Objectives:

To determine maxi tolerated dose of farnesyl transferase inhibitor, SCH 66336, when administered w TEMODAR®.

To characterize any toxicity associated w combo of farnesyl transferase inhibitor, SCH 66336, & TEMODAR®.

To observe pts for clinical antitumor response when treated w combo of farnesyl transferase inhibitor, SCH 66336, & TEMODAR®.

To assess pharmacokinetics of SCH 66336 for pt on & not on enzyme inducing antiepileptic drugs.

2 separate strata accrued independently of each other: Stratum1-pts receiving Dilantin, Tegretol / phenobarbital. Stratum2-pts on anti-convulsants other than Dilantin, Tegretol / phenobarbital / pts not on any anti-convulsants. Each stratum treated & escalated independent of each other.Temozolomide administered orally at dose of 150mg/m2 daily for 5 days, at bedtime, for 1st cycle & escalated to 200mg/m2 daily for 5days, at bedtime during subsequent cycles if tolerated. Treatment cycles may be repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice day, approximately every 12hrs. Initial doses will be 125mg BID for stratum 1 & 75mg for stratum 2. Treatment cycles may be repeated every 4 wks following dose of Temozolomide from previous cycle.

Subjects are pts w MG histologically confirmed at diagnosis, who were treated previously w conventional external beam XRT & w/without chemo, & have stable disease, recurrence/relapse at time of enrollment. Approximately 48 subjects will be enrolled.

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. Hypersensitivity reactions have not yet been noted w Temozolomide. As is case w many anti-cancer drugs,Temozolomide may be carcinogenic. Rats given Temozolomide have developed breast cancer. Significance of this finding for humans is not presently known.

Significant adverse events observed included vomiting, diarrhea, anorexia, headaches, reversible renal toxicities, & hematological toxicities. SCH 66336, although not genotoxic, inhibits rapidly proliferating cells & at high doses inhibits spermatogenesis in male rats. It is not clear that inhibition of spermatogenesis is reversible,& pts advised of possibility of irreversible sterility.

• Gliosarcoma
• Glioblastoma
• Anaplastic Astrocytoma

• Experimental: Pts receiving EIAEDs
• Experimental: Pts not receiving EIAEDs

Inclusion Criteria:

• Pts with MG histologically confirmed at diagnosis, who were treated previously with conventional external beam radiation & with or without chemotherapy, & have stable disease, recurrence or relapse at the time of enrollment.
• Age > 18 years.
• Pts who have had previous surgical resection are eligible:

Interval of at least 3 weeks between prior surgical resection, 2 weeks between prior radiotherapy, or 4 weeks between prior chemotherapy, unless there is unequivocal evidence of tumor progression after surgery, radiotherapy, or chemotherapy.

• Karnofsky performance score >60%.
• Adequate hematologic, renal & liver function as demonstrated by lab values performed within 14 days, inclusive, prior to administration of chemotherapy:
• ANC >1500/mm3
• Platelet count >100,000/mm3
• Hemoglobin >10 gm/dL
• BUN and serum creatinine <1.5 times upper limit of lab normal
• Total serum bilirubin <1.5 times upper limit of lab normal
• SGOT <2.5 times upper limit of lab normal
• Pts must have recovered from any effects of major surgery.
• Pts must have life expectancy of greater than 12 weeks.
• Pts or legal guardian must give written, informed consent.

Exclusion Criteria:

• Pts requiring immediate radiation therapy.
• Pts who have not recovered from surgery.
• Pts who are not neurologically stable for 2 weeks prior to study entry.
• Pts who are poor medical risks because of non-malignant systemic disease as well as those with acute infection treated with intravenous antibiotics.
• Frequent vomiting or medical condition that could interfere with oral medication intake.
• Pt is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
• Known HIV positivity or AIDS-related illness.
• Pregnant or nursing women.
• Women of childbearing potential who are not using an effective method of contraception. Women of childbearing potential must have a negative serum pregnancy test 72 hours prior to administration of study drug and be practicing medically approved contraceptive precautions.
• Men who are not advised to use an effective method of contraception.
• Pts taking immuno-suppressive agents other than prescribed corticosteroids.
• Pts previously treated with farnesyl transferase inhibitors.
• Pts with significant QTc prolongation (>500 msec)as evaluated by an EKG.
• Pt having presented prior disease progression on TEMODAR.
• Pt having presented any grade 4 hematologic toxicity or grade 3 or 4 non-hematologic toxicity on TEMODAR in the past.