Recurrent Central Nervous System Neoplasm
Conditions
Keywords
adult glioblastoma, adult gliosarcoma, adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult mixed glioma, recurrent adult brain tumor
Brief summary
RATIONALE: 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. PURPOSE: This phase II trial is studying how well temozolomide works in treating patients with recurrent high-grade glioma.
Detailed description
OBJECTIVES: Primary * Determine the efficacy, as measured by 6-month progression-free survival, of a dose-intense temozolomide treatment schedule in patients with recurrent high-grade glioma. Secondary * Assess the toxicities of this dose-intense temozolomide. * Determine the overall survival of patients treated with this dose-intense schedule. * Determine whether methylation status of the MGMT gene within patients' tumors predicts greater efficacy (progression-free survival), in patients treated on this protocol. * Determine whether patients' tumors have functional alterations of the mismatch repair (MMR) system by PCR analysis for microsatellite instability (MSI) and whether such alterations may influence outcome in patients treated on this protocol. * Determine how initial success with temozolomide may influence outcome in recurrent patients treated on this protocol by evaluating patients progressing after two first-line adjuvant courses of temozolomide, patients progressing within 6 months after the 6th adjuvant course of temozolomide, and patients progressing 6 months after temozolomide is voluntarily discontinued. OUTLINE: Patients receive oral temozolomide once daily on days 1-7 and days 15-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Formalin-fixed paraffin-embedded tissue blocks or unstained paraffin slides from available surgical samples are evaluated for molecular abnormalities in the tumor, including (but not limited to) MGMT status and microsatellite instability. After completion of study therapy, patients are followed every 3 months for survival. PROJECTED ACCRUAL: A total of 40 patients with WHO II grade 4 tumors (glioblastoma multiforme \[GBM\]) and 20 patients with WHO II grade 3 tumors (non-GBM) will be accrued for this study.
Interventions
DRUGtemozolomide
single arm study
Sponsors
National Cancer Institute (NCI)
University of California, San Francisco
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
* Patients with radiographically proven recurrent, intracranial malignant glioma will be eligible for this protocol. * All patients must sign an informed consent * Patients must have had external beam radiation; there is no limit to the number of prior chemotherapies used. * Patients must be \> 18 years old, and with a life expectancy \> 8 weeks. * Patients must have a Karnofsky performance status of \> 60. * At the time of registration: Patients must have recovered from the toxic effects of prior therapy: * Patients must have adequate bone marrow function. * Patients must have shown unequivocal radiographic evidence for tumor progression by MRI * Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: They have recovered from the effects of surgery. Residual disease following resection of recurrent intracranial malignant glioma is not mandated for eligibility into the study. * Patients must have failed prior radiation therapy and must have an interval of greater than or equal to 42 days from the completion of radiation therapy to study entry. * Patients with prior therapy that included interstitial brachytherapy, stereotactic radiosurgery, or Gliadel wafers must have confirmation of true progressive disease rather than radiation necrosis based upon either PET or MR spectroscopy or surgical documentation of disease. * Male and female patients with reproductive potential must use an approved contraceptive method
Exclusion criteria
* Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy * Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible. * Patients must not have active infection or serious intercurrent medical illness. * Patients must not be pregnant/breast feeding and must agree to practice adequate contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Month Progression-free Survival | First day of treatment until progression or until 6 months mark | Efficacy of dose-intense temozolomide treatment schedule, as measured by 6 months progression-free survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | up to 2 years after treatment | — |
| Patients With Tumors With Functional Alterations of the Mismatch Repair (MMR) System | prior to start of study | PCR analysis of tumor tissue for microsatellite instability (MSI). Tissue was obtained during surgeries prior this study. |
| Progression-free Survival (PFS) Based on Tumor MGMT (O(6)-Methylguanine-DNA Methyltransferase) Promoter Methylation Status. | First day of treatment until progression or until 6 months mark | Progression-free survival data (obtained for Primary Outcome Measure) was correlated with tumor MGMT (O(6)-methylguanine-DNA methyltransferase) promoter methylation status, obtained from patients as part of the study. |
| Patients Progressing Within 6 Months After 6th Adjuvant Course of Temozolomide | Within 6 months after 6th adjuvant course of temozolomide | — |
| Patients Progressing 6 Months After Temozolomide is Voluntarily Discontinued | From beginning of voluntarily temozolomide discontinued up to 6 months | — |
| Patients Progressing After Two First-line Adjuvant Courses of Temozolomide | After two first-line adjuvant courses of temozolomide | — |
Countries
United States
Participant flow
Recruitment details
Patients recruited from within established neuro oncology clinic at UCSF. First paient 11.5.2007 and last patient 1.24.2012
Participants by arm
| Arm | Count |
|---|---|
| Glioblastoma Glioblastoma patients were treated with temozolomide at a dose of 150mg/m\^2 daily for seven consecutive days of every other week.
One 28-day cycle included treatment with temozolomide on days 1-7 and days 15-21 with no treatment on days 8-14 | 40 |
| Grade III Glioma Grade III glioma patients were treated with temozolomide at a dose of 150mg/m\^2 daily for seven consecutive days of every other week.
One 28-day cycle included treatment with temozolomide on days 1-7 and days 15-21 with no treatment on days 8-14 | 20 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
Baseline characteristics
| Characteristic | Glioblastoma | Total | Grade III Glioma |
|---|---|---|---|
| Age, Continuous | 55 years | 53 years | 48 years |
| Region of Enrollment United States | 40 participants | 60 participants | 20 participants |
| Sex: Female, Male Female | 12 Participants | 22 Participants | 10 Participants |
| Sex: Female, Male Male | 28 Participants | 38 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 60 |
| other Total, other adverse events | 38 / 60 |
| serious Total, serious adverse events | 0 / 60 |
Outcome results
Primary
6 Month Progression-free Survival
Efficacy of dose-intense temozolomide treatment schedule, as measured by 6 months progression-free survival
Time frame: First day of treatment until progression or until 6 months mark
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glioblastoma | 6 Month Progression-free Survival | 10 percentage of patients |
| Grade III Glioma | 6 Month Progression-free Survival | 50 percentage of patients |
Secondary
Overall Survival
Time frame: up to 2 years after treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glioblastoma | Overall Survival | 21.6 weeks |
| Grade III Glioma | Overall Survival | 100.6 weeks |
Secondary
Patients Progressing 6 Months After Temozolomide is Voluntarily Discontinued
Time frame: From beginning of voluntarily temozolomide discontinued up to 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glioblastoma | Patients Progressing 6 Months After Temozolomide is Voluntarily Discontinued | 4 Participants |
| Grade III Glioma | Patients Progressing 6 Months After Temozolomide is Voluntarily Discontinued | 4 Participants |
Secondary
Patients Progressing After Two First-line Adjuvant Courses of Temozolomide
Time frame: After two first-line adjuvant courses of temozolomide
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glioblastoma | Patients Progressing After Two First-line Adjuvant Courses of Temozolomide | 3 Participants |
| Grade III Glioma | Patients Progressing After Two First-line Adjuvant Courses of Temozolomide | 0 Participants |
Secondary
Patients Progressing Within 6 Months After 6th Adjuvant Course of Temozolomide
Time frame: Within 6 months after 6th adjuvant course of temozolomide
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glioblastoma | Patients Progressing Within 6 Months After 6th Adjuvant Course of Temozolomide | 4 Participants |
| Grade III Glioma | Patients Progressing Within 6 Months After 6th Adjuvant Course of Temozolomide | 1 Participants |
Secondary
Patients With Tumors With Functional Alterations of the Mismatch Repair (MMR) System
PCR analysis of tumor tissue for microsatellite instability (MSI). Tissue was obtained during surgeries prior this study.
Time frame: prior to start of study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Glioblastoma | Patients With Tumors With Functional Alterations of the Mismatch Repair (MMR) System | 0 Participants |
| Grade III Glioma | Patients With Tumors With Functional Alterations of the Mismatch Repair (MMR) System | 0 Participants |
Secondary
Progression-free Survival (PFS) Based on Tumor MGMT (O(6)-Methylguanine-DNA Methyltransferase) Promoter Methylation Status.
Progression-free survival data (obtained for Primary Outcome Measure) was correlated with tumor MGMT (O(6)-methylguanine-DNA methyltransferase) promoter methylation status, obtained from patients as part of the study.
Time frame: First day of treatment until progression or until 6 months mark
Population: Tumor tissue was available for the exploratory MGMT methylation analysis in 48 patients. In 7 samples the tissue was inadequate for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glioblastoma | Progression-free Survival (PFS) Based on Tumor MGMT (O(6)-Methylguanine-DNA Methyltransferase) Promoter Methylation Status. | 8.14 weeks |
| Grade III Glioma | Progression-free Survival (PFS) Based on Tumor MGMT (O(6)-Methylguanine-DNA Methyltransferase) Promoter Methylation Status. | 7.57 weeks |
| Grade III Glioma With Methylated MGMT | Progression-free Survival (PFS) Based on Tumor MGMT (O(6)-Methylguanine-DNA Methyltransferase) Promoter Methylation Status. | 38.1 weeks |
| Grade III Glioma With Unmethylated MGMT | Progression-free Survival (PFS) Based on Tumor MGMT (O(6)-Methylguanine-DNA Methyltransferase) Promoter Methylation Status. | 48.6 weeks |