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Bevacizumab and Sorafenib in Treating Patients With Recurrent Glioblastoma Multiforme

Phase II Trial of Bevacizumab in Combination With Sorafenib in Recurrent Glioblastoma Multiforme

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00621686
Enrollment
54
Registered
2008-02-22
Start date
2008-09-30
Completion date
2014-02-19
Last updated
2018-05-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Brain and Central Nervous System Tumors

Keywords

adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor

Brief summary

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. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with sorafenib may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and how well giving bevacizumab together with sorafenib works in treating patients with recurrent glioblastoma multiforme.

Detailed description

OBJECTIVES: Primary * Identify the clinical efficacy of bevacizumab and sorafenib, as measured by 6-month progression-free survival, in patients with recurrent glioblastoma multiforme. Secondary * Assess time to progression of this patient population. * Assess overall survival of this patient population. OUTLINE: This is a multicenter study. Patients receive oral sorafenib once daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and plasma sample collection at baseline and then periodically during study treatment for translational research studies. Translational research studies include analysis of circulating endothelial cells and circulating endothelial progenitor cells by flow cytometry and measurement of angiogenic proteins in plasma by ELISA. DNA and buffy coat are extracted and collected from the blood samples for pharmacogenetic studies. Quality of life is assessed at baseline, prior to every other treatment course, and at the end of treatment. After completion of study treatment, patients are followed at 28-42 days, every 3 months for 5 years, and then annually for 10 years.

Interventions

BIOLOGICALbevacizumab
DRUGsorafenib tosylate

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Alliance for Clinical Trials in Oncology
Lead SponsorOTHER

Study design

Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

DISEASE CHARACTERISTICS: * Histologically confirmed glioblastoma multiforme as determined by pre-registration central pathology review * Gliosarcoma allowed * Must have evidence of tumor progression by MRI or CT scan following radiotherapy or the most recent anti-tumor therapy * No more than 1 chemotherapy regimen for progressive or recurrent disease * Bidimensionally measurable or evaluable disease by MRI or CT scan * No evidence of CNS hemorrhage on baseline CT or MRI * Patients with T1 hyperintensity confined to the surgical cavity which is felt likely due to post surgical blood contaminating the intracavity cerebrospinal fluid or irrigation that have not yet absorbed and which is not felt to clinically or radiographically represent new spontaneous hemorrhage are eligible * Patients with old blood products or hemosiderin without a history of spontaneous bleeding are eligible PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin \> 9.0 g/dL * Total bilirubin ≤ 1.5 times upper limit of normal * AST ≤ 3 times upper limit of normal * Creatinine ≤ upper limit of normal * Urine protein:creatinine ratio \< 1 OR urine protein \< 1,000 mg by 24-hour urine collection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for six months after completion of study treatment * Able to complete questionnaire(s) alone or with assistance * Willing to return to NCCTG enrolling institution for follow-up * Willing to provide mandatory blood samples for research purposes * Not immunocompromised (other than that related to the use of corticosteroids) * No known HIV positivity * No concurrent uncontrolled illness including, but not limited to, the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness/social situations that would limit compliance with study requirements * No inadequately controlled hypertension (i.e., systolic blood pressure \[BP\] \> 150 mm Hg or diastolic BP \> 100 mm Hg while on antihypertensive medications) * Patients with well-controlled hypertension are eligible * No myocardial infarction or unstable angina within the past 6 months * No congestive heart failure requiring the use of ongoing maintenance therapy for life-threatening ventricular arrhythmias * No New York Heart Association class II-IV congestive heart failure * No significant vascular disease (e.g., aortic aneurysm or aortic dissection) * No peripheral arterial thrombosis within the past 6 months * No stroke or transient ischemic attack within the past 6 months * No history of hypertensive crisis or hypertensive encephalopathy * No evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation) * No active or recent history of hemoptysis (i.e., ≥ ½ teaspoon of bright red blood per episode) within the past 30 days * No serious, nonhealing wounds, ulcers, or bone fractures * No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation) * No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * No significant traumatic injury within the past 28 days * No known hypersensitivity to any of the components of sorafenib or bevacizumab * No other active malignancy within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the cervix * Patients with a history of prior malignancy must not be receiving specific treatment (other than hormonal therapy) for that malignancy * No co-morbid systemic illness or other concurrent severe disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or significantly interfere with the proper assessment of safety and toxicity of the prescribed study regimen PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 12 weeks since prior radiotherapy * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) * More than 2 weeks since prior small molecule cell cycle inhibitors * At least 1 week since prior fixed-dose corticosteroids (or no corticosteroids) * No prior intratumoral chemotherapy, stereotactic radiosurgery or interstitial brachytherapy unless there is a separate lesion on MRI that is not part of the prior treatment field OR there is proof of recurrent disease based on biopsy, MRI spectroscopy, or PET scan * No prior antiangiogenic therapy * No prior surgical procedures affecting absorption * More than 7 days since prior core biopsy or other minor surgical procedures * Placement of a vascular access device is allowed * More than 28 days since prior major surgical procedure or open biopsy * No concurrent major surgical procedure * No other concurrent investigational agents * No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin, fosphenytoin, carbamazepine, phenobarbital, or primidone) * No other concurrent potent CYP3A4 inducers (e.g., rifampin or St. John's wort) * No concurrent therapeutic anticoagulation with warfarin * Prophylactic anticoagulation (i.e., low-dose warfarin) for venous or arterial access devices allowed provided the INR \< 1.5 * Therapeutic anticoagulation with low molecular weight heparin allowed

Design outcomes

Primary

MeasureTime frameDescription
6-month Progression-free Survivalat 6 monthsPrimary Endpoint: 6-month progression free survival (PFS6): The proportion of successes will be estimated using the binomial point estimator (number of successes divided by the total number of evaluable patients) and the binomial 95% confidence interval estimated. To be classified as a success, an evaluable patient must be alive and progression-free 6 months after registration to the study. Patients who die prior to 6 months after study registration will be considered to have failed. Progression is defined as a \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.

Secondary

MeasureTime frameDescription
Time to ProgressionTime from study registration to a) date of disease progression, or b) last follow-up; Up to 15 yearsTime to progression (TTP) is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0 of the protocol, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Time to progression curves were compared via the log-rank test. Progression is defined as a \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.
Overall SurvivalTime from date of registration to a) date of death due to any cause or b) last follow-up; Up to 15 yearsOverall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up.

Countries

United States

Participant flow

Participants by arm

ArmCount
Sorafenib + Bevacizumab/Group A
Patients receive oral sorafenib 400 mg (200 mg twice daily) days 1-5 and 8-12 and 5 mg/kg bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days.
19
Sorafenib + Bevacizumab /Group B
Patients receive oral sorafenib 200 mg once daily on days 1-14 and 5 mg/kg bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days.
35
Total54

Baseline characteristics

CharacteristicSorafenib + Bevacizumab/Group ASorafenib + Bevacizumab /Group BTotal
Age, Continuous54 years55 years55 years
Region of Enrollment
United States
19 participants35 participants54 participants
Sex: Female, Male
Female
7 Participants12 Participants19 Participants
Sex: Female, Male
Male
12 Participants23 Participants35 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
19 / 1935 / 35
serious
Total, serious adverse events
9 / 199 / 35

Outcome results

Primary

6-month Progression-free Survival

Primary Endpoint: 6-month progression free survival (PFS6): The proportion of successes will be estimated using the binomial point estimator (number of successes divided by the total number of evaluable patients) and the binomial 95% confidence interval estimated. To be classified as a success, an evaluable patient must be alive and progression-free 6 months after registration to the study. Patients who die prior to 6 months after study registration will be considered to have failed. Progression is defined as a \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.

Time frame: at 6 months

ArmMeasureValue (NUMBER)
Sorafenib + Bevacizumab/Group A6-month Progression-free Survival0.263 proportion of participants
Sorafenib + Bevacizumab /Group B6-month Progression-free Survival0.171 proportion of participants
Secondary

Overall Survival

Overall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up.

Time frame: Time from date of registration to a) date of death due to any cause or b) last follow-up; Up to 15 years

ArmMeasureValue (MEDIAN)
Sorafenib + Bevacizumab/Group AOverall Survival5.58 months
Sorafenib + Bevacizumab /Group BOverall Survival5.62 months
Secondary

Time to Progression

Time to progression (TTP) is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0 of the protocol, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Time to progression curves were compared via the log-rank test. Progression is defined as a \>25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan.

Time frame: Time from study registration to a) date of disease progression, or b) last follow-up; Up to 15 years

ArmMeasureValue (MEDIAN)
Sorafenib + Bevacizumab/Group ATime to Progression3.61 months
Sorafenib + Bevacizumab /Group BTime to Progression2.66 months
p-value: 0.069Log Rank

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026