Brain and Central Nervous System Tumors
Conditions
Keywords
adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma
Brief summary
RATIONALE: Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving bortezomib together with temozolomide and radiation therapy may kill more tumor cells and allow doctors to save the part of the body where the cancer started. PURPOSE: This phase II trial is studying the side effects and how well bortezomib works when given together with temozolomide and regional radiation therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma.
Detailed description
OBJECTIVES: Primary * Estimate the overall survival at 2 years of patients with newly diagnosed glioblastoma multiforme treated with bortezomib in combination with temozolomide and regional radiotherapy followed by maintenance therapy comprising bortezomib and temozolomide. Secondary * Investigate further the safety and tolerability of this regimen in these patients. * Determine the molecular characterization of tumor tissue and correlate these findings with response. OUTLINE: This is a multicenter study. * Adjuvant chemotherapy: Patients receive bortezomib IV on days 1, 4, 8, 11, 29, 32, 36, and 39 and oral temozolomide on days 1-42. Patients undergo external-beam fractionated regional radiotherapy 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity. * Maintenance: Beginning 2-6 weeks after radiotherapy, patients receive bortezomib IV on days 1, 4, 8, and 11 and oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Tumor tissue samples are collected at baseline (from surgery) and periodically during study for further analysis. After completion of study therapy, patients are followed up periodically.
Interventions
DRUGbortezomib + temozolomide+ radiation therapy
Patients will be treated with Bortezomib at 1.3 mg/m2 IV on days1,4,8,11,29,32,36 and 39 and Temozolomide on 75mg/m2 daily during radiation. External beam fractionated regional radiation will be given on consecutive week days at 200 centigray (cGy) daily doses to a total dose of 6000 cGy.
Sponsors
Millennium Pharmaceuticals, Inc.
Jonsson Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be \>- 18 years old, with a life expectancy \> 8 weeks * Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma * Must submit an unstained paraffin block or slides from surgical procedure * Patients without prior treatment and with prior diagnosis of lower-grade gliomas that have been upgraded to GBM after repeated resection allowed * At least 21 days since cranial MRI or contrast CT scan OR ≥ 96 hours since cranial MRI or contrast CT scan for patients who underwent surgical resection * Measurable or assessable disease * Voluntary written informed consent obtained before performance of any study related procedure not part of normal medical care. * Karnofsky performance status \> 60% * White Blood Count (WBC) ≥ 3,000/mm\^3 * absoulte neutrophil count(ANC) ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 10 g/dL (transfusion allowed) * Bilirubin \< 2.5 times upper limit of normal (ULN) * serum glutamic-oxaloacetic transaminase (SGOT) \< 2.5 times ULN * Creatinine \< 1.5 mg/dL * Creatinine clearance ≥ 20 mL/minute * Serum sodium \> 130 mmol/L * Negative pregnancy test * Fertile patients must use effective contraception * Patients on Enzyme-Inducing Antiepileptic Drugs (EIAED) must be transitioned to non- EAIED for ≥ 2 weeks * Concurrent full-dose warfarin or its equivalent (e.g., unfractionated and/or low molecular weight heparin) allowed
Exclusion criteria
* peripheral neuropathy ≥ grade 2 * Myocardial infarction within the past 6 months * New York Heart Association (NYHA) class III or IV heart failure * Uncontrolled angina * Severe uncontrolled ventricular arrhythmias * Electrocardiographic evidence of acute ischemia or active conduction system abnormalities * hypersensitivity to bortezomib, boron, or mannitol * serious medical or psychiatric illness that would interfere with study participation including, but not limited to, any of the following: * Ongoing or active infection requiring IV antibiotics * Psychiatric illness and/or social situations that would limit compliance with study requirements * Disorders associated with a significant immunocompromised state (e.g., HIV, systemic lupus erythematosus) * history of stroke within the past 6 months * other malignancy within the past 3 years except completely resected basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy (i.e., cervical cancer), or low-risk prostate cancer after curative therapy * significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy * disease that will obscure toxicity or dangerously alter drug metabolism * viral hepatitis (HBV surface antigen positive) or active hepatitis C infection * Prior or concurrent corticosteroids, automated external defibrillator, analgesics, and other drugs to treat symptoms or prevent complications allowed * concurrent investigational drugs that must be stopped at least 4 months prior to therapy. * prior radiotherapy to the brain * prior cytotoxic or noncytotoxic drug therapy or experimental drug therapy (including chemotherapy, hormonal therapy, or immunotherapy) directed against the brain tumor * prior polifeprosan 20 with carmustine implant (Gliadel wafer) * concurrent stereotactic radiosurgery or brachytherapy * concurrent sargramostim * concurrent inducers of CYP450 3A4 (e.g., enzyme-inducing anti-epileptic drugs \[EIAED\])
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2 years | Estimate the overall survival in subjects with newly-diagnosed glioblastoma (GBM) treated with bortezomib/temozolomide/radiation followed by bortezomib/temozolomide for 24 cycles until progression is detected or for up to 24 cycles (\ 2 years). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | 2 years | — |
| Time to Progression | From the completion of radiation treatment to tumor progression | Median time to tumor progression. Because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. A 7-point scale was used to guide Magnetic resonance imaging (MRI) assessment to determine progression in this study. A -2 or -3 assessment will be taken as progression. The 7-point scale is listed below. complete resolution of tumor: 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 new lesion: -3 |
| Survival at 1 Year | 1 year | Overall Survival at 12 months from completion of radiation treatment |
| Tumor Progression as Assessed by Magnetic Resonance Imaging (MRI) and Neurologic Exam | at 6, 12, 18 and 24 months from completion of radiation treatment. | MRI will be done 2 weeks after completion of radiation and then every 8 weeks. Neurologic exam to be performed every 2 weeks during radiation therapy, then every every 4 weeks after radiation is completed. |
Countries
United States
Participant flow
Recruitment details
Recruitment period: 10/03/2011 - 4/17/2015 Location: University of California at Los Angeles, Columbia University, New York.
Pre-assignment details
There are no pre-assignment details to describe.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Patients receive bortezomib IV on days 1, 4, 8, 11, 29, 32, 36, and 39 and oral temozolomide on days 1-42.Patients undergo external-beam fractionated regional radiotherapy 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity.2-6 weeks after radiotherapy, patients receive bortezomib IV on days 1, 4, 8, and 11 and oral temozolomide on days 1-5.Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
bortezomib + temozolomide+ radiation therapy: Patients will be treated with Bortezomib at 1.3 mg/m2 IV on days1,4,8,11,29,32,36 and 39 and Temozolomide on 75mg/m2 daily during radiation. External beam fractionated regional radiation will be given on consecutive week days at 200 centigrays (cGy) daily doses to a total dose of 6000 cGy. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Experimental |
|---|---|
| Age, Continuous Age Range | 57 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 24 |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 5 / 24 |
Outcome results
Primary
Overall Survival
Estimate the overall survival in subjects with newly-diagnosed glioblastoma (GBM) treated with bortezomib/temozolomide/radiation followed by bortezomib/temozolomide for 24 cycles until progression is detected or for up to 24 cycles (\ 2 years).
Time frame: 2 years
Population: From completion of radiation treatment to tumor progression
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Experimental | Overall Survival | 19.1 months |
Secondary
Survival at 1 Year
Overall Survival at 12 months from completion of radiation treatment
Time frame: 1 year
Population: 12 months from completion of radiation treatment to tumor progression.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Survival at 1 Year | 87.5 percentage of participants |
Secondary
Time to Progression
Median time to tumor progression. Because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. A 7-point scale was used to guide Magnetic resonance imaging (MRI) assessment to determine progression in this study. A -2 or -3 assessment will be taken as progression. The 7-point scale is listed below. complete resolution of tumor: 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 new lesion: -3
Time frame: From the completion of radiation treatment to tumor progression
Population: From the completion of radiation treatment to tumor progression
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental | Time to Progression | 6.2 months |
Secondary
Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.
Time frame: 2 years
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Radiotherapy phase | Grade 4 Toxicity | 1 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Radiotherapy phase | < Grade 3 Toxicity | 17 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Radiotherapy phase | Grade 3 toxicity | 6 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Post Radiotherapy phase | Grade 3 toxicity | 7 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Post Radiotherapy phase | Grade 4 Toxicity | 0 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Post Radiotherapy phase | < Grade 3 Toxicity | 17 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Follow-up phase | Grade 3 toxicity | 0 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Follow-up phase | Grade 4 Toxicity | 0 Participants |
| Experimental | Toxicity Assessed According to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. | Follow-up phase | < Grade 3 Toxicity | 24 Participants |
Secondary
Tumor Progression as Assessed by Magnetic Resonance Imaging (MRI) and Neurologic Exam
MRI will be done 2 weeks after completion of radiation and then every 8 weeks. Neurologic exam to be performed every 2 weeks during radiation therapy, then every every 4 weeks after radiation is completed.
Time frame: at 6, 12, 18 and 24 months from completion of radiation treatment.
Population: Outcome was not analyzed separately, MRI and Neurological exam were to determine the progression status, and finally reflected as Progression Free Survival and Overall Survival
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Experimental | Tumor Progression as Assessed by Magnetic Resonance Imaging (MRI) and Neurologic Exam | Progression Free Survival rate at 12 months | 29.2 percentage of participants |
| Experimental | Tumor Progression as Assessed by Magnetic Resonance Imaging (MRI) and Neurologic Exam | Progression Free Survival rate at 6 months | 54.2 percentage of participants |
| Experimental | Tumor Progression as Assessed by Magnetic Resonance Imaging (MRI) and Neurologic Exam | Progression Free Survival rate at 18 months | 25.0 percentage of participants |
| Experimental | Tumor Progression as Assessed by Magnetic Resonance Imaging (MRI) and Neurologic Exam | Progression Free Survival rate at 24 moths | 25 percentage of participants |