Temozolomide in Treating Patients With Recurrent High-Grade Glioma

Study Overview
=================
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.

Official Title
-----------------
Phase II Study of 7 Days On/7 Days Off Temozolomide in Patients With High-Grade Glioma

Conditions
-----------------
Recurrent Central Nervous System Neoplasm

Intervention / Treatment
-----------------
* Drug: temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temozolomide<br>single arm trial; Patients treated with temozolomide at a dose of 150mg/m2 daily for seven consecutive days of every other week. One 28-day cycle will include treatment with temozolomide on days 1-7 and days 15-21 with no treatment on days 8-14 | Drug: temozolomide<br>* single arm study<br>* Other names: temodar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Month Progression-free Survival | Efficacy of dose-intense temozolomide treatment schedule, as measured by 6 months progression-free survival | First day of treatment until progression or until 6 months mark | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | First day of treatment until progression or until 6 months mark | 
| Overall Survival |  | up to 2 years after treatment | 
| 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. | prior to start of study | 
| Patients Progressing After Two First-line Adjuvant Courses of Temozolomide |  | After two first-line adjuvant courses of temozolomide | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult glioblastoma, adult gliosarcoma, adult anaplastic astrocytoma, adult anaplastic oligodendroglioma, adult mixed glioma, recurrent adult brain tumor