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Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma

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.
 
ClinicalTrials.gov Identifier: NCT00611325
Recruitment Status : Completed
First Posted : February 8, 2008
Results First Posted : February 4, 2014
Last Update Posted : March 12, 2014
Sponsor:
Collaborators:
Millennium Pharmaceuticals, Inc.
Genentech, Inc.
Information provided by (Responsible Party):
Duke University

Tracking Information
First Submitted Date  ICMJE January 28, 2008
First Posted Date  ICMJE February 8, 2008
Results First Submitted Date  ICMJE December 18, 2013
Results First Posted Date  ICMJE February 4, 2014
Last Update Posted Date March 12, 2014
Study Start Date  ICMJE May 2008
Actual Primary Completion Date September 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 18, 2013)
6-month Progression-free Survival (PFS) [ Time Frame: 6 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 7, 2008)
6 month progression-free survival among patients receiving EIAED and patients not receiving EIAED. [ Time Frame: 6 - 9 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2013)
  • Median Progression Free Survival (PFS) [ Time Frame: Time in months from the start of study treatment to the date of first progression or death. Assessed up to 60 months. ]
    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 Frame: Time in months from the start of study treatment to date of death due to any cause. Assessed up to 60 months. ]
    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 [ Time Frame: 60 months ]
    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 [ Time Frame: 60 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 7, 2008)
  • Radiographic response. Progression free survival and overall survival. [ Time Frame: 6 - 9 months ]
  • Grade 3 or greater, treatment related, non-hematologic toxicities. [ Time Frame: 6 - 9 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Avastin + Bortezomib for Patients With Recurrent Malignant Glioma
Official Title  ICMJE Phase II Trial of Avastin Plus Bortezomib for Patients With Recurrent Malignant Glioma
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Gliosarcoma
Intervention  ICMJE
  • Drug: Avastin
    Avastin was administered intravenously at the dose 15 mg/kg every 3 weeks.
    Other Name: Bevacizumab
  • Drug: Bortezomib
    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.
    Other Name: Velcade
Study Arms  ICMJE
  • Experimental: EIAED
    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.
    Interventions:
    • Drug: Avastin
    • Drug: Bortezomib
  • Experimental: Non-EIAED
    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.
    Interventions:
    • Drug: Avastin
    • Drug: Bortezomib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 28, 2013)
56
Original Estimated Enrollment  ICMJE
 (submitted: February 7, 2008)
64
Actual Study Completion Date  ICMJE October 2013
Actual Primary Completion Date September 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00611325
Other Study ID Numbers  ICMJE Pro00003596
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Duke University
Study Sponsor  ICMJE Duke University
Collaborators  ICMJE
  • Millennium Pharmaceuticals, Inc.
  • Genentech, Inc.
Investigators  ICMJE
Principal Investigator: Katherine B Peters, MD Duke University Health System
PRS Account Duke University
Verification Date February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP