Brain and Central Nervous System Tumors
Conditions
Keywords
adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma
Brief summary
RATIONALE: Celecoxib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. It is not yet known whether the effectiveness of celecoxib in treating glioblastoma multiforme is decreased in patients who are receiving anticonvulsant drugs and undergoing radiation therapy. PURPOSE: Phase II trial to study the effectiveness of celecoxib in treating patients who are receiving anticonvulsant drugs and undergoing radiation therapy for newly diagnosed glioblastoma multiforme.
Detailed description
OBJECTIVES: Primary * Determine the effects of hepatic enzyme-inducing drugs, such as anticonvulsants, on the pharmacokinetics of celecoxib in patients with newly diagnosed glioblastoma multiforme undergoing radiotherapy. * Determine the effects of steroids on the pharmacokinetics of celecoxib in these patients. Secondary * Determine the safety of celecoxib in these patients. * Determine the duration of survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Patients are assigned to 1 of 2 groups based on anticonvulsant therapy. * Group A: Patients treated with any of the following anticonvulsant drugs that induce hepatic metabolic enzymes: * Phenytoin * Carbamazepine * Phenobarbital * Primidone * Oxcarbazepine * Group B: Patients treated with any of the following anticonvulsant drugs that cause modest or no induction of hepatic metabolic enzymes OR no anticonvulsant drug: * Gabapentin * Lamotrigine * Valproic acid * Levetiracetam * Tiagabine * Topiramate * Zonisamide * Felbamate * Induction therapy: Patients in both groups receive oral celecoxib twice\* daily on weeks 1-11 and undergo radiotherapy 5 days a week on weeks 2-7. * Maintenance therapy: Patients receive oral celecoxib twice daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients receive only 1 dose on the first day of celecoxib administration. Patients are followed every 2 months. PROJECTED ACCRUAL: A total of 44 patients (22 per group) will be accrued for this study within approximately 8 months.
Interventions
RADIATIONradiation therapy
Radiation is standard treatment 6000cGy in 30 fractions. Patients will receive celecoxib 400 mg bid during RT treatment
DRUGCelecoxib
Celecoxib will begin 1 week prior to RT at 400mg bid orally. One day 1 only 1 dose will be administered. Starting on day 2 and throughout treatment until progression, 2 doses will be administered at least 12 hours apart. Celecoxib will continue throughout the 6 week course of RT.
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed glioblastoma multiforme * Supratentorial * Grade IV astrocytoma PATIENT CHARACTERISTICS: Age * 18 and over Performance status * Karnofsky 60-100% Life expectancy * Not specified Hematopoietic * Absolute neutrophil count at least 1,500/mm\^3 * Platelet count at least 100,000/mm\^3 * Hemoglobin at least 9.0 g/dL Hepatic * Bilirubin no greater than 1.5 mg/dL * Transaminases no greater than 4 times upper limit of normal Renal * Creatinine no greater than 1.7 mg/dL * Creatinine clearance at least 60 mL/min * No prior renal toxicity with nonsteroidal anti-inflammatory drugs Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Mini mental score at least 15 * No history of peptic disease * No serious concurrent infection * No other medical illness that would preclude study participation * No other malignancy within the past 5 years except curatively treated carcinoma in situ or basal cell skin cancer * No allergy to sulfonamides * Able to tolerate cyclo-oxygenase-2 (COX-2) inhibitors PRIOR CONCURRENT THERAPY: Biologic therapy * No prior immunotherapy or biologic agents for the malignancy, including any of the following: * Immunotoxins * Immunoconjugates * Antisense agents * Peptide receptor antagonists * Interferons * Interleukins * Tumor-infiltrating lymphocytes * Lymphokine-activated killer cells * Gene therapy * No concurrent prophylactic growth factors (e.g., filgrastim \[G-CSF\] or sargramostim \[GM-CSF\]) Chemotherapy * No prior chemotherapy for the malignancy Endocrine therapy * No prior hormonal therapy for the malignancy * Prior glucocorticoid therapy allowed * Concurrent corticosteroids allowed provided there has been no dose increase within the past 5 days Radiotherapy * No prior radiotherapy for the malignancy Surgery * Recovered from prior surgery Other * At least 1 week since prior fluconazole * More than 10 days since prior anticonvulsant drugs that induce hepatic metabolic enzymes (Group A) * No other prior therapy for the malignancy * No concurrent enrollment in another therapeutic clinical trial * No concurrent fluconazole
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effects of Hepatic Enzyme Inducing Drugs Such as Anticonvulsants, on the PK of Celecoxib | First dose of celecoxib through completion of radiation, 6 weeks. | subjects will take one dose of celecoxib and will then have 6 hours of blood draws, day 2 subject will take 2 doses of celecoxib 8 hours apart with 2 additional blood samples, one hour apart. Subject, will continue to take 2 doses of celecoxib for 6 weeks, with a sample (PK) drawn every week prior to the first dose of the week. Comparison of Cmax of Celecoxib is reported |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | date pt started treatment to date pt last known alive | duration of survival when celecoxib is administered concurrently with radiation in pts with newly diagnosed glioblastoma multiforme |
Countries
United States
Participant flow
Recruitment details
pts were enrolled on this study from October 2003 to September 2004. Pts were enrolled in an outpatient clinical setting
Pre-assignment details
pts were assigned to an arm at the time of enrollment
Participants by arm
| Arm | Count |
|---|---|
| p450 ( +EIASD) on p450 inhibitor (Patients taking anttiseizure drugs that are known to induce the hepatic drug-metabolizing enzymes - including phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine) | 22 |
| nonp450 (-EIASD) not on p450 inhibitor (Patients either NOT taking anti-seizure drugs or ones that are known to not significantly influence the hepatic drug-metabolizing enzymes - including gabapentin, lamotrigine, valproic acid, levetiracetam, tiagabine,topiramate, zonisamide and filbamate. | 13 |
| Total | 35 |
Baseline characteristics
| Characteristic | nonp450 (-EIASD) | p450 ( +EIASD) | Total |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 17 | 58 years STANDARD_DEVIATION 12 | 57 years STANDARD_DEVIATION 26 |
| Corticosteroid therapy No | 2 Participants | 4 Participants | 6 Participants |
| Corticosteroid therapy Yes | 11 Participants | 18 Participants | 29 Participants |
| Karnofsky Perfomance Status (KPS) | 83 scores on a scale STANDARD_DEVIATION 9 | 88 scores on a scale STANDARD_DEVIATION 11 | 86 scores on a scale STANDARD_DEVIATION 10 |
| Mini Mental State Exam Score | 28 scores on a scale STANDARD_DEVIATION 3 | 28 scores on a scale STANDARD_DEVIATION 4 | 28 scores on a scale STANDARD_DEVIATION 3 |
| Prior Surgery Biopsy | 3 Participant | 1 Participant | 4 Participant |
| Prior Surgery Craniotomy | 10 Participant | 21 Participant | 31 Participant |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 14 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 22 | 13 / 13 |
| serious Total, serious adverse events | 0 / 22 | 0 / 13 |
Outcome results
Primary
Effects of Hepatic Enzyme Inducing Drugs Such as Anticonvulsants, on the PK of Celecoxib
subjects will take one dose of celecoxib and will then have 6 hours of blood draws, day 2 subject will take 2 doses of celecoxib 8 hours apart with 2 additional blood samples, one hour apart. Subject, will continue to take 2 doses of celecoxib for 6 weeks, with a sample (PK) drawn every week prior to the first dose of the week. Comparison of Cmax of Celecoxib is reported
Time frame: First dose of celecoxib through completion of radiation, 6 weeks.
Population: pts who had PK data for the first dose of celecoxib. observations were excluded if sample was not collected within 12 +/- 2h after taking prior dose, was drawn after dosing on same day or determine to be outlier by dixon's test.~PK data was available for 15 pts in the +EIASD group and 12 pts in the -EIASD group
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| nonp450 | Effects of Hepatic Enzyme Inducing Drugs Such as Anticonvulsants, on the PK of Celecoxib | 1752 (ng/ml) | Standard Deviation 550 |
| p450 | Effects of Hepatic Enzyme Inducing Drugs Such as Anticonvulsants, on the PK of Celecoxib | 1813 (ng/ml) | Standard Deviation 813 |
Comparison: two independent group comparisonsp-value: 0.8295% CI: [1.5, 5.5]t-test, 2 sided
Secondary
Overall Survival
duration of survival when celecoxib is administered concurrently with radiation in pts with newly diagnosed glioblastoma multiforme
Time frame: date pt started treatment to date pt last known alive
Population: latest survial data was obtained on May 30, 2006. 31/35 pts had died (89%) 21 in the +EIASD group and 10 in -EIASD group
| Arm | Measure | Value (MEAN) |
|---|---|---|
| nonp450 | Overall Survival | 11.5 months |
| p450 | Overall Survival | 16 months |
p-value: 0.1195% CI: [1.1, 6.3]Log Rank