Phase III Trial of Anaplastic Glioma Without 1p/19q Loss of Heterozygosity (LOH)

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. 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. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known whether giving temozolomide during and/or after radiation therapy is more effective than radiation therapy alone in treating anaplastic glioma. PURPOSE: This randomized phase III trial is studying giving temozolomide during and/or after radiation therapy to see how well it works compared to radiation therapy alone in treating patients with anaplastic glioma.

Detailed Description
-----------------
OBJECTIVES: Primary To assess whether concurrent radiotherapy with daily temozolomide improves overall survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic glioma. To assess whether adjuvant temozolomide improves survival as compared to no adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma. Secondary To assess whether concurrent and adjuvant temozolomide prolongs progression-free survival and neurological deterioration-free survival in patients with non-1p/19q deleted anaplastic glioma. To assess the safety of concurrent and adjuvant temozolomide in patients with non-1p/19q deleted anaplastic glioma, including late effects on cognition. To assess the impact of concurrent and adjuvant temozolomide on the quality of life of patients with non-1p/19q deleted anaplastic glioma. OUTLINE: This is a multicenter study. Patients are stratified according to institution, World Health Organization (WHO) performance status (0 vs > 0), age (≤ 50 vs > 50), presence of 1p LOH only (yes vs no), presence of oligodendroglial elements (yes vs no), and O6-methylguanine-DNA methyltransferase promoter methylation status (methylated vs unmethylated vs indeterminate). Patients are randomized to 1 of 4 treatment arms. Arm I: Patients undergo radiotherapy* once daily, 5 days a week, for 6.5 weeks (total of 33 fractions). Arm II: Patients undergo radiotherapy* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy). Arm III: Patients undergo radiotherapy* once daily, 5 days a week for 6.5 weeks (total of 33 fractions). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses. Arm IV: Patients undergo radiotherapy* once daily, 5 days a week and receive oral temozolomide once daily for 6.5 weeks (total of 33 fractions of radiotherapy). Beginning 4 weeks after completion of radiotherapy, patients receive adjuvant oral temozolomide once daily on days 1-5. Treatment with adjuvant temozolomide repeats every 28 days for up to 12 courses. Patients must begin radiotherapy within 8 days after randomization and within 7 weeks after surgery. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients complete quality-of-life questionnaires, including EORTC core quality of life questionnaire (QLQ-C30) version 3, EORTC brain cancer module (BCM20), and the Mini Mental Status Exam at baseline, 4 weeks after the completion of radiotherapy, and then every 3 months for 5 years. Tissue samples are collected at baseline for histology review, 1p/19q analysis, methylation status of the O6-methylguanine-DNA methyltransferase promoter, and isocitrate dehydrogenase mutation analysis. After completion of study treatment, patients are followed every 3 months.

Official Title
-----------------
Phase III Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma. The CATNON Intergroup Trial.

Conditions
-----------------
Brain and Central Nervous System Tumors

Intervention / Treatment
-----------------
* Drug: temozolomide
* Genetic: DNA methylation analysis
* Other: laboratory biomarker analysis
* Procedure: adjuvant therapy
* Procedure: quality-of-life assessment
* Radiation: radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed diagnosis of 1 of the following: Anaplastic oligodendroglioma Anaplastic oligoastrocytoma Anaplastic astrocytoma Newly diagnosed disease Prior surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression Absence of combined 1p/19q loss Tumor material available for central 1p/19q assessment, central O6-methylguanine-DNA methyltransferase promoter methylation status assessment, isocitrate dehydrogenase mutation analysis, and central pathology review Patients must be on a stable or decreasing dose of steroids for at least two weeks prior to randomization PATIENT CHARACTERISTICS: WHO performance status 0-2 Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9 cells/L Platelet count ≥ 100 x 10^9 cells/L Bilirubin < 1.5 x upper limit of normal (ULN) Alkaline phosphatase < 2.5 x ULN Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 2.5 x ULN Serum creatinine < 1.5 x ULN Not pregnant or nursing Fertile patients must use effective contraception No known HIV infection or chronic hepatitis B or hepatitis C infection No other serious medical condition that would interfere with follow-up No medical condition that could interfere with oral medication intake (e.g., frequent vomiting or partial bowel obstruction) No other prior malignancies except for any malignancy which was treated with curative intent more than 5 years prior to registration and adequately controlled limited basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix No prior or concurrent malignancies at other sites except for surgically cured carcinoma in situ of the cervix or nonmelanoma skin cancer No psychological, familial, sociological, or geographical condition that would potentially hamper compliance with the study protocol and follow-up schedule PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy, including carmustine-containing wafers (Gliadel®) No prior radiotherapy to the brain No concurrent growth factors unless vital for the patient No other concurrent investigational treatment No other concurrent anticancer agents

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Radiotherapy (RT) alone<br>radiation therapy alone | Genetic: DNA methylation analysis<br>* O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status is used for stratification at randomization.<br>Other: laboratory biomarker analysis<br>* Prognostic factor analyses<br>Procedure: quality-of-life assessment<br>* Quality of Life analysis will also be used to assess neurological deterioration free progression<br>Radiation: radiation therapy<br>* Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule<br>|
| Active Comparator: RT & Concurrent CT<br>Radiotherapy and concurrent temozolomide chemotherapy | Drug: temozolomide<br>* Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.<br>* Other names: Temodal;Genetic: DNA methylation analysis<br>* O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status is used for stratification at randomization.<br>Other: laboratory biomarker analysis<br>* Prognostic factor analyses<br>Procedure: quality-of-life assessment<br>* Quality of Life analysis will also be used to assess neurological deterioration free progression<br>Radiation: radiation therapy<br>* Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule<br>|
| Active Comparator: RT + Adjuvant CT<br>Radiotherapy plus adjuvant temozolomide chemotherapy | Drug: temozolomide<br>* Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.<br>* Other names: Temodal;Genetic: DNA methylation analysis<br>* O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status is used for stratification at randomization.<br>Other: laboratory biomarker analysis<br>* Prognostic factor analyses<br>Procedure: adjuvant therapy<br>* Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting period after the end of radiotherapy.<br>Procedure: quality-of-life assessment<br>* Quality of Life analysis will also be used to assess neurological deterioration free progression<br>Radiation: radiation therapy<br>* Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule<br>|
| Active Comparator: RT & Concurrent CT + adjuvant CT<br>Radiotherapy and concurrent chemotherapy plus adjuvant temozolomide chemotherapy | Drug: temozolomide<br>* Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily dose of 75 mg/m² during radiotherapy.<br>* Other names: Temodal;Genetic: DNA methylation analysis<br>* O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status is used for stratification at randomization.<br>Other: laboratory biomarker analysis<br>* Prognostic factor analyses<br>Procedure: adjuvant therapy<br>* Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting period after the end of radiotherapy.<br>Procedure: quality-of-life assessment<br>* Quality of Life analysis will also be used to assess neurological deterioration free progression<br>Radiation: radiation therapy<br>* Radiotherapy will consist of a conventionally fractionated regimen for 6.5 weeks in a once daily schedule<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival as Measured From the Day of Randomization | The duration of survival is the time interval between randomization and the date of death due to any cause. Patients not reported dead or lost to follow up will be censored at the date of the last follow up examination. | from date from enrollment till the date of death (time till death is up to 10.9 years after patient enrollment in the study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Disease progression is defined as radiological or neurological/clinical progression (whichever occurs first); progression free survival (PFS) is the time interval between the date of randomization and the date of disease progression or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination. Radiological progression was defined as increase of contrast enhancing area on MRI or CT scans of more than 25% as measured by two perpendicular diameters compared to the smallest measurements ever recorded for the same lesion by the same technique. The appearance of new lesions with or without contrast enhancement Neurological/clinical progression was defined as:decrease in WHO performance status,deterioration of neurological functions,appearance of signs/symptoms of increased intracranial pressure,and/or start of corticosteroid or increase of corticosteroid dosage by 50% for control of neurological symptoms. | from randomization till the date of disease progression or death (time till death is up to 10.9 years after patient enrollment in the study) | 
| Quality of Life of the Patient | Quality of life was assessed by the EORTC Quality of Life Questionnaire (QLQ-C30) version 3 and the Brain Cancer Module-20 | from 14 days prior to randomization till five years or death (time till death is up to 10.9 years after patient enrollment in the study) | 
| Neurological Deterioration Free Survival | Neurological deterioration is defined as a decrease in WHO performance status as follows: decrease in WHO performance status for patients with baseline WHO performance status 0: deterioration to WHO performance status 2 or worse for which no other explanation is present, and which is maintained for at least three months for patients with baseline WHO performance status 1 or 2: deterioration to WHO performance status 3 or worse for which no other explanation is present and which is maintained for at least three months The date of neurological deterioration will be the first date the persistent decrease in performance status was diagnosed. Neurological deterioration free progression is the time interval between the date of randomization and the date of neurological deterioration or death whichever occurs first. If neither event has been observed, the patient is censored at the date of the last follow up examination | within 2 weeks of randomization; during radiotherapy at week 4 and 6; 4 weeks after the end of radiotherapy; Six monthly after the end of radiotherapy; Prior to each cycle of adjuvant therapy; Every six months after the documentation of first progression. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult anaplastic oligodendroglioma, adult anaplastic astrocytoma