Evaluation of the Irinotecan/Bevacizumab Association for Naive Unresectable Glioblastoma

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”

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 .

Intervention(s) in this Clinical Trial

• Drug: Avastin + Campto / radiotherapy + Temodal + Avastin (4 cures)
• Drug: Temodal/radiotherapy

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Bevacizumab/Irinoecan
• Active Comparator: Stupp

Primary Measures

• 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
    Safety Issue?: Yes

Secondary Measures

• To determine if bevacizumab-based regimen increases the overall survival in comparison of the Stupp regimen
  • Time Frame: december 2011
    Safety Issue?: Yes
• 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.
  • Time Frame: december 2011
    Safety Issue?: No
• 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)
  • Time Frame: december 2011
    Safety Issue?: Yes

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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Centre Georges Francois Leclerc Other

Overall Clinical Trial Officials and Contacts

Bruno Chauffert Principal Investigator Centre Georges Francois Leclerc  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01022918

Study ID Number: TemAvIr

ClinicalTrials.gov Identifier: NCT01022918

Health Authority: France: Afssaps - French Health Products Safety Agency