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Enzyme Inhibitors

Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs)such as carbamazepine, phenobarbitol, phenytoin, phosphenytoin, oxcarbamazepine, primadone)

Patients on non CYP3A4-inducing anti-convulsants or patients not on any anti-convulsants.

2 separate strata accrued independently: Stratum 1-pts receiving CYP3A4-inducing anticonvulsants. Stratum 2-pts on non CYP3A4-inducing anticonvulsants or pts not on any anti-convulsants. Each strata treated \& escalated independent of each other. Temozolomide administered orally at dose of 150 mg/m2 daily for 5 days, at bedtime, for 1st cycle \& escalated to 200 mg/m2 daily for 5 days, at bedtime during subsequent cycles if tolerated. Treatment cycles repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice daily, approximately every 12hrs. Except as specifically noted, pts advised to take capsules wh morning \& evening meals, with approximately 240ml of non-carbonated water. Initial doses will be 125mg BID for stratum 1 \& 75mg BID for stratum2. Treatment cycles repeated every 4 wks following dose of Temozolomide from previous cycle.

Temodar and SCH 66336

Annick Desjardins, MD

Objectives:

To determine maximum 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 patients for clinical antitumor response when treated with combination of farnesyl transferase inhibitor, SCH 66336, \& TEMODAR®.

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

2 separate strata accrued independently of each other: Stratum1-Patients receiving Dilantin, Tegretol / phenobarbital. Stratum2-Patients on anti-convulsants other than Dilantin, Tegretol / phenobarbital / Patients 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 5 days, at bedtime during subsequent cycles if tolerated. Treatment cycles may be repeated every 4 weeks 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 weeks following dose of Temozolomide from previous cycle.

Subjects are patients with malignant glioma histologically confirmed at diagnosis, who were treated previously with conventional external beam radiation (XRT) \& with or 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 with 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 with Temozolomide. As is case with 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 for SCH66336 have 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,\& patients should be advised of possibility of irreversible sterility.

PH I Addition of Farnesyl Transferase Inhibitor to Temozolomide for Pts w Gr 3 & 4 Malignant Gliomas

A Phase I Trial of the Addition of the Farnesyl Transferase Inhibitor, SCH 66336, to Temodar for Patients With Grade 3 and 4 Malignant Gliomas

Schering-Plough

Duke University

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