Presurgery Bortezomib for Recurrent Malignant Gliomas Followed by Postop Bortezomib & Temozolomide

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: NCT00990652
Recruitment Status : Completed
First Posted : October 7, 2009
Results First Posted : January 13, 2014
Last Update Posted : January 13, 2014
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Jeffrey Raizer, Northwestern University

October 6, 2009
October 7, 2009
December 11, 2013
January 13, 2014
January 13, 2014
May 2009
April 2011   (Final data collection date for primary outcome measure)
Number of Patients Surviving Without Disease Progression After 6 Months [ Time Frame: From date of first treatment until disease progression, death, or early discontinuation of treatment (up to 24 months) ]

Patients will be monitored from date of first treatment to the date of first observation of progressive disease, non-reversible neurologic progression or increasing steroid requirements, death due to any cause, or early discontinuation of treatment. Progression-free survival will be defined as the absence of any of the above after 6 months.

Progression (defined by MacDonald Criteria) is a 25% increase in the sum of products of all measurable lesions over smallest sum observed compared to baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to the cancer).

Progression-free survival at 6 months
Complete list of historical versions of study NCT00990652 on Archive Site
  • Number of Participants Achieving a Response to Treatment (Either Complete or Partial Response) as Defined by MacDonald Criteria [ Time Frame: Day of treatment post-surgery and then approximately every 8 weeks thereafter until off treatment ]

    This measure was assessed only in patients who had residual tumor post-operatively. Per MacDonald Criteria:

    Complete Response requires complete disappearance of all measurable & evaluable disease, no new lesions, no evidence of non-evaluable disease, and only minimal or no use of steroids.

    Partial Response is defined as >= 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, and no new lesions. Responders must be on the same or decreasing doses of steroid.

    Response was assessed by imaging (MRI or CT with contrast).

  • Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0) [ Time Frame: Days 1, 4, 8 pre-surgery, and then at the start of every cycle (approximately every 4 weeks) post-surgery while on treatment ]

    Adverse events (AEs) were graded according to the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0. In general, AEs are graded according to the following:

    Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

  • Overall Survival (in Days) [ Time Frame: Days 1, 4, 8 pre-surgery, once per cycle (every 4 weeks) while on treatment post-surgery, and then every 3 months up to 2 years during follow-up ]
  • Overall Survival Rate at 6 Months [ Time Frame: After 6 months on study ]
    The rate of overall survival at 6 months (regardless of disease progression) was calculated.
  • Overall survival
  • Response rate (complete or partial response)
  • Toxicity
  • Pharmacokinetics
  • Correlation of Expression of NFKBIA Gene With Response to Therapy and Survival. [ Time Frame: Tissue samples for analysis were obtained on the day of surgery for all patients ]
    The effects of bortezomib on the endogenous modulators of NF-Kappa B pathways, especially the NFKBIA gene (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) were assessed using novel assay technology; expression of NFKBIA was then correlated with response to therapy and patient survival.
  • Change in MGMT Methylation Status as Well as Other Methylation Patterns in Plasma [ Time Frame: Blood samples drawn on days 1, 4, and 8 pre-surgery, and then prior to cycle 1 and every 2 cycles thereafter ]
    To determine MGMT methylation status as well as other methylation patterns in plasma
  • Pharmacokinetics of Bortezomib in Tumor Tissue Taken at the Time of Surgery. [ Time Frame: Tissue sample taken at the time of surgery for all patients. ]
Not Provided
Presurgery Bortezomib for Recurrent Malignant Gliomas Followed by Postop Bortezomib & Temozolomide
A Phase II Trial Evaluating the Effects of Bortezomib in Patients With Recurrent Malignant Gliomas Treated Prior to Surgery and Then Bortezomib and Temozolomide Post-operatively

Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bortezomib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bortezomib together with temozolomide after surgery may kill any tumor cells that remain after surgery.

This phase II trial is studying how well giving bortezomib before surgery followed by giving bortezomib together with temozolomide after surgery works in treating patients with recurrent malignant glioma.

Patients receive bortezomib IV on days 1, 4, and 8. Patients then undergo surgical resection of the tumor on day 8 or 9.

Beginning approximately 14 days after surgery, patients receive oral temozolomide on days 1-7 and 14-21 and bortezomib IV on days 7 and 21. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

Tumor tissue and blood samples are collected periodically for biomarker analysis, gene methylation studies, and pharmacokinetic studies.

After completion of study therapy, patients are followed up every 3 months for 2 years.

Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Drug: Bortezomib
    Before surgery, an injection of bortezomib is given on days 1, 4, and 8. After surgery, bortezomib is given on days 7 and 21 of each cycle (1 cycle = 28 days).
    Other Name: Velcade
  • Drug: Temozolomide
    After surgery, temozolomide is taken by mouth on days 1-7 and 14-21 of each cycle (1 cycle = 28 days).
    Other Name: Temodar
Experimental: Bortezomib + Temozolomide
Patients receive an injection of bortezomib 1.7mg/m^2 on days 1, 4 and 8. Patients then undergo their standard of care surgery on day 8 or 9 to remove the tumor. Once recovered from surgery, patients receive combination treatment with temozolomide and bortezomib in periods called cycles (1 cycle = 28 days). Temozolomide is taken by mouth on days 1-7 and 14-21 of each cycle, and bortezomib injections are given on days 7 and 21 of each cycle.
  • Drug: Bortezomib
  • Drug: Temozolomide
Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
October 2012
April 2011   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically confirmed malignant glioma, including any of the following subtypes:

    • Glioblastoma multiforme
    • Gliosarcoma
    • Anaplastic astrocytoma
    • Anaplastic oligodendroglioma
    • Anaplastic mixed oligoastrocytoma
    • Malignant astrocytoma not otherwise specified
  • Must show unequivocal evidence of tumor recurrence or progression by MRI or CT scan with contrast
  • Candidate for surgery AND requires surgery

    • Evaluable or measurable disease following resection of recurrent tumor is not required
  • Failed prior standard radiotherapy and temozolomide

    • Patients who have undergone stereotactic radiosurgery must have confirmation of true progressive disease (rather than radiation necrosis) by PET scan, magnetic resonance spectroscopy (MRS), or magnetic resonance perfusion (MRP) prior to surgery
    • Patients with lower-grade gliomas that have undergone radiographic malignant transformation allowed provided they failed radiotherapy (with or without temozolomide) and require surgery
  • Life expectancy > 12 weeks

Exclusion Criteria:

  • Not pregnant or nursing
  • Negative pregnancy test
  • No other medical issues (e.g., bleeding, infection, HIV, or serious medical or psychiatric illness) that would preclude study therapy
  • Myocardial infarction within the past 6 months
  • No other active cancer(s) except non-melanoma skin cancer or carcinoma in situ of the cervix, unless in complete remission and off of all therapy for that cancer for ≥ 3 years
  • No hypersensitivity to bortezomib, boron, or mannitol
  • More than 4 weeks since prior radiotherapy
  • At least 4 weeks since prior cytotoxic therapy (6 weeks for nitrosoureas)
  • At least 3 weeks since prior investigational drugs
  • At least 2 weeks since prior enzyme-inducing anticonvulsants
  • Concurrent non-enzyme-inducing anticonvulsants allowed
  • No other concurrent standard or investigational anticancer treatment
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
United States
NU 08C5
STU00008280 ( Other Identifier: Northwestern University IRB )
Not Provided
Not Provided
Jeffrey Raizer, Northwestern University
Northwestern University
Millennium Pharmaceuticals, Inc.
Principal Investigator: Jeffrey Raizer, MD Northwestern University
Northwestern University
December 2013

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