A Study of Avastin® (Bevacizumab) in Combination With Temozolomide and Radiotherapy in Patients With Newly Diagnosed Glioblastoma - Full Text View

Purpose

This 2 arm study investigated the efficacy and safety of the addition of bevacizumab (Avastin®) to the current standard of care (multimodality therapy of concurrent radiotherapy plus temozolomide followed by adjuvant temozolomide) as compared to the current standard of care alone. Patients were randomly assigned to either the Avastin® (10 mg/kg iv q2w) or the placebo arm, in combination with radiation therapy (total dose 60 Gy, administered as 2 Gy fractions, 5 days/week)plus temozolomide (75 mg/m2 po daily) for 6 weeks. After a 4 week treatment break, patients continued to receive Avastin® (10 mg/kg iv q2w) or placebo, plus temozolomide (150-200 mg/m2 po daily on days 1-5 of each 4 week cycle) for 6 cycles of maintenance treatment. Following the maintenance phase, Avastin® (15 mg/kg iv q3w) or placebo monotherapy was continued. The anticipated time on study treatment was until disease progression/unacceptable toxicity.

Condition	Intervention	Phase
Glioblastoma	Drug: bevacizumab [Avastin®] Drug: Placebo Drug: temozolomide Radiation: Radiation therapy	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment

Resource links provided by NLM:

Drug Information available for: Temozolomide Bevacizumab

U.S. FDA Resources

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:

Co-Primary: Progression-free Survival (PFS) as Assessed by Investigator [ Time Frame: Randomization until Progressive Free Survival Event [Until data cutoff= 31 March 2012 (up to 34 months)] ] [ Designated as safety issue: No ]
PFS was defined as the time from randomization to disease progression or death due to any cause.

Disease progression (PD) was assessed by the investigator using adapted Macdonald response criteria (modified World Health Organization (WHO) criteria) based on 3 components: radiological tumor assessments using Magnetic Resonance Imaging (MRI) scans, neurological assessment and changes in corticosteroid use.

PD was determined as ≥ 25% increase in the sum of the products of the perpendicular longest diameters of all index lesions (enhancing, measurable) compared with the smallest recorded sum (nadir) during the study or unequivocal progression of existing non-index lesions (non-enhancing and enhancing, non-measurable) or unequivocal appearance of new lesions); or neurological worsening (if corticosteroid dose is stable or increased) with no need for a confirmatory scan.

Data from the final analysis is presented.
Co-Primary: Overall Survival (OS) [ Time Frame: Randomization until Overall Survival Event ] [ Designated as safety issue: No ]
Overall Survival was defined as the time from randomization to death due to any cause.

Secondary Outcome Measures:

Progression-free Survival (PFS) as Assessed by an Independent Review Facility [ Time Frame: Randomization until Progressive Free Survival Event [Until data cutoff= 31 March 2012 (up to 34 months)] ] [ Designated as safety issue: No ]
An Independent Review Facility reviewed the magnetic resonance imaging (MRI) scans used by the investigator to evaluate radiological tumor response. PFS was defined as the time from randomization to disease progression or death due to any cause.
Percentage of Participants With One-Year Survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Percentage of participants who are still alive 1 year post randomization.
Percentage of Participants With Two-year Survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Percentage of participants who are still alive 2 years post randomization.
Duration of Stable/Improved Health Related Quality of Life (HRQoL) Using the European Organisation for Research and Treatment of Cancer Scales (EORTC) QLQ-C30 and BN20 [ Time Frame: Randomization until Progressive Free Survival Event [Until data cutoff= 31 March 2012 (up to 34 months)] ] [ Designated as safety issue: No ]
Stable and Improved HRQoL during PFS time was determined using the EORTC QLQ-C30 and BN20 questionnaires. The EORTC QLQ-C30 is a 30-item self-reported questionnaire in 5 functional scales (physical,role,emotional,cognitive,social), 3 symptoms scales, 6 single-item measures and a global health status/QoL scale.Patients rated the items on a 4-point scale: 1=not at all to 4=very much.Global health status/QoL items were rated on a 7-point scale: 1=very poor to 7=excellent. The BN20 consisted of 20 questions in 4 scales(future uncertainty,visual disorder,motor dysfunction,communication deficit) and 7 single-item measures rated on a 4-point scale: 1=not at all to 4=very much. A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100. Stable HRQoL was defined as a change from baseline within 10 points.Improved HRQoL is defined as an increase of at least 10 points for functioning/global health status and a decrease of at least 10 points for symptoms.
Number of Participants With Adverse Events, Serious Adverse Events and Death [ Time Frame: Until data cutoff= 31 March 2012 (up to 34 months) ] [ Designated as safety issue: No ]
An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events.

A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Enrollment:	921
Study Start Date:	June 2009
Estimated Study Completion Date:	October 2013
Primary Completion Date:	March 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Bevacizumab + RT+Temozolomide In the Concurrent Phase participants received radiotherapy (RT) in daily fractions of 2 Gy given 5 days per week for 6 week and temozolomide 75 mg/m^2 daily for a maximum of 49 days and bevacizumab 10 mg/kg intravenous (IV) every 2 weeks for 6 weeks. There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The participants then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.	Drug: bevacizumab [Avastin®] 10 mg/kg intravenously every 2 weeks in the Concurrent and Maintenance Phases. 15 mg/kg intravenously every 3 weeks in the Monotherapy Phase. Drug: temozolomide 75 mg/m2 once daily for 6 weeks, followed by 150-200 mg/m2 once daily on days 1-5 of each 6 x 4 week cycle. Radiation: Radiation therapy 30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks
Placebo Comparator: Placebo + RT+ Temozolomide In the Concurrent Phase participants received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 week and temozolomide 75 mg/m^2 daily for a maximum of 49 days and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The participants then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.	Drug: Placebo Intravenously every 2 weeks in the Concurrent and Maintenance Phases and every 3 weeks in the Monotherapy Phase. Drug: temozolomide 75 mg/m2 once daily for 6 weeks, followed by 150-200 mg/m2 once daily on days 1-5 of each 6 x 4 week cycle. Radiation: Radiation therapy 30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks

Arms

Assigned Interventions

Experimental: Bevacizumab + RT+Temozolomide

In the Concurrent Phase participants received radiotherapy (RT) in daily fractions of 2 Gy given 5 days per week for 6 week and temozolomide 75 mg/m^2 daily for a maximum of 49 days and bevacizumab 10 mg/kg intravenous (IV) every 2 weeks for 6 weeks. There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of bevacizumab 10 mg/kg IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The participants then entered the Monotherapy Phase where they received bevacizumab 15 mg/kg IV every 3 weeks until disease progression/unacceptable toxicity.

Drug: bevacizumab [Avastin®]

10 mg/kg intravenously every 2 weeks in the Concurrent and Maintenance Phases. 15 mg/kg intravenously every 3 weeks in the Monotherapy Phase.

Drug: temozolomide

75 mg/m2 once daily for 6 weeks, followed by 150-200 mg/m2 once daily on days 1-5 of each 6 x 4 week cycle.

Radiation: Radiation therapy

30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks

Placebo Comparator: Placebo + RT+ Temozolomide

In the Concurrent Phase participants received radiotherapy in daily fractions of 2 Gy given 5 days per week for 6 week and temozolomide 75 mg/m^2 daily for a maximum of 49 days and placebo IV every 2 weeks for 6 weeks. There was a 4 week treatment break. Participants then entered the Maintenance Phase where they received six 28-day cycle of placebo IV every 2 weeks and temozolomide 150 to 200 mg/m^2 daily in the first 5 days of each cycle. The participants then entered the Monotherapy Phase where they received placebo IV every 3 weeks until disease progression/unacceptable toxicity.

Drug: Placebo

Intravenously every 2 weeks in the Concurrent and Maintenance Phases and every 3 weeks in the Monotherapy Phase.

Drug: temozolomide

75 mg/m2 once daily for 6 weeks, followed by 150-200 mg/m2 once daily on days 1-5 of each 6 x 4 week cycle.

Radiation: Radiation therapy

30 fractions of 2 Gy delivered on days 1-5 per week for 6 weeks

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

adult patients, >=18 years of age;
newly diagnosed glioblastoma;
World Health Organization (WHO) performance status <=2;
stable or decreasing corticosteroid dose within 5 days prior to randomization.

Exclusion Criteria:

evidence of recent hemorrhage or 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 >=grade 2 hemoptysis within 1 month prior to randomization;
previous centralized screening for Methylguanine-DNA methyltransferase (MGMT) status for enrollment into a clinical trial.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00943826

Show 132 Study Locations

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

Study Director:

Clinical Trials

Hoffmann-La Roche

More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Chinot OL, Macdonald DR, Abrey LE, Zahlmann G, Kerloëguen Y, Cloughesy TF. Response assessment criteria for glioblastoma: practical adaptation and implementation in clinical trials of antiangiogenic therapy. Curr Neurol Neurosci Rep. 2013 May;13(5):347. doi: 10.1007/s11910-013-0347-2.

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00943826 History of Changes
Other Study ID Numbers:	BO21990, 2008-006146-26
Study First Received:	July 17, 2009
Results First Received:	March 29, 2013
Last Updated:	May 24, 2013
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine

Bevacizumab
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

ClinicalTrials.gov processed this record on June 18, 2013