Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01067469
Recruitment Status : Completed
First Posted : February 11, 2010
Last Update Posted : October 31, 2016
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
The goal of this clinical research study is to learn if the combination of bevacizumab and lomustine can help to control glioblastoma. The safety of this combination will also be studied.

Condition or disease Intervention/treatment Phase
Brain Cancer Glioblastoma Drug: Standard Dose Bevacizumab Drug: Low Dose Bevacizumab Drug: Lomustine Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 83 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) In Adults With Recurrent Glioblastoma Multiforme
Study Start Date : January 2010
Actual Primary Completion Date : October 2016
Actual Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Standard Dose Bevacizumab
Bevacizumab 10 mg/kg by vein (IV) over 90 minutes on Days 1, 15, and 29 of 6 week cycle.
Drug: Standard Dose Bevacizumab
10 mg/kg by vein (IV) over 90 minutes on Days 1, 15, and 29 of 6 week cycle.
Other Names:
  • Avastin
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF

Experimental: Low Dose Bevacizumab + Lomustine
Bevacizumab 5 mg/kg IV over 90 minutes on Day 1 and 22 (every 3 weeks) of 6 week cycle. Lomustine starting dose of 75 mg/m2 administered orally at sleep time on Day 3 of every 6 week cycle.
Drug: Low Dose Bevacizumab
5 mg/kg IV over 90 minutes on Day 1 and 22 (every 3 weeks) of 6 week cycle.
Other Names:
  • Avastin
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF

Drug: Lomustine
Starting dose of 75 mg/m2 administered orally at sleep time on Day 3 of every 6 week cycle.
Other Names:
  • CeeNU
  • CCNU

Primary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Baseline to 6 months minimally, progression documented after 6 week treatment cycle ]
    Number of participants with no disease progression as measured by magnetic resonance imaging (MRI) scans. Participants followed by MRI scans, as used for baseline tumor measurements, and removed from study if progression is documented after any cycle of treatment. PFS determined from date of registration in the trial and not date of randomization into chemotherapy arms (i.e. after surgery for resection of recurrent tumor).

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Signed Informed Consent Form
  2. Age >/= 18 years
  3. Histologically confirmed glioblastoma in first, second or third relapse. A pathology report constitutes adequate documentation of histology for study inclusion. Subjects with an initial diagnosis of a lower grade glioma are eligible if a subsequent biopsy is determined to be glioblastoma. The amount of prior systemic therapy for this population is, nevertheless, restricted to three regimens, with one including temozolomide.
  4. Radiographic demonstration of disease progression following prior therapy
  5. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one diameter on MRI performed within 14 days prior to registration (Day 1). Baseline MRIs for subjects who underwent salvage surgery after first or second relapse must be obtained >/= 4 weeks after the procedure. If receiving corticosteroids, subjects must be on a stable or decreasing dose of corticosteroids for >/= 5 days prior to baseline MRI.
  6. Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: 1) They have recovered from the effects of surgery. 2) Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. 3) To best assess the extent of residual measurable disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively. .
  7. An interval of >/= 4 weeks since surgical resection is required prior to starting protocol therapy.
  8. Prior standard radiation for glioblastoma
  9. Prior chemotherapy: All first-relapse subjects must have received temozolomide. All second- and third-relapse subjects must have received temozolomide. Patients may not have received prior nitrosoureas.
  10. Recovery from the effects of prior therapy, including the following: Four weeks from cytotoxic agents (3 weeks from procarbazine, 2 weeks from vincristine); Four weeks from any investigational agent; One week from non-cytotoxic agents(eg accutane, thalidomide); Eight weeks from radiotherapy to minimize the potential for MRI changes related to radiation necrosis that might be misdiagnosed as progression of disease, or 4 weeks if a new lesion, relative to the pre-radiation MRI, develops that is outside the primary radiation field; Patients may have had gliadel wafers during their original surgery but they must be >/= 9 months post their original surgery date.
  11. Prior therapy with gamma knife or other focal high-dose radiation is allowed, but the subject must have subsequent histologic documentation of recurrence or positron emission tomography (PET) or MR Spectroscopic documentation of tumor, unless the recurrence is a new lesion outside the irradiated field
  12. Patients must have adequate bone marrow function (WBC >/= 3,000/µl, absolute neutrophil count (ANC) >/= 1,500/mm^3, platelet count of >/= 100,000/mm^3, and hemoglobin >/= 10 gm/dl), adequate liver function (SGPT < 3 times normal and alkaline phosphatase < 2 times normal, bilirubin <1.5 mg/dl), adequate renal function (creatinine </= 1.5 mg/dL or creatinine clearance >/= 60 cc/min/1.73 m^2) and a urine protein:creatinine ratio of </=1 before starting therapy. These tests must be performed within 14 days prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
  13. Patients must have a Karnofsky performance status (KPS) equal or greater than 60
  14. Use of an effective means of contraception in males and in females of childbearing potential. Women of childbearing potential must have a negative β-human chorionic gonadotropin (HCG) pregnancy test documented within 14 days prior to registration. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  15. Ability to comply with study and follow-up procedures
  16. Patients receiving treatment with other antiepileptic medications will not be excluded. Patients should preferably be treated with non-enzyme inducing anti-epileptic medications to avoid any potential interactions with lomustine. However, the use of non-enzyme inducing anti-epileptic medications is not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be considered, as considered clinically appropriate by the treating physician.
  17. Patients on the following medications will be included: Anticoagulants/Anti-platelets: Patients on stable dose anticoagulants (e.g. warfarin, low molecular-weight heparin) and in-range international normalized ratio (INR) (2-3) are eligible. Patients are allowed to take aspirin, clopidogrel, ticlopidine, Aggrenox, ibuprofen and other NSAIDS.
  18. Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while enrolled in the study.
  19. This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race. Minorities will actively be recruited to participate.

Exclusion Criteria:

  1. Prior treatment with anti-angiogenesis (eg bevacizumab, sorafenib, sunitinib) agent or nitrosurea (eg. lomustine, carmustine, nimustine).
  2. Prior treatment with polifeprosan 20 with carmustine wafer except for the patients with gliadel wafers >/= 9 months post their original surgery date.
  3. Patients must not have received any investigational agents within 28 days prior to commencing study treatment.
  4. Prior intracerebral agents
  5. Need for urgent palliative intervention for primary disease (e.g., impending herniation)
  6. Evidence of recent hemorrhage on baseline MRI of the brain with the following exceptions: (1) Presence of hemosiderin (2) Resolving hemorrhagic changes related to surgery (3) Presence of punctate hemorrhage in the tumor
  7. Blood pressure of > 140 mmHg systolic and > 90 mmHg diastolic
  8. History of hypertensive encephalopathy
  9. New York Heart Association (NYHA) Grade II or greater chronic heart failure(CHF)
  10. History of myocardial infarction or unstable angina within 6 months prior to Day 1
  11. History of stroke or transient ischemic attack within 6 months prior to study enrollment
  12. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to Day 1
  13. Evidence of bleeding diathesis or coagulopathy or INR >1.5 unless on a stable dose of anticoagulation therapy. History of significant bleeding disorder unrelated to cancer, including: (1) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) (2) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) (3) Ongoing or recent (</= 3 months) significant gastrointestinal bleeding
  14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 1
  15. History of intracerebral abscess within 6 months prior to Day 1
  16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, anticipation of need for major surgical procedure during the course of the study
  17. Minor surgical procedures (excluding placement of a vascular access device), stereotactic biopsy, fine needle aspirations, or core biopsies within 7 days prior to Day 1
  18. Serious non-healing wound, ulcer, or bone fracture
  19. Pregnancy (positive pregnancy test) or lactation
  20. Known hypersensitivity to any component of bevacizumab
  21. History of any other malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible
  22. Pregnant or nursing females
  23. Unstable systemic disease, including active infection, uncontrolled hypertension, or serious cardiac arrhythmia requiring medication
  24. Subjects unable to undergo an MRI with contrast
  25. Patients with a known allergy to bevacizumab, or a known allergy to nitrosoureas (eg. lomustine, carmustine, nimustine) will be excluded
  26. Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study. Inability to comply with protocol or study procedures (for example, an inability to swallow tablets) will be an exclusion criteria.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01067469

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Study Chair: John DeGroot, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT01067469     History of Changes
Other Study ID Numbers: 2009-0597
NCI-2011-00559 ( Registry Identifier: NCI CTRP )
First Posted: February 11, 2010    Key Record Dates
Last Update Posted: October 31, 2016
Last Verified: October 2016

Keywords provided by M.D. Anderson Cancer Center:
Central Nervous System
malignant brain tumor
Recurrent Glioblastoma Multiforme

Additional relevant MeSH terms:
Brain Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors
Antineoplastic Agents, Alkylating