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

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