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

Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

Sponsor score: 0

ClinicalTrials ID:NCT00626990

This Phase III trial evaluates the efficacy of temozolomide with radiation therapy in non-1p/19q deleted anaplastic glioma. Patients are randomized into four arms, receiving varying combinations of radiotherapy and temozolomide. The study assesses overall survival, progression-free survival, safety, and quality of life. Interventions include temozolomide, DNA methylation analysis, and quality-of-life assessments.

Patient Parameters

Parameter	Options

Program Overview

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.

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.

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

Locations

FACILITY	CITY	STATE
Arizona Oncology Services Foundation	Phoenix	Arizona
Cedars-Sinai Medical Center	Los Angeles	California
UCSF University of California San Francisco Medical Center-Mount Zion	San Francisco	California
University of Florida	Gainesville	Florida
Mayo Clinic in Florida	Jacksonville	Florida
Florida Hospital	Orlando	Florida
Emory University	Atlanta	Georgia
Memorial Health University Medical Center	Savannah	Georgia
Northwestern University	Chicago	Illinois
Loyola University Medical Center	Maywood	Illinois

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