Brain Tumors, Central Nervous System(CNS)Malignancies, Osteoporosis
Conditions
Keywords
osteoporosis, adult anaplastic astrocytoma, adult giant cell glioblastoma, adult anaplastic oligodendroglioma, adult gliosarcoma, adult mixed glioma, recurrent adult brain tumor, adult glioblastoma
Brief summary
RATIONALE: Zoledronate may prevent bone loss in patients with primary malignant glioma. PURPOSE: This phase II trial is studying how well zoledronate works in preventing osteoporosis in patients with primary malignant glioma.
Detailed description
This is an open-labeled trial to determine the incidence of osteoporosis in brain tumor patients and effect of Zometa every three months. Zometa will be given at 4 mg intravenously over 15 minutes every 3 months for 1 year. The patients will undergo a baseline bone densitometry test that will be repeated at six months and one year. Information on the patient's tolerability of Zometa as well as any skeletal-related complications that happen will be collected. Data with respect to the dose and duration of glucocorticoids and anticonvulsants will be collected since both of these therapies have shown to directly affect bone density. Serial markers (N-telopeptide) of bone turn over will be collected at baseline and every 3 months prior to the infusion of Zometa. Karnofsky performance status will be monitored as a function of mobility. Accrual Goal 60 patients over a 18-month period, averaging 3-4 new enrollees per month. Thirty-five patients to reach the 6-month assessment. OBJECTIVES: * To determine the bone mineral density of the patients at baseline and any changes over 12 months while receiving Zometa every 3 months. * To determine the incidence of skeletal-related complications in this cohort of brain tumor patients. * To determine the safety and tolerability of Zometa in brain tumor patients. * To determine the effects of glucocorticoids and anticonvulsants on bone density. Response Criteria The primary efficacy endpoint will be the patient's bone densitometry, and how it changes over the course of one year of Zometa therapy. The bone densitometry after 6 months and 12 months of Zometa will be compared to the baseline. The secondary efficacy variable will be the prevention of skeletal-related events (compression fracture, any fracture requiring surgery) which given the heterogeneity of the patient population will be a qualitative variable. Date with respect to the dose and duration of glucocorticoids and anticonvulsants will be collected since both of these therapies have shown to directly affect bone density. Serial markers (N-telopeptide) of bone turn over will be collected. Outcome assessment The patient's bone densitometry will be determined by Dexa-scan at the baseline, after six months of Zometa and after one year of Zometa. The bone density (Dexa- scan) will be reviewed by the outside radiologist or Duke radiology in conjunction with the primary investigator. A decrease of \> -0.5 on the T-score will be coded as a treatment failure and patients will be discontinued from the study and referred to Endocrinology or Orthopedic Surgery for best clinical management. In addition, any skeletal-related event (fractures) will be coded as a treatment failure. The patient population will be heterogeneous in terms of their functional capacity, exercise capacity, anticonvulsant and glucocorticoid dos
Interventions
DRUGIV Zometa
Zometa will be given at 4 mg intravenously over 15 minutes every 3 months for 1 year.
Sponsors
Novartis
National Institute of Neurological Disorders and Stroke (NINDS)
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have histologically confirmed diagnosis of a primary brain tumor. 2. Patients must be on Depakote ( Valproic Acid) or one of the following enzyme inducing anticonvulsants (EIAC) therapies. Phenobarbital, Dilantin, Trileptal, Tegretol and/or on more than physiologic replacement steroid therapy (Dexamethasone \>0.75 mg/d, prednisone \>5 mg/d or hydrocortisone \>20 mg/d). 3. Age \> 18 years. 4. Karnofsky performance score \> 60% 5. Adequate renal and liver function as demonstrated by laboratory values performed within 14 days, inclusive, prior to the administration of Zometa, except for the creatinine, which will be within 72 hs of Zometa administration: * Serum creatinine \< 2.0 mg/dl and calculated creatinine clearance of \>60 mL/min * Total serum bilirubin \< 1.5 times upper limit of laboratory normal * Serum glutamoc-oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) \< 2.5 times upper limit of laboratory normal * Alkaline phosphatase of \<2 times upper limit of laboratory normal 6. Patients must have recovered from any effects of major surgery. 7. Patients must have a life expectancy of greater than 12 weeks. 8. Patients or legal guardian must give written, informed consent.
Exclusion criteria
1. Patients who are poor medical risks because of non-malignant systemic disease as well as those with acute infection treated with intravenous antibiotics. 2. Previous or concurrent malignancies at other sites with the exception of surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin. 3. Known HIV positivity or AIDS-related illness. 4. Pregnant or nursing women. 5. Women of childbearing potential who are not using an effective method of contraception. Women of childbearing potential must have a negative serum pregnancy test 72hours prior to administration of study and be practicing medically approved contraceptive precautions. 6. Men who are not advised to use and effective method of contraception. 7. Patients previously diagnosed with osteoporosis requiring oral bisphosphonates. 8. Known hypersensitivity to Zometa® (zoledronic acid) or other bisphosphonates 9. Current active dental problems including infection of the teeth or jawbone osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures. 10. Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients With Change in Combined Bone Mass Density T-score <= -0.5. | 6 and 12 months | Percent of patients who failed treatment as defined by a decrease of 0.5 or more from baseline in the combined T-score as measured by Dexa-scan. The patient's bone densitometry was determined by Dexa-scan at baseline, after 6 months of Zometa and after 1 year of Zometa. The t-score, which is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex, was generated by Dexa-scan for the spine and femur. The combined T-score is the minimum of the T-score for the spine and femur. A lower t-score implies a lower BMD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Skeletal-related Complications | 1 year | Number of patients who experience skeletal-related complications during the administration of Zoledronate. |
| Mean Change in Bone Mass Density (BMD) | 6 & 12 months | Mean change in the combined t-score was measured by Dexa-scan. The patients bone density was determined by Dexa-scan at baseline, after 6 months Zometa and after 12 months of Zometa. The t-score, which is a comparison of a person's bone density with that of a healthy 30-year old of the same sex, was generated by Dexa-scan for the spine and femur. A lower t-score implies a lower BMD. The combined t-score is the minimum of the t-score for the spine and that for the femur. BMD change from baseline at 6 and 12 months in the combined t-score was defined as the follow-up combined t-score minus the baseline combined t-score. |
Countries
United States
Participant flow
Recruitment details
Patients were accrued between February 2006 and January 2008 within the clinic at Duke Comprehensive Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| IV Zometa Zometa will be given at 4 mg intravenously over 15 minutes every 3 months for 1 year. | 59 |
| Total | 59 |
Baseline characteristics
| Characteristic | IV Zometa |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 49 Participants |
| Age Continuous | 54.7 years STANDARD_DEVIATION 9.4 |
| Anticonvulsant use no | 5 participants |
| Anticonvulsant use yes | 54 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 38 Participants |
| Steroid use no | 18 participants |
| Steroid use yes | 41 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 59 |
| serious Total, serious adverse events | 16 / 59 |
Outcome results
Primary
Percent of Patients With Change in Combined Bone Mass Density T-score <= -0.5.
Percent of patients who failed treatment as defined by a decrease of 0.5 or more from baseline in the combined T-score as measured by Dexa-scan. The patient's bone densitometry was determined by Dexa-scan at baseline, after 6 months of Zometa and after 1 year of Zometa. The t-score, which is a comparison of a person's bone density with that of a healthy 30-year-old of the same sex, was generated by Dexa-scan for the spine and femur. The combined T-score is the minimum of the T-score for the spine and femur. A lower t-score implies a lower BMD.
Time frame: 6 and 12 months
Population: 59 patients were accrued; however only 27 had a follow-up assessment at 6 months and 19 at 12 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IV Zometa | Percent of Patients With Change in Combined Bone Mass Density T-score <= -0.5. | At 6 months (n=27) | 3.7 percentage of patients |
| IV Zometa | Percent of Patients With Change in Combined Bone Mass Density T-score <= -0.5. | At 12 months (n=19) | 10.5 percentage of patients |
Secondary
Mean Change in Bone Mass Density (BMD)
Mean change in the combined t-score was measured by Dexa-scan. The patients bone density was determined by Dexa-scan at baseline, after 6 months Zometa and after 12 months of Zometa. The t-score, which is a comparison of a person's bone density with that of a healthy 30-year old of the same sex, was generated by Dexa-scan for the spine and femur. A lower t-score implies a lower BMD. The combined t-score is the minimum of the t-score for the spine and that for the femur. BMD change from baseline at 6 and 12 months in the combined t-score was defined as the follow-up combined t-score minus the baseline combined t-score.
Time frame: 6 & 12 months
Population: 59 patients were accrued to the study; however follow-up at 6 months was available from 27 patients and at 12 months data was available from 19 patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IV Zometa | Mean Change in Bone Mass Density (BMD) | Change in combined BMD at 6 months (n=27) | .01 T score units | Standard Deviation 0.21 |
| IV Zometa | Mean Change in Bone Mass Density (BMD) | Change in combined BMD at 12 months (n=19) | -.06 T score units | Standard Deviation 0.31 |
Comparison: 59 patients were accrued to the study. The 27 patients with follow-up at 6 months are included in an analysis to assess the association between baseline steroid use and bone mass density at 6 months using linear regression.p-value: 0.2212Regression, Linear
Comparison: 59 patients were accrued to the study. The 27 patients with follow-up at 6 months are included in an analysis to assess the association between baseline anticonvulsant use and bone mass density at 6 months using linear regressionp-value: 0.0413Regression, Linear
Comparison: 59 patients were accrued to the study. The 19 patients with follow-up at 12 months are included in an analysis to assess the association between baseline steroid use and bone mass density at 12 months using linear regressionp-value: 0.0418Regression, Linear
Comparison: 59 patients were accrued to the study. The 19 patients with follow-up at 12 months are included in an analysis to assess the association between baseline anti-convulsant use and bone mass density at 12 months using linear regressionp-value: 0.1026Regression, Linear
Secondary
Skeletal-related Complications
Number of patients who experience skeletal-related complications during the administration of Zoledronate.
Time frame: 1 year
Population: All patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Zometa | Skeletal-related Complications | 0 participants |