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

Brain and Central Nervous System Tumors Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00990652
• Other study ID #: NU 08C5
• Secondary ID: STU00008280
• Status: Completed
• Phase: Phase 2
• First received: October 6, 2009
• Last updated: December 11, 2013
• Start date: May 2009
• Est. completion date: October 2012

Study information

• Verified date: December 2013
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: October 2012
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

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

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Northwestern University	Millennium Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Correlation of Expression of NFKBIA Gene With Response to Therapy and Survival.	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.	Tissue samples for analysis were obtained on the day of surgery for all patients	No
Other	Change in MGMT Methylation Status as Well as Other Methylation Patterns in Plasma	To determine MGMT methylation status as well as other methylation patterns in plasma	Blood samples drawn on days 1, 4, and 8 pre-surgery, and then prior to cycle 1 and every 2 cycles thereafter	No
Other	Pharmacokinetics of Bortezomib in Tumor Tissue Taken at the Time of Surgery.		Tissue sample taken at the time of surgery for all patients.	No
Primary	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).	From date of first treatment until disease progression, death, or early discontinuation of treatment (up to 24 months)	No
Secondary	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).	Day of treatment post-surgery and then approximately every 8 weeks thereafter until off treatment	No
Secondary	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	Days 1, 4, 8 pre-surgery, and then at the start of every cycle (approximately every 4 weeks) post-surgery while on treatment	Yes
Secondary	Overall Survival (in Days)		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	No
Secondary	Overall Survival Rate at 6 Months	The rate of overall survival at 6 months (regardless of disease progression) was calculated.	After 6 months on study	No