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

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Primary Purpose

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Bortezomib

Temozolomide

About this trial

This is an interventional treatment trial for Brain and Central Nervous System Tumors focused on measuring brain tumor

Eligibility Criteria

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

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

Sites / Locations

Northwestern University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bortezomib + Temozolomide

Arm Description

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.

Outcomes

Primary Outcome Measures

Number of Patients Surviving Without Disease Progression After 6 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).

Secondary Outcome Measures

Number of Participants Achieving a Response to Treatment (Either Complete or Partial Response) as Defined by MacDonald Criteria

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)

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)

Overall Survival Rate at 6 Months

The rate of overall survival at 6 months (regardless of disease progression) was calculated.

Full Information

NCT ID

NCT00990652

First Posted

October 6, 2009

Last Updated

December 11, 2013

Sponsor

Northwestern University

Collaborators

Millennium Pharmaceuticals, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT00990652

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2013

Overall Recruitment Status

Completed

Study Start Date

May 2009 (undefined)

Primary Completion Date

April 2011 (Actual)

Study Completion Date

October 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Northwestern University

Collaborators

Millennium Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Brain and Central Nervous System Tumors

Keywords

brain tumor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bortezomib + Temozolomide

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Bortezomib

Other Intervention Name(s)

Velcade

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Temozolomide

Other Intervention Name(s)

Temodar

Intervention Description

After surgery, temozolomide is taken by mouth on days 1-7 and 14-21 of each cycle (1 cycle = 28 days).

Primary Outcome Measure Information:

Title

Number of Patients Surviving Without Disease Progression After 6 Months

Description

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).

Time Frame

From date of first treatment until disease progression, death, or early discontinuation of treatment (up to 24 months)

Secondary Outcome Measure Information:

Title

Number of Participants Achieving a Response to Treatment (Either Complete or Partial Response) as Defined by MacDonald Criteria

Description

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).

Time Frame

Day of treatment post-surgery and then approximately every 8 weeks thereafter until off treatment

Title

Number of Grade 1, 2, 3, 4, and 5 Adverse Events Observed During Study Treatment (Defined by CTCAE v 3.0)

Description

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

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

Title

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

Title

Overall Survival Rate at 6 Months

Description

The rate of overall survival at 6 months (regardless of disease progression) was calculated.

Time Frame

After 6 months on study

Other Pre-specified Outcome Measures:

Title

Correlation of Expression of NFKBIA Gene With Response to Therapy and Survival.

Description

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.

Time Frame

Tissue samples for analysis were obtained on the day of surgery for all patients

Title

Change in MGMT Methylation Status as Well as Other Methylation Patterns in Plasma

Description

To determine 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

Title

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jeffrey Raizer, MD

Organizational Affiliation

Northwestern University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Northwestern University

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Brain and Central Nervous System Tumors

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial