A Study of Avastin (Bevacizumab) And Fotemustine in Patients With Recurrent Glioblastoma
- Conditions
- Glioblastoma Multiforme
- Interventions
- Registration Number
- NCT01474239
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This randomized, non-comparative study will evaluate the efficacy and safety of Avastin (bevacizumab) in patients with recurrent glioblastoma. Patients will be randomized to receive Avastin 10 mg/kg intravenously every 2 weeks or fotemustine 75 mg/m2 on days 1, 8 and 15, followed by, after a 5 weeks interval, 100 mg/m2 intravenously every 3 weeks. Treatment with fotemustine serves as a calibration arm and no formal efficacy comparison will be made between the two treatment arms. The anticipated time of study treatment is until disease progression or unacceptable toxicity.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 91
- Adult patients, >/=18 years of age
- Diagnosis of recurrent glioblastoma multiforme (Grade IV)
- Previous treatment with temozolomide and radiotherapy
- First recurrence after standard adjuvant treatment (surgery, followed by radiotherapy and chemotherapy)
- Adequate hematological, biochemical and organ functions
- Previous treatment with Avastin or other anti-angiogenic drugs
- Residual relevant toxicity resulting from previous therapy
- Radiotherapy within the 3 months prior to the diagnosis of disease progression
- Chemotherapy in the previous 4 weeks
- Other active or inactive malignancies (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma)
- Clinically significant cardiovascular diseases
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Investigational Arm bevacizumab [Avastin] - Calibration Arm fotemustine -
- Primary Outcome Measures
Name Time Method Percentage of Participants Alive 6 Months After Start of Treatment 6 months Overall survival (OS) was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of magnetic resonance imaging (MRI) assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Overall Survival (OS) Baseline until death (up to 691 days) OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Who Were Alive and Progression Free 6 Months After Start of Treatment 6 months Progression-free survival (PFS) was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using Response Assessment in Neuro-Oncology (RANO) or Macdonald Response Criteria, whichever occurred first. As per the RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per the Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.
Progression-Free Survival (PFS) Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days) PFS was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by the Kaplan-Meier method. Progression was assessed using the RANO or the Macdonald Response Criteria, whichever occurred first. As per RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.
Percentage of Participants Alive 9 Months After Start of Treatment 9 months OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Percentage of Participants Alive 12 Months After Start of Treatment 12 months OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Percentage of Participants Alive 30 Days After Last Dose of Study Drug 30 days after last dose of study drug (up to Day 600) OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by the Kaplan-Meier method.
Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days) Percentage of participants achieving CR or PR as overall response between first drug administration and documented disease progression were calculated. Tumor response was evaluated according to both the RANO and the Macdonald response criteria. As per Macdonald criteria, CR was defined as the disappearance of all enhancing disease, sustained for at least 4 weeks, and no new lesions along with clinical features of clinically stable or improved, with no corticosteroid; PR was defined as a 50% or more decrease of all measurable enhancing lesions, sustained for at least 4 weeks, and no new lesion along with clinical features of clinically stable or improved, with stable or reduced corticosteroids. RANO criteria defined CR and PR the same as Macdonald criteria with the following additions: CR - improved non enhancing T2/FLAIR lesions; PR - no progression of non-measurable disease, stable or improved non enhancing FLAIR/T2 lesions.
Change From Screening in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores at Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72 Screening, Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72 EORTC QLQ-C30: included global health status/quality of life (QOL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; a higher score for Global QOL/functional scales indicates better level of QOL/functioning, or a higher score for symptom scale indicates greater degree of symptoms.
Percentage of Participants With Corticosteroid Initiation During the Study Period Baseline until recurrence (up to 691 days) Corticosteroid initiation was assessed in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage greater than equal to (\>/=) 2 mg dexamethasone equivalent.
Time to Corticosteroid Initiation Baseline until recurrence (up to 691 days) Time to corticosteroid initiation was defined as the time from screening to the start date of the first corticosteroid administration in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage ≥2 mg dexamethasone equivalent. Instead, if the participant was not known to have the event, time was censored at the last available visit date. Time to corticosteroid initiation was estimated using Kaplan Meier method.
Percentage of Participants in Each Class of Corticosteroid Use Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, post-treatment follow-up (up to Day 691) Corticosteroid use was classified as: 1. No Change (if corticosteroid dose at each assessment was equal to baseline); 2. Decreased (if corticosteroid dose at each assessment was lower than baseline); 3. Increased (corticosteroid dose at each assessment was greater than baseline).
Percentage of Participants With Karnofsky Performance Status (KPS) Deterioration Baseline until KPS deterioration (up to 691 days) Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks.
Time to Karnofsky Performance Status (KPS) Deterioration Baseline until KPS deterioration (up to 691 days) Time to KPS deterioration was defined as the time from screening to the first date of deterioration of the KPS score. Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Time to KPS deterioration was estimated using Kaplan Meier method. If the participant was not known to have the event, time was censored at the last available visit date.
Percentage of Participants With World Health Organization (WHO) Performance Status (PS) Deterioration Baseline until WHO PS deterioration (Up to 691 days) WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks.
Time to WHO PS Deterioration Baseline until WHO PS deterioration (Up to 691 days) Time to WHO PS deterioration was defined as the time from randomization to the first date of deterioration of the WHO performance status score. WHO PS deterioration was defined as a decrease of at least 1 point with respect to the screening value. WHO PS is a 6-level score which ranges between 0 (fully active) to 5 (death); a lower score represents a higher ability to perform daily tasks.