A Study of Bevacizumab and Extended Treatment of Temozolomide in Patients With Recurrent Glioblastoma Multiforme

Study Overview
=================
Brief Summary
-----------------
This is a Phase II, national, multicenter, open-label, non-comparative study to investigate the efficacy and safety of bevacizumab and temozolomide in patients with recurrent glioblastoma multiforme (GBM) after a first treatment failure. Patients will receive bevacizumab 10 mg/kg intravenously every two weeks until disease progression, consent withdrawal, or unacceptable toxicity. Anticipated time on study treatment is 12-24 months.

Official Title
-----------------
A Single Arm Phase II Study of Bevacizumab and Extended Treatment of Temozolomide in Patients With Recurrent Glioblastoma Multiforme

Conditions
-----------------
Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Drug: bevacizumab [Avastin]
* Drug: temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >= 18 years Histological diagnosis of glioblastoma multiforme (GBM) documented by surgical resection or biopsy. They should be patients in a first relapse treated with radiotherapy and chemotherapy and chemotherapy based on temozolomide 150-200 mg/m2 on days 1 to 5 every 28 days (Stupp regimen) for at least three cycles. At least 4 weeks must have lapsed since previous chemotherapy and 3 months since the last dose of radiotherapy. Use of an effective contraceptive method by patients and their partners. Stable or decreasing corticosteroid dose for the five days prior to study entry Adequate hematological function Adequate liver function Adequate kidney function Exclusion Criteria: Signs of recent bleeding at the MRI of the brain. However, patients with clinically asymptomatic presence of hemosiderin, resolving bleeding changes related to surgery, and presence of punctate hemorrhage in the tumor will be allowed to participate in the study. Prior treatment with bevacizumab Poorly controlled arterial hypertension History of hypertensive crises or hypertensive encephalopathy New York Health Association (NYHA) Class II or higher congestive heart failure History of myocardial infarction or unstable angina pectoris within six months of study entry History of stroke or TIA within six months of study entry Significant vascular disease within six months of study entry History of hemoptysis > grade 2 according to the NCI CTC criteria within one month of study entry Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) Major surgery, open biopsy, intracranial biopsy, ventriculoperitoneal shunt, or major traumatic lesion within 28 days of study entry. Core needle biopsy (excluding intracranial biopsy) or other minor surgery within seven days of randomization. Placement of a central vascular access device (CVAD) if performed in the two days prior to bevacizumab administration History of abdominal fistula or gastrointestinal perforation within six months of study entry History of intracranial abscess within six months of randomization Any prior malignant neoplasm treated with curative intent in the five years prior to study entry, except for adequately controlled limited basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix Patients with any other metabolic or psychological disease Hypersensitivity to products derived from Chinese hamster ovary cells or to other humanized or recombinant human antibodies

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: bevacizumab [Avastin]<br>* Bevacizumab 10 mg/kg body weight will be administered intravenously every two weeks<br>Drug: temozolomide<br>* Daily by the oral route (dose, 150 mg/m2) on days 1 to 7 and 15 to 21 of each cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) - Percentage of Participants With an Event | PFS was defined as the time, in weeks, from the date of inclusion in the study to the date of the first documentation of disease progression or death of the participant due to any cause. Participants that did not have an event at the time the analysis was performed were censored at the date of last contact. Participants that began a treatment other than those planned in this study (bevacizumab or temozolomide) were censored on the start date of the new treatment. | Baseline (BL), every 28 days, until progression, death or end-of-study, an average of 32 weeks | 
| PFS - Time to Event | PFS was defined as the time, in weeks, from the date of inclusion in the study to the date of the first documentation of disease progression or death of the participant due to any cause. Participants that did not have an event at the time the analysis was performed were censored at the date of last contact. Participants that began a treatment other than those planned in this study (bevacizumab or temozolomide) were censored on the start date of the new treatment. PFS was estimated using the Kaplan-Meier method. | BL, every 28 days, until progression, death or end-of-study, an average of 32 weeks | 
| PFS: Probability of Remaining Progression Free at 24 Weeks After Beginning the Study |  | BL, 24 weeks (after 6th cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival - Percentage of Participants With an Event | Overall survival was defined as the time transpired (in weeks) between the date of the participant's inclusion in the trial until the date of his/her death by any cause. Participants that were alive at the time the analysis was performed were censored on the date of last contact. | BL, every 28 days, until death or end-of-study, an average of 32 weeks | 
| Overall Survival - Time to Event | Overall survival was defined as the time transpired (in weeks) between the date of the participant's inclusion in the trial until the date of his/her death by any cause. Participants that were alive at the time the analysis was performed were censored on the date of last contact. Median overall survival was estimated using the Kaplan-Meier method. | BL, every 28 days, until death or end-of-study, an average of 32 weeks | 
| Percentage of Participants Achieving an Overall Response of Complete Response (CR) or Partial Response (PR) | Overall response was defined as the percentage of participants who obtained CR or PR using adapted MacDonald criteria. CR: disappearance of all index and non-index lesions, confirmed no less than 4 weeks after assessment, no evidence of disease progression; corticosteroid dosage at or below 20 mg hydrocortisone daily; no neurological changes or an improvement as compared to last disease assessment. PR was defined as: Fifty percent or greater decrease in the sum of products of the larger diameter and the larger perpendicular diameter of all index lesions confirmed no less than 4 weeks after assessment, no evidence of disease progression and the absence of progressive, or non-evaluable disease status for non-index legions; unchanged, or decreased corticosteroid dose as compared to the last disease assessment; no neurological changes or an improvement as compared to the neurological examination at last disease assessment. | BL, every 28 days, until progression, death or end-of-study, an average of 32 weeks |