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van CCT (UK)

Bevacizumab versus bevacizumab plus lomustine versus lomustine in recurrent glioblastoma.

- candidate number6156
- NTR NumberNTR1929
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR27-jul-2009
- Secondary IDs2009-12186-63 EudraCT
- Public TitleBevacizumab versus bevacizumab plus lomustine versus lomustine in recurrent glioblastoma.
- Scientific TitleRandomized phase II study of Bevacizumab versus Bevacizumab plus Lomustine versus Lomustine in patients with recurrent Glioblastoma: The BELOB trial.
- hypothesisThe following hypothesis will be made:
1. P0 is the largest OS probability at 9 months which, if true, implies that the therapeutic activity of that regimen is too low. In the present trial, P0 has been taken as 35%;
2. P1 is the lowest OS probability at 9 months which, if true, implies that the therapeuticactivity of Bevacizumab-Lomustine combination is adequate. In the present trial, P1 has been taken as 55%;
3. α is the probability of accepting adequate activity of a drug with a true success rate equal to or lower than P0. In the present trial, α has been taken as 0.10;
4. β is the probability of rejecting adequate activity of a drug with a true success rate at least equal to P1. In the present trial, β has been taken as 0.10.

Under those hypotheses, based on a 1:1:1 randomization, the total sample size will be 44 eligible patients in each treatment arm, for a total of 132 eligible patients. A decision rule for activity will be performed amongst the 44 eligible patients enrolled in the each of the 3 treatment arms:
1. If ≤ 19 patients still alive at 9 months out of 44 are observed, the conclusion will be that the specific treatment arm should not be further investigated;
2. If ≥ 20 patients still alive at 9 months are observed, we will conclude that the specific treatment arm warrants further investigation.

No formal test of comparison between the three treatment arms will be performed.
- Healt Condition(s) or Problem(s) studiedBevacizumab , Recurrent glioblastoma, Lomustine
- Inclusion criteria1. Age ≥ 18 years;
2. WHO Performance status 0 - 2;
3. Histologically or biopsy proven glioblastoma multiforme including patients with anaplastic oligoastrocytomas with necrosis (which meets WHO 2007 criteria for glioblastoma;
4. First relapse after prior treatment with combined chemo-irradiation with temozolomide;
5. Patient may have undergone surgery for the recurrence. If operated, residual and measurable disease after surgery is not required but surgery must have confirmed the recurrence. In case of operation, post-operative MRI must be made within 48 hours following surgery. Minimum interval of at least 4 weeks between surgery and the start of Bevacizumab treatment, and patients should have fully recovered from the surgery;
6. For non operated patients, recurrent disease must be at least one bidimensionally measurable target lesion (contrast enhancing lesion) with one diameter of at least 2cm, based on MRI scan done within two weeks prior to start of treatment;
7. Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan;
8. No prior treatment with Lomustine or other nitrosourea’s;
9. No prior treatment with Bevacizumab or other VEGF-R signalling inhibitors;
10. No radiotherapy within the three months prior to the diagnosis of progression;
11. No chemotherapy in the past four weeks;
12. No radiotherapy with a dose over 65 Gy, stereotactic radiosurgery or brachytherapy unless the recurrence is histologically proven;
13. Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/l, platelets ≥100 x 109 cells/l, Hb ≥ 6.2 mmol/l;
14. Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT/ALAT) < 2.5 x ULN, INR < 1.5;
15. Normal renal function:
A. Calculated (Cockcroft-Gault) or measured creatinine clearance > 30 mL/min;
B. Urine dipstick for proteinuria < 2+. Patients with >2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate ≤1 g of protein/24 hr.
16. Women of reproductive potential, female patients within one year of entering the menopause as well as males must agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last dose of Bevacizumab;
17. No other diseases, interfering with follow up;
18. No geographical, psychological or other non-medical conditions interfering with follow-up;
19. Written informed consent.
- Exclusion criteria1. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding;
2. Arterial or venous thrombosis ≤ 12 months prior to registration;
3. History of myocardial infarction (≤ 6 months prior to inclusion), unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication;
4. Uncontrolled hypertension defined by a systolic pressure > 150 mm Hg and/or diastolic pressure > 100 mm Hg, with or without anti-hypertensive medication. Patients with initial blood pressure elevation are eligible if initiation or adjustment of anti-hypertensive medication lowers pressure to meet the entry criteria;
5. Current or recent (within 10 days of first dose of Bevacizumab) use of aspirin (> 325 mg/day) or other NSAID with anti-platelet activity or treatment with dipyramidole, ticlopidine, clopidogrel and cilostaz;
6. Use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic (as opposed to prophylactic) purposes;
7. Clinically serious (as judged by the investigator) non-healing wounds, active skin ulcers or incompletely healed bone fracture;
8. History of active gastroduodenal ulcer(s);
9. History of abdominal fistula as well as non-GI fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to inclusion;
10. Evidence of any active infection requiring hospitalization or antibiotics, within 2 weeks prior to day 1 of cycle 1;
11. Invasive procedures (major surgical procedure, open biopsy or significant traumatic injury) within 4 weeks prior to randomization, or anticipation of the need for major surgery during the course of the study treatment. Placement of a vascular access device is not considered as a major surgical procedure if performed more than 24 hours prior to Bevacizumab administration;
12. Current or recent (within 4 weeks of enrollment) treatment with another investigational drug or participation in another investigational study;
13. Known hypersensitivity to any part of the Bevacizumab formulation;
14. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibody;
15. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to randomization;
16. Previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in situ of the cervix and non-melanoma skin cancer.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 9-jan-2009
- planned closingdate1-aug-2011
- Target number of participants144
- InterventionsTreatment with Bevacizumab (Avastin) versus Bevacizumab and Lomustine versus Lomustine.
- Primary outcome9 month overall survival (9 mo OS).
- Secondary outcome1. Objective response rate;
2. Median PFS;
3. PFS at 6 months and 12 months;
4. Median Overall Survival (OS);
5. OS at 6 and 12 months;
6. Toxicity;
7. Neurological deterioration free survival;
8. Quality of Life;
9. Steroid use.
Response will only be assessed in patients with measurable disease.
- Timepoints1. 9 months OS;
2. Median PFS, PFS6, PFS12, OS6, OS12 and median OS, objective response rates and median duration of objective response;
3. Overall and progression free survival will be measured from the day of randomization;
4. End of study occurs when all of the following criteria have been satisfied:
A. The trial is mature for the analysis of the primary endpoint;
B. The database has been fully cleaned and locked for this analysis.
- Trial web siteN/A
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESProf. Dr. M.J. Bent, van den
- CONTACT for SCIENTIFIC QUERIESProf. Dr. M.J. Bent, van den
- Sponsor/Initiator Daniel den Hoed Cancer Center, Erasmus Medical Center, Rotterdam
- Funding
(Source(s) of Monetary or Material Support)
Roche Nederland BV, KWF Kankerbestrijding
- PublicationsN/A
- Brief summaryBevacizumab is currently registered in the US for use in recurrent glioblastoma. However, its effectiveness and the best use in this tumor type has bot been established, nor is it clear if this drug should be combined with other cytotoxic drugs to improve activity. This randomized phase II trial will explore the activity of bevacizumab and of bevacizumab with lomustine in recurrent glioblastoma. The primary endpoint is 9 months overall survival, with several progression free and overall survival measures as a secondary endpoint. Quality of life studies are incorporated to establish the clinical significance of so-called pseudo-responses that have been described in bevacizumab treated patients. Translational research studies are aiming to identify early responders.
- Main changes (audit trail)19-Nov-2010: Amendment 3.1 changed the study design from a two arm study into a three arm study, by adding a lomustine control arm. Because of that, the primary endpoint was changed into 9 months overall survival. This increases the total sample size from 86 patients to 144 patients - NM
- RECORD27-jul-2009 - 19-nov-2010

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