Phase III Trial of Anaplastic Glioma Without 1p/19q LOH
Phase III Trial of Anaplastic Glioma Without 1p/19q LOH
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.
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, 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.

 NOTE: *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 QLQ-C30 version 3, 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.
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

 -  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

 -  AST and 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