Trial Information

Phase I Trail of Temodar Plus O6-Benzylguanine (O6-BG) (NSC 637037) Plus Irinotecan (CPT-11) (NSC 616348) in the Treatment of Patients With Recurrent / Progressive Cerebral Anaplastic Gliomas

Objectives of study: to determine maximum tolerated dose of CPT-11 when administered
following Temodar + O6-benzylguanine (O6-BG); to characterize any toxicity associated w
combo of CPT-11 + Temodar + O6-BG; to observe pts for clinical antitumor response when
treated w combo of CPT-11 + Temodar plus O6-BG. Pts have histologically confirmed diagnosis
of recurrent primary malignant glioma. 2 separate strata accrued independently of each
other: Stratum 1-pts receiving Dilantin, Tegretol/phenobarbital. Stratum 2-pts on
anti-convulsants other than Dilantin, Tegretol/phenobarbital/pts not on any
anti-convulsants. Each strata will be treated & escalated independent of each other.

Pre-chemo, O6-BG administered intravenously at 120 mg/m2, over 1hr, prior to administration
of Temodar on day 1 of 21-day cycle. Post-chemo, O6-BG administered intravenously at 30
mg/m2/day, over 48hrs, immediately after completion of the CPT-11 infusion on day 1 of
21-day cycle. Temodar administered orally at 355 mg/m2, in fasting state, within 60
minutes of the end of 1hr O6-BG infusion. Treatment cycles may be repeated every 3 weeks
following dose of Temozolomide from previous cycle. CPT-11 will be administered
intravenously in fasting state over 90min. CPT-11 infusion will begin 1hr after Temozolomide
administration. Initial doses 60 mg/m2 for stratum 1 & 40 mg/m2 for stratum 2. Treatment
cycles may be repeated every 3 wks following dose of CPT-11 from previous cycle.

Major toxicities associated w CPT- 11 are myelosuppression & diarrhea. 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. O6-BG
toxicities include transient lymphopenia has been seen w O6-BG as single agent. O6-BG in
combo w other agents could cause exacerbation of any adverse event currently known to be
caused by other agent,/ combo may result in events never previously associated w either
agent. Animal studies indicated that agitation, lethargy, convulsions, nausea, vomiting,
rapid heart rate, elevated liver functions, leukopenia, lymphopenia could be seen.