• 6 month progression-free survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Relationship between tumor AGT at original diagnosis & response to Temozolomide + O6-BG [ Time Frame: 6 months ] [ Designated as safety issue: No ]

• 6 month progression-free survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Relationship between tumor AGT at original diagnosis & response to Temo + O6-BG [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Objectives:

To define role of O6-Benzylguanine (BG) in restoring Temodar sensitivity in pts w Temodar-resistant malignant glioma.

To further define toxicity of combo therapy using Temodar + BG.

2 separate strata accrued independently of each other: Stratum 1-pts w GM. Stratum 2-pts w AA.

O6-BG at 120mg/m2 administered intravenously over 1hr followed immediately by 48hr infusion at 30mg/m2/ 24hrs. Temozolomide 472mg/m2 administered orally, in fasting state, within 60mins of end of 1hr administration of O6-BG infusion. Treatment cycles may be repeated every 28 days following dose of Temozolomide from previous cycle.

Temozolomide has been well tolerated by both adults & children w most common toxicity being mild myelosuppression. Other, less likely, potential toxicities include nausea & vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, hepatotoxicity, anorexia, fatigue and hyperglycemia. Hypersensitivity reactions have not yet been noted with Temozolomide. As in the case w many anti-cancer drugs, Temozolomide may be carcinogenic. O6-BG toxicities include agitation, lethargy, nausea, vomiting, rapid heart rate, elevated liver functions, & leukemia; but, not with O6-BG as single agent. Transient lymphopenia has been seen w O6-BG as single agent.

• Glioblastoma
• Gliosarcoma

• Experimental: Pts w GBM
• Experimental: Pts w AA

Inclusion Criteria:

• Pts have recurrent/progressive MG. Stereotactic biopsy at time of recurrence/progression is only required if radiation-induced necrosis is suspected
• Pt have MG resistant to Temozolomide, which is defined as >25 percent increase in tumor growth on contrast enhanced MRI/CT <8 wks of last dose of Temozolomide-Age >18 yrs
• Evidence of measurable enhancing disease on contrast-enhanced MRI, unless medically contraindicated.
• Interval of >2 wks between prior surgical resection/ 4wks between prior XRT/chemo, & enrollment on protocol unless there is unequivocal evidence of tumor progression. However, pts treated w chemo agents such as VP-16 who would normally be retreated after shorter intervals may be treated at usual starting time even if <4 wks from last prior dose of chemo
• Karnofsky performance score >60 percent
• Hematocrit > 29 percent, ANC > 1,500 cells/microliter, platelets > 100,000 cells/microliter
• Serum creatinine <1.5 mg/dl, BUN <25 mg/dl, serum SGOT & bilirubin <1.5 x ULN
• For pts on corticosteroids, they must have been on stable dose for 1wk prior to entry, if clinically possible, & dose should not be escalated over entry dose level
• Signed informed consent approved by IRB prior to pt entry
• If sexually active, pts will take contraceptive measures for duration of treatments

Exclusion criteria:

• Pregnancy
• Co-medication that may interfere w study results

• Keryx / AOI Pharmaceuticals, Inc.
• National Institutes of Health (NIH)