450 cytochrome
proteinuria ≥ 1g/L
concurrent anticoagulant or platelet anti-aggregant treatment
congenital haemorrhagic pathology (haemophilia, Willebrandt)
sign of brain haemorrhage on the RMI initial exam
non resolved infectious disease
non controlled arterial hypertension (≥170 mmHg)
intracranial high pressure not controlled by a stable dose of steroids for at least 7 days
pregnancy or refusal of the contraception for women and men
psychiatric, behavioural disorders or geographical situation precluding the administration or follow-up of the protocol (including claustrophobia)
digestive haemorrhage and / or gastro-duodenal ulcer occurring in the last 3 months
pregnant, nursing woman, or without contraception
private individuals of freedom or under tutelage (including legal guardianship)

Sites / Locations

Centre Georges François Leclerc

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Bevacizumab/Irinoecan

Stupp

Arm Description

Neoadjuvant Treatment Patient will receive bevacizumab 10mg/kg plus irinotecan 125mg/m² 4 times every two weeks. Radiochemotherapy Then they will receive conformational radiotherapy for 6 weeks (30 Gy, 2Gy/fractions) associated with Temodal ( 75mg/m²/day) from first day up to the end of radiotherapy and 4 injections of Avastin (15mg/kg Day 1, day 15, day 29 and day 43). Adjuvant treatment: Patients will receive bevacizumab 15mg/kg plus irinotecan 125mg/m² 12 times every two weeks.

patient will receive 6 weeks chemotherapy treatment associating conformational 30 Gy (2Gy/ fraction)and Temodal(75mg/m²/day, followed by 6 months adjuvant therapy consisting in 5 days every 28 days of Temodal (150-200mg/m².

Outcomes

Primary Outcome Measures

To determine the rate of non-progressive disease at 6 months after inclusion in each arms

Secondary Outcome Measures

To determine if bevacizumab-based regimen increases the overall survival in comparison of the Stupp regimen

To evaluate if any bevacizumab-based regimen increases the survival without neurologic degradation and the quality of life according to the QLC-C30 and the specific Brain Cancer Module QLQ-BN20 scales.

To evaluate the tolerance of the bevacizumab-based regimens according to the NCI-CTCAE, version 3.0 scale. To record the rate of serious adverse events (mainly the theoretical risk of brain hemorrhage with bevacizumab)

Full Information

NCT ID

NCT01022918

First Posted

November 26, 2009

Last Updated

September 24, 2012

Sponsor

Centre Georges Francois Leclerc

Collaborators

National Cancer Institute, France, Association de Neuro-Oncologues d'Expression Francaise, UNICANCER, Hoffmann-La Roche, Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT01022918

Brief Title

Evaluation of the Irinotecan/Bevacizumab Association for Naive Unresectable Glioblastoma

Acronym

TemAvIr

Official Title

Evaluation of the Irinotecan/Bevacizumab Association as Neo-adjuvant and Adjuvant Treatment of Chemoradiation With Temozolomide for Naive Unresectable Glioblastoma. Phase II Randomized Study With Comparison to Chemoradiation With Temozolomide

Study Type

Interventional

2. Study Status

Record Verification Date

September 2012

Overall Recruitment Status

Completed

Study Start Date

January 2009 (undefined)

Primary Completion Date

July 2010 (Actual)

Study Completion Date

January 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Georges Francois Leclerc

Collaborators

National Cancer Institute, France, Association de Neuro-Oncologues d'Expression Francaise, UNICANCER, Hoffmann-La Roche, Pfizer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Treatment of glioblastoma (GBM) is based on surgery when possible, and chemoradiation with temozolomide, which became a standard since the EORTC study (Stupp, 2005). However, the prognosis of unresectable GBM remains poor despite chemoradiation with an estimated 10 month median survival, in the range of the comparable patients in the RPA class V from the EORTC study (Miramanoff, 2006). Vredenburgh et al. from the Duke University (Durham, NC) reported at ASCO 2006 (fully published in J Clin Oncol, 2007) a 57 % unexpected response rate using a bevacizumab/irinotecan schedule in patients with relapsed GBM or grade 3 astrocytomas. This unusual high response rate, sometimes with major and sustained responses, was confirmed by a cooperative french study of ANOCEF (Guiu et al., 2008). Such a major improvement of treatment effectiveness lead ANOCEF, which federates most of the active neuro-oncology teams in France, to propose a neo-adjuvant and adjuvant bevacizumab-based chemotherapy framing a standard temozolomide-based chemoradiation with the aim to improve the prognosis of unresectable GBM. The bevacizumab/temozolomide combination as neo-adjuvant is presently being evaluated by the Duke University. We believe that an ambitious comparison of the bevacizumab/irinotecan-schedule with the ''standard'' temozolomide-based chemoradiation is a fascinating challenge to improve the treatment of this awful disease. The ANOCEF proposal '' Evaluation of the irinotecan/bevacizumab association as neo-adjuvant and adjuvant treatment of chemoradiation with temozolomide for naive unresectable glioblastoma. Phase II randomized study with comparison to chemoradiation with temozolomide'' has been successfully granted by INCA (Institut National du Fancer, France) through its research program ( PHRC : Programme Hospitalier de Recherche Clinique). Implementation of this program is now starting .

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Naive Unresectable Glioblastoma

Keywords

unresectable glioblastoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

134 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bevacizumab/Irinoecan

Arm Type

Experimental

Arm Description

Arm Title

Stupp

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Avastin + Campto / radiotherapy + Temodal + Avastin (4 cures)

Intervention Type

Drug

Intervention Name(s)

Temodal/radiotherapy

Primary Outcome Measure Information:

Title

To determine the rate of non-progressive disease at 6 months after inclusion in each arms

Time Frame

after half of each arms has been completed at 6 months of treatment

Secondary Outcome Measure Information:

Title

To determine if bevacizumab-based regimen increases the overall survival in comparison of the Stupp regimen

Time Frame

december 2011

Title

Time Frame

december 2011

Title

Time Frame

december 2011

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: All the eligibility criteria must be met before registration : delay upper or equal to 14 days from stereotaxic biopsy and 28 days from surgical biopsy Histopathologically proven diagnosis of glioblastoma (WHO grade IV astrocytoma) Patient belonging to the RPA V class or associated only supratentorial glioblastoma Diagnosis must be obtained by a stereotactic or surgical biopsy Age between 18 and 70 A contrast-enhanced MRI must be performed within 28 days prior to study registration Total or partial surgical resection deemed as not possible by a neurosurgeon Karnofsky Index (KI) performance status over 50 Life expectancy of at least 3 months A stable dose of corticosteroid for at least 7 days to control intracranial pressure and neurological symptoms Adequate blood function : absolute neutrophil count > 1.5 x 109/L, platelets count > 100 x 109/L platelets; hemoglobin > 10 g/dl after blood transfusion if required Adequate liver function: bilirubin < 1.5 ULN (upper limit of normal), ALT and AST < 2.5 ULN, Prothrombin rate > 75 % Adequate renal function: creatinine < 1.2 ULN; proteinuria test 0 or trace (or urine protein concentration < 1g/24h if proteinuria test is + or ++). Negative pregnancy test for women of childbearing potential and adequate contraception for men and women. systolic arterial blood pressure at rest ≤ 170 mmHg Patient must have been informed and must have signed the specific informed consent form. holder of a coverage by the health insurance Exclusion Criteria: patient belonging to the RPA III or IV prior malignant tumor in the recent 5 years or concomitant malignancy prior anti-tumoral chemotherapy or radiotherapy prior gross resection of the brain tumor patient receiving gliadel cardiovascular contra-indications to bevacizumab : prior angina pectoris, prior myocardial infarction, prior brain stroke, even transient, distal severe arteriopathy, uncontrolled high blood pressure anticomitial drug p450 cytochrome inductors other substances inducing p450 cytochrome proteinuria ≥ 1g/L concurrent anticoagulant or platelet anti-aggregant treatment congenital haemorrhagic pathology (haemophilia, Willebrandt) sign of brain haemorrhage on the RMI initial exam non resolved infectious disease non controlled arterial hypertension (≥170 mmHg) intracranial high pressure not controlled by a stable dose of steroids for at least 7 days pregnancy or refusal of the contraception for women and men psychiatric, behavioural disorders or geographical situation precluding the administration or follow-up of the protocol (including claustrophobia) digestive haemorrhage and / or gastro-duodenal ulcer occurring in the last 3 months pregnant, nursing woman, or without contraception private individuals of freedom or under tutelage (including legal guardianship)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bruno Chauffert, Professor

Organizational Affiliation

Centre Hospitalier Universitaire, Amiens

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centre Georges François Leclerc

City

Dijon

State/Province

Bourgogne

ZIP/Postal Code

21000

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

24723487

Citation

Chauffert B, Feuvret L, Bonnetain F, Taillandier L, Frappaz D, Taillia H, Schott R, Honnorat J, Fabbro M, Tennevet I, Ghiringhelli F, Guillamo JS, Durando X, Castera D, Frenay M, Campello C, Dalban C, Skrzypski J, Chinot O. Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEFdagger. Ann Oncol. 2014 Jul;25(7):1442-1447. doi: 10.1093/annonc/mdu148. Epub 2014 Apr 9.

Results Reference

derived

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Evaluation of the Irinotecan/Bevacizumab Association for Naive Unresectable Glioblastoma

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