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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Annick Desjardins, MD
Duke University Health System
United States: Food and Drug Administration
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