Please select the eligibility criteria that correspond to the clinical trial below.
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
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 .


Options:
A: Inclusion Criteria-

Among other criteria, patients must meet the following conditions to be eligible for the study:

1. Adult patients, ≥ 18 years old
2. Newly diagnosed glioblastoma
3. Attempted surgical resection followed by conventional chemoradiation
4. Documented EGFRvIII positive tumor status by a Sponsor designated laboratory
5. No evidence of progressive disease from the post-operative period to the post-chemoradiation period
6. Candidate for, and agrees to receive, adjuvant (maintenance) temozolomide therapy
7. Systemic corticosteroid therapy at ≤2 mg of dexamethasone or equivalent per day for at least 3 days prior to randomization
8. WHO-ECOG Performance Status ≤ 2
9. Patients of childbearing/reproductive potential will be instructed to use birth control as defined by your doctor.

Exclusion Criteria-

Among other criteria, patients who meet the following conditions are NOT eligible for the study:

1. Stereotactic biopsy only (without further surgical resection)
2. Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease.
3. History, presence, or suspicion of metastatic disease
4. Patients who have received any additional treatment for glioblastoma, aside from surgical resection and chemoradiation with temozolomide
5. Active systemic infection requiring treatment
6. History of any malignancy (other than glioblastoma) during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer, cured, early-stage prostate cancer in a patient with PSA level less than ULN,or other carcinoma in situ that has been adequately treated and cured.
7. Planned major surgery
8. Evidence of current drug or alcohol abuse
9. Known allergy or hypersensitivity to keyhole limpet hemocyanin (KLH), GM-CSF (sargramostim; LEUKINE®), polysorbate 80 or yeast derived products, or a history of anaphylactic reactions to shellfish proteins
10. Severe acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with participating in a clinical trial
11. Women who are pregnant or lactating
B: 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)
C: Inclusion Criteria:

1. Pathological evidence of GBM using WHO classification criteria.
2. \> 18 years of age.
3. Received maximal debulking surgery and radiotherapy concomitant with Temozolomide (45-70Gy):

   1. Patients may enroll in the study if received Gliadel wafers before entering the trial
   2. Any additional treatments received prior to enrollment will be considered an exclusion.
   3. Minimal dose for concomitant radiotherapy is 45 Gy
4. Karnofsky scale ≥ 70
5. Life expectancy at least 3 months
6. Participants of childbearing age must use effective contraception.
7. All patients must sign written informed consent.
8. Treatment start date at least 4 weeks out from surgery.
9. Treatment start date at least 4 weeks out but not more than 7 weeks from the later of last dose of concomitant Temozolomide or radiotherapy.

Exclusion Criteria:

1. Progressive disease (according to MacDonald Criteria). If pseudoprogression is suspected, additional imaging studies must be performed to rule out true progression.
2. Actively participating in another clinical treatment trial
3. Pregnant
4. Significant co-morbidities at baseline which would prevent maintenance Temozolomide treatment:

   1. Thrombocytopenia (platelet count \< 100 x 103/μL)
   2. Neutropenia (absolute neutrophil count \< 1.5 x 103/μL)
   3. CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)
   4. Significant liver function impairment - AST or ALT \> 3 times the upper limit of normal
   5. Total bilirubin \> upper limit of normal
   6. Significant renal impairment (serum creatinine \> 1.7 mg/dL)
5. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
6. Infra-tentorial tumor
7. Evidence of increased intracranial pressure (midline shift \> 5mm, clinically significant papilledema, vomiting and nausea or reduced level of consciousness)
8. History of hypersensitivity reaction to Temozolomide or a history of hypersensitivity to DTIC.
D: Key Inclusion Criteria:

* newly diagnosed glioblastoma
* World Health Organization (WHO) performance status less than or equal to (\<=2)
* stable or decreasing corticosteroid dose within 5 days prior to randomization

Key Exclusion Criteria:

* evidence of recent hemorrhage on postoperative magnetic resonance imaging (MRI) of brain
* any prior chemotherapy or immunotherapy for glioblastomas and low grade astrocytomas
* any prior radiotherapy to brain
* clinically significant cardiovascular disease
* history of greater than or equal to (\>=) grade 2 hemoptysis within 1 month prior to randomization
* previous centralized screening for Methylguanine-DNA methyltransferase (MGMT) status for enrollment into a clinical trial

Answer: B