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Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma

Primary Purpose

Glioblastoma, Gliosarcoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Avastin
Bortezomib
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Glioblastoma, Gliosarcoma, Glioblastoma multiforme, Recurrent malignant glioma, GBM, Recurrent GBM, Malignant glioma, Brain tumor, Avastin, Bevacizumab, Bortezomib, Velcade

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients have histologically confirmed diagnosis of recurrent/progressive WHO grade IV malignant glioma (MG)

  • Age >18 yrs
  • No prior treatment with bortezomib, & no Avastin in last 3 months, not allowed to have progressed to Avastin regimen. No history of > or equal to grade 2 CNS hemorrhage or grade 3 or higher toxicities while on Avastin
  • At least 6 weeks from surgical resection, 4 weeks from end of radiotherapy & enrollment in this study
  • Karnofsky Performance Status (KPS) > or equal to 70%
  • Hemoglobin (Hgb) > or = to 9 g/deciliter (dL), absolute neutrophil count (ANC) > or = to 1,500 cells/microliter, platelets > or = to 125,000 cells/microliter;
  • Serum creatinine <1.5 mg/dL, serum glutamic oxalocetic transaminase (SGOT) & bilirubin <1.5 x upper limit of normal
  • Signed informed consent approved by IRB;
  • If sexually active, patients must agree to take contraceptive measures for duration of treatments
  • May have had up to 3 biological therapies (such as tyrosine kinase inhibitors, topoisomerase I or II inhibitors, or rapamycin)

Exclusion Criteria:

  • Gr 2 or greater peripheral neuropathy at time of study enrollment
  • No prior taxanes, as it predisposes to sensory neuropathy
  • Co-medication that may interfere with study results, e.g. immuno-suppressive agents other than corticosteroids
  • Greater than 3 prior recurrences
  • Evidence of CNS hemorrhage on baseline MRI on CT scan (except for grade 1 hemorrhage that has been stable for at least 3 months)
  • History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months
  • Requires therapeutic anti-coagulation
  • At least 4 weeks from Day 0 of prior monthly chemotherapy (at least 6 weeks if a nitrosourea). At least 1 week from last dose of daily chemotherapy (such as metronomic temozolomide, cytoxan) or targeted therapies administered daily (such as gleevec, tarceva)
  • Pregnancy or breast feeding
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state
  • Patients with another primary malignancy that has required treatment within past year.

Avastin-Specific Concerns:

  • Any prior history of hypertensive crisis or hypertensive encephalopathy
  • Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg
  • Unstable angina
  • New York Heart Association Gr II or > congestive heart failure
  • History of myocardial infarction within 6 months
  • History of stroke within 6 months
  • Clinically significant peripheral vascular disease
  • Evidence of bleeding diathesis, coagulopathy as documented by an elevated prothrombin time (PT), partial thromboplastin time (PTT)/bleeding time
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during course of study
  • Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0
  • Urine protein: creatinine ratio > or = to 1.0 at screening
  • History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 0
  • Serious, non-healing wound, ulcer, or bone fracture
  • Known hypersensitivity to any component of Avastin
  • Inability to comply with study and/or follow-up procedures

Sites / Locations

  • Duke University Health System

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

EIAED

Non-EIAED

Arm Description

Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.

Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.

Outcomes

Primary Outcome Measures

6-month Progression-free Survival (PFS)
Percentage of participants surviving six months from the initiation of treatment without progression of disease. PFS was defined as the time from the initiation of treatment to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.

Secondary Outcome Measures

Median Progression Free Survival (PFS)
Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Median Overall Survival (OS)
Time in months from the start of study treatment to the date of death. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Radiographic Response Rate
The percentage of participants with a complete or partial response at any assessment as determined by the Macdonald criteria. A confirmation of response was not required. Per Macdonald criteria, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions, no new lesions and stable or decreasing steroid dose. Objective response =CR+PR. Tumor assessments were done at baseline and at the end of each 6 week treatment cycle, and overall best response was recorded.
Number of Patients With Grade 3 or Greater, Treatment-related, Non-hematologic Toxicities
Number of patients with grade 3 or greater, treatment-related, non-hematologic toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Full Information

First Posted
January 28, 2008
Last Updated
February 7, 2014
Sponsor
Duke University
Collaborators
Millennium Pharmaceuticals, Inc., Genentech, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00611325
Brief Title
Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma
Official Title
Phase II Trial of Avastin Plus Bortezomib for Patients With Recurrent Malignant Glioma
Study Type
Interventional

2. Study Status

Record Verification Date
February 2014
Overall Recruitment Status
Completed
Study Start Date
May 2008 (undefined)
Primary Completion Date
September 2009 (Actual)
Study Completion Date
October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Millennium Pharmaceuticals, Inc., Genentech, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Primary Objective To estimate 6-month progression free survival probability of patients with recurrent glioblastoma multiforme treated with bortezomib plus Avastin. This efficacy assessment will be made separately among patients on enzyme-inducing anti-epileptic drugs and non enzyme-inducing anti-epileptic drugs. Secondary Objectives To evaluate safety & tolerability of bortezomib plus Avastin among patients with recurrent malignant glioma. To evaluate radiographic response, progression free survival & overall survival of patients with recurrent malignant glioma treated with bortezomib plus Avastin
Detailed Description
This is an open-label, 2-arm Phase II study assessing safety & efficacy of bortezomib in combination with Avastin for patients with recurrent glioblastoma multiforme (gbm). 56 total patients with recurrent WHO grade IV malignant gliomas have been enrolled on study. Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, & 32 of a 42-day cycle. The dose of bortezomib was 1.7 mg/m2 for non-EIAED patients & 2.5 mg/m2 for EIAED patients. Treatment continued until either evidence of progressive disease, unacceptable toxicity, non-compliance with study follow-up / withdrawal of consent. Brain MRIs were obtained after every cycle. Bortezomib administration is associated with mild toxicity in most patients, such as fatigue, diarrhea & nausea, constipation & peripheral neuropathy. Less common, bortezomib administration leads to more significant hematologic toxicities & peripheral neuropathies. Most significant toxicities associated with Avastin in recently completed phase II clinical trial at Duke were thrombotic complications & grade 2 proteinuria. "Unacceptable" toxicities rates of 15 percent or less were considered desirable, while rates of 40 percent or greater were considered undesirable. The statistical hypothesis that needed testing differentiated between 15% & 40% rate of unacceptable toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, Gliosarcoma
Keywords
Glioblastoma, Gliosarcoma, Glioblastoma multiforme, Recurrent malignant glioma, GBM, Recurrent GBM, Malignant glioma, Brain tumor, Avastin, Bevacizumab, Bortezomib, Velcade

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
56 (Actual)

8. Arms, Groups, and Interventions

Arm Title
EIAED
Arm Type
Experimental
Arm Description
Patients taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 2.5 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Arm Title
Non-EIAED
Arm Type
Experimental
Arm Description
Patients not taking enzyme-inducing anti-epileptic drugs (EIAEDs). Avastin was administered intravenously at a dose of 15 mg/kg every 3 weeks. Bortezomib was adminstered intravenously at a dose of 1.7 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day cycle.
Intervention Type
Drug
Intervention Name(s)
Avastin
Other Intervention Name(s)
Bevacizumab
Intervention Description
Avastin was administered intravenously at the dose 15 mg/kg every 3 weeks.
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
Bortezomib was administered on days 1, 4, 8, 11, 22, 25, 29, & 32 of a 42-day cycle. Bortezomib was 1.7 mg/m2 for patients not taking EIAEDs & 2.5 mg/m2 for patients taking EIAEDs.
Primary Outcome Measure Information:
Title
6-month Progression-free Survival (PFS)
Description
Percentage of participants surviving six months from the initiation of treatment without progression of disease. PFS was defined as the time from the initiation of treatment to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion or clinical deterioration.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Median Progression Free Survival (PFS)
Description
Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Per Macdonald, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame
Time in months from the start of study treatment to the date of first progression or death. Assessed up to 60 months.
Title
Median Overall Survival (OS)
Description
Time in months from the start of study treatment to the date of death. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame
Time in months from the start of study treatment to date of death due to any cause. Assessed up to 60 months.
Title
Radiographic Response Rate
Description
The percentage of participants with a complete or partial response at any assessment as determined by the Macdonald criteria. A confirmation of response was not required. Per Macdonald criteria, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions, no new lesions and stable or decreasing steroid dose. Objective response =CR+PR. Tumor assessments were done at baseline and at the end of each 6 week treatment cycle, and overall best response was recorded.
Time Frame
60 months
Title
Number of Patients With Grade 3 or Greater, Treatment-related, Non-hematologic Toxicities
Description
Number of patients with grade 3 or greater, treatment-related, non-hematologic toxicities based on Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time Frame
60 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients have histologically confirmed diagnosis of recurrent/progressive WHO grade IV malignant glioma (MG) Age >18 yrs No prior treatment with bortezomib, & no Avastin in last 3 months, not allowed to have progressed to Avastin regimen. No history of > or equal to grade 2 CNS hemorrhage or grade 3 or higher toxicities while on Avastin At least 6 weeks from surgical resection, 4 weeks from end of radiotherapy & enrollment in this study Karnofsky Performance Status (KPS) > or equal to 70% Hemoglobin (Hgb) > or = to 9 g/deciliter (dL), absolute neutrophil count (ANC) > or = to 1,500 cells/microliter, platelets > or = to 125,000 cells/microliter; Serum creatinine <1.5 mg/dL, serum glutamic oxalocetic transaminase (SGOT) & bilirubin <1.5 x upper limit of normal Signed informed consent approved by IRB; If sexually active, patients must agree to take contraceptive measures for duration of treatments May have had up to 3 biological therapies (such as tyrosine kinase inhibitors, topoisomerase I or II inhibitors, or rapamycin) Exclusion Criteria: Gr 2 or greater peripheral neuropathy at time of study enrollment No prior taxanes, as it predisposes to sensory neuropathy Co-medication that may interfere with study results, e.g. immuno-suppressive agents other than corticosteroids Greater than 3 prior recurrences Evidence of CNS hemorrhage on baseline MRI on CT scan (except for grade 1 hemorrhage that has been stable for at least 3 months) History of thrombotic or hemorrhagic stroke or myocardial infarction within 6 months Requires therapeutic anti-coagulation At least 4 weeks from Day 0 of prior monthly chemotherapy (at least 6 weeks if a nitrosourea). At least 1 week from last dose of daily chemotherapy (such as metronomic temozolomide, cytoxan) or targeted therapies administered daily (such as gleevec, tarceva) Pregnancy or breast feeding Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring IV antibiotics & psychiatric illness/social situations that would limit compliance with study requirements, or disorders associated with significant immunocompromised state Patients with another primary malignancy that has required treatment within past year. Avastin-Specific Concerns: Any prior history of hypertensive crisis or hypertensive encephalopathy Systolic blood pressure (BP) > 150 mmHg or diastolic BP > 100 mmHg Unstable angina New York Heart Association Gr II or > congestive heart failure History of myocardial infarction within 6 months History of stroke within 6 months Clinically significant peripheral vascular disease Evidence of bleeding diathesis, coagulopathy as documented by an elevated prothrombin time (PT), partial thromboplastin time (PTT)/bleeding time Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during course of study Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0 Urine protein: creatinine ratio > or = to 1.0 at screening History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to Day 0 Serious, non-healing wound, ulcer, or bone fracture Known hypersensitivity to any component of Avastin Inability to comply with study and/or follow-up procedures
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Katherine B Peters, MD
Organizational Affiliation
Duke Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Health System
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.cancer.duke.edu/btc/
Description
The Preston Robert Tisch Brain Tumor Center at DUKE

Learn more about this trial

Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma

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