Motexafin Gadolinium, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of motexafin gadolinium (MGd) when given concurrently
with temozolomide and radiotherapy in patients with newly diagnosed supratentorial
glioblastoma multiforme (GBM) or gliosarcoma.

II. Estimate the overall survival of patients treated with concurrent radiotherapy,
temozolomide, and MGd followed by post-radiation temozolomide.

III. Determine the short- and long-term adverse effects in patients treated with this
treatment.

IV. Estimate the progression-free survival of patients with newly diagnosed supratentorial
GBM or gliosarcoma treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of motexafin gadolinium (MGd).

PHASE I: Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and
36-40. Beginning the night before the first dose of radiotherapy and ending the night before
the last dose of radiotherapy, patients receive concurrent oral temozolomide once daily on
days 0-39. Patients also receive MGd IV over 30 minutes prior to radiotherapy once daily on
days 1-5 and 8-12 and then on days 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, and 40.
Beginning 28 days after the completion of radiotherapy, patients receive oral temozolomide
once daily on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence
of disease progression or unacceptable toxicity.

Cohorts of 3-7 patients receive escalating doses of MGd until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which no more than 6
eligible patients experience dose-limiting toxicity.

PHASE II: Patients undergo radiotherapy and receive temozolomide as in phase I. Patients also
receive MGd as in phase I at the MTD determined in phase I.

After completion of study treatment, patients are followed every 2 months for 1 year, every 3
months for 2 years, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

- Histologically confirmed glioblastoma multiforme (GBM) or gliosarcoma

- Newly diagnosed by surgical biopsy or excision within the past 5 weeks

- Supratentorial location, as determined by the following:

- Contrast-enhanced MRI performed preoperatively

- MRI performed postoperatively within 28 days prior to study entry (preferably
within 72 hours of surgery)

- Postoperative scan not required if diagnosed by stereotactic biopsy and
pre-operative MRI was performed

- No gliomas graded < GBM

- No recurrent malignant gliomas

- No tumor foci detected below the tentorium or beyond the cranial vault

- No multifocal disease or leptomeningeal spread

- Zubrod performance status 0-1

- Neurologic function status 0-2

- Absolute neutrophil count ≥ 1,800 cells/mm^3

- Platelet count ≥ 100,000 cells/mm^3

- Hemoglobin ≥ 8 g/dL (transfusion allowed)

- BUN ≤ 25 mg/dL

- Creatinine ≤ 1.5 mg/dL

- Bilirubin ≤ 1.5 mg/dL

- ALT or AST ≤ 2 times upper limit of normal

- Fertile patients must use effective contraception during and for 2 months after
completion of study treatment

- Negative pregnancy test

- Not pregnant or nursing

- No prior invasive malignancies, except for nonmelanomatous skin cancer and carcinoma
in situ of the uterine cervix or bladder, unless disease-free for ? 3 years

- No severe, active comorbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the past 6 months

- Transmural myocardial infarction within the past 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at study
entry

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days prior to
study entry

- Coagulation defects

- Known AIDS

- No prior allergic reaction to the study drugs

- No history of porphyria or G6PD deficiency

- No allergy to gadolinium or contraindications to MRI

- No other concurrent chemotherapy

- Recovered from effects of surgery or postoperative infection and other complications

- No prior systemic chemotherapy, including polifeprosan 20 with carmustine implant
(Gliadel wafer), for the current GBM

- Prior chemotherapy for a different cancer allowed

- No prior radiotherapy to the head and neck (except for T1 glottic cancer) that would
result in overlap of radiation therapy fields

- No prophylactic filgrastim (G-CSF) during the first course of study treatment

- No concurrent sargramostim (GM-CSF)