Bevacizumab and Lomustine for Recurrent GBM

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

592 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-10-31

Study Completion Date

2020-04-30

Brief Summary

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RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as lomustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which regimen of bevacizumab given together with lomustine is most effective in treating patients with glioblastoma multiforme in first recurrence.

PURPOSE: The primary objective of this study is to investigate whether the addition of bevacizumab to lomustine improves overall survival (OS) in patients with recurrent glioblastoma compared to treatment with lomustine alone.

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Detailed Description

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OBJECTIVES:

* To determine the therapeutic role of bevacizumab as well as the most favorable approach to treatment optimization for sequencing the combination of bevacizumab and lomustine in patients with glioblastoma multiforme in first recurrence.

OUTLINE: This is a multicenter study. Patients are stratified according to institution, WHO performance status (0 vs \> 0), steroid administration (yes vs no), and largest diameter of tumor (≤ 40 mm vs \> 40 mm). Patients are randomized at 2:1 ratio to 1 of 2 treatment arms.

* Arm 1: Lomustine 90 mg/m² every 6 weeks (cap. 160 mg) + bevacizumab 10 mg/kg every 2 weeks (at further progression treatment will be according to investigators discretion). In the absence of hematological toxicity \> grade 1 during the first cycle the dose of lomustine can be escalated to 110 mg/m² (cap 200 mg) in their second cycle.
* Arm 2 (control arm): Lomustine single agent 110 mg/m² every 6 weeks (cap. 200 mg) (at further progression treatment will be according to investigators discretion).

One cycle will be defined arbitrarily (due to the lomustine sequencing) as 6 weeks for all arms. Day 1 of a cycle will be the first day when medication is taken.

Previously collected blood and tumor tissue samples are analyzed for MGMT methylation status, isocitrate dehydrogenase 1, and biomarkers of the VEGF pathway.

Patients and their caregivers/relatives complete quality-of-life questionnaires (EORTC QLQ-C30 and EORTC-BN20) at baseline, at 12 weeks, and then every 12 weeks after completion of study therapy. Patients also undergo neurocognitive assessment at baseline, at 12 weeks, and then every 12 weeks after completion of study therapy.

After completion of study treatment, patients are followed every 12 weeks.

Conditions

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Glioblastoma Multiforme Cognition Disorders Disability Evaluation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm 1

Lomustine 90 mg/m² every 6 weeks (cap. 160 mg) + bevacizumab 10 mg/kg every 2 weeks (at further progression treatment will be according to investigators discretion). In the absence of hematological toxicity \> grade 1 during the first cycle the dose of lomustine can be escalated to 110 mg/m² (cap 200 mg) in their second cycle.

Group Type EXPERIMENTAL

bevacizumab

Intervention Type BIOLOGICAL

lomustine

Intervention Type DRUG

DNA methylation analysis

Intervention Type GENETIC

laboratory biomarker analysis

Intervention Type OTHER

cognitive assessment

Intervention Type PROCEDURE

quality-of-life assessment

Intervention Type PROCEDURE

Arm 2

Lomustine single agent 110 mg/m² every 6 weeks (cap. 200 mg) (at further progression treatment will be according to investigators discretion).

Group Type ACTIVE_COMPARATOR

lomustine

Intervention Type DRUG

DNA methylation analysis

Intervention Type GENETIC

laboratory biomarker analysis

Intervention Type OTHER

cognitive assessment

Intervention Type PROCEDURE

quality-of-life assessment

Intervention Type PROCEDURE

Interventions

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bevacizumab

Intervention Type BIOLOGICAL

lomustine

Intervention Type DRUG

DNA methylation analysis

Intervention Type GENETIC

laboratory biomarker analysis

Intervention Type OTHER

cognitive assessment

Intervention Type PROCEDURE

quality-of-life assessment

Intervention Type PROCEDURE

Eligibility Criteria

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Inclusion Criteria

* No evidence of active infection requiring hospitalization or antibiotics, within 2 weeks prior to randomization.
* No other diseases, interfering with follow up.
* Normal hematological functions: neutrophils ≥ 1.5 x 109 cells/l, platelets ≥ 100 x 109 cells/l and Hb ≥ 6.2 mmol/l (9.9 g/dl).
* Normal liver function: bilirubin \< 1.5 x upper limit of the normal range (ULN), alkaline phosphatase and transaminases (ASAT) \< 2.5 x ULN.
* Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance \> 30 mL/min; 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.
* Age ≥ 18 years
* WHO Performance status 0 - 2
* Absence of pregnancy. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and 6 months beyond stop of treatment in such a manner that the risk of pregnancy is minimized. In general, the decision for appropriate methods to prevent pregnancy should be determined by discussions between the investigator and the study subject. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Females should not be breast feeding.
* Post menopause is defined as: amenorrhea ≥ 12 consecutive months without another cause or for women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL
* Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicide) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.
* Women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
* Female patients within one year of entering the menopause must agree to use an effective non-hormonal method of contraception during the treatment period and for at least 6 months after the last study treatment.
* Males must agree to use an effective method of contraception during the treatment period and for at least 6 months after the last study treatment.
* Absence of any psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; such conditions should be assessed with the patient before randomization in the trial.
* Before patient randomization and study related procedures (that would not have been performed as part as standard care), written informed consent must be given according to ICH/GCP, and national/local regulations. Informed consent should also be given for biological material to be stored and used for future research on brain tumors.
* Patients with a buffer range from the normal values of +/- 5 % for hematology and +/- 10% for biochemistry are acceptable. A maximum of +/- 2 days for timelines may be acceptable (one day for post operative MRI).

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No