Gossypol (AT-101) and Temozolomide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of gossypol (AT-101) when administered with radiotherapy (RT) and concurrent temozolomide (TMZ) in patients with newly diagnosed glioblastoma multiforme.
• Determine the MTD of gossypol when administered with adjuvant TMZ after standard RT and concurrent TMZ in these patients.

Secondary

• Assess the toxicity of these treatment regimens.
• Assess and describe the pharmacokinetics of gossypol.
• Determine, preliminarily, the therapeutic activities of these regimens.
• Determine the relationship between these regimens and cellular and molecular features identified in tumor biopsy specimens.

OUTLINE: This is a multicenter, open-label, nonrandomized, dose-escalation study of gossypol. Patients are assigned to 1 of 2 treatment groups. Patients who participate in group I are NOT eligible for group II.

• Group I: Patients receive oral gossypol and undergo radiotherapy once daily 5 days a week for up to 6 weeks. Patients also receive oral temozolomide once daily for up to 6 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Group II: Patients receive oral temozolomide on days 1-5 and oral gossypol once daily on days 1-21. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-10 patients per treatment group receive escalating doses of gossypol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 or 3 of 10 patients experience dose-limiting toxicity.

Patients undergo blood collection periodically for pharmacokinetic studies. Tumor tissue samples are examined for biomarkers including, but not limited to, Bcl-2 family protein expression (e.g., Bcl-2, Bcl-xL, MCl-1, Bax, Bak, and BH3 domain), MGMT gene methylation status, and gene expression array.

After completion of study treatment, patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme)
• Meets 1 of the following criteria:

• Completed surgery within the past 6 weeks (group I)
• Received radiotherapy and concomitant temozolomide at least 4 weeks but no more than 7 weeks prior to start of study treatment (group II)
• Must be on a stable corticosteroid regimen (no increase for 5 days)

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Hemoglobin ≥ 10 g/dL
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤1.5 mg/dL
• Bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 2.5 times upper limit of normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after completion of study treatment
• Mini Mental State Exam score ≥ 15
• Must be able to swallow and retain oral medication
• No serious concurrent infection or medical illness that would preclude study participation
• No other malignancy within the past 5 years, except for curatively treated carcinoma in situ or basal cell carcinoma of the skin
• No sensory neuropathy ≥ grade 2
• No allergies to gossypol
• No symptomatic hypercalcemia or hypercalcemia > grade 2
• No gastrointestinal disease including any of the following:

• Malabsorption syndrome
• Disease significantly affecting gastrointestinal function
• Ulcerative colitis
• Inflammatory bowel disease
• Partial or complete small bowel obstruction

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from the immediate postoperative period
• No prior radiotherapy, chemotherapy, immunotherapy, therapy with biologic agents (including immunotoxins, immunoconjugates, antisense agents, peptide-receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocyte therapy, lymphokine-activated killer cells or gene therapy), or hormonal therapy for this brain tumor (group I)

• Prior glucocorticoid therapy allowed
• No prior polifeprosan 20 with carmustine implant (Gliadel wafers) (group I)
• No prior gossypol
• No prior radiosurgery or brachytherapy
• No prior resection of the stomach or small intestine
• No other concurrent anticancer therapy (i.e., chemotherapeutics or investigational agents)
• No concurrent cytochrome p450 enzyme-inducing anticonvulsant drugs
• No concurrent prophylactic filgrastim (G-CSF)
• No concurrent iron supplements

• Nutritional supplements containing iron allowed
• No concurrent intensity-modulated radiotherapy
• No concurrent electron, particle, implant, or stereotactic radiosurgery boost