ph. i temozolomide + o6-bg + irinotecan in treatment of pts w recurrent / progressive cerebral anaplastic gliomas

Conditions: Glioblastoma; Gliosarcoma

Summary: objectives: to determine maximum tolerated dose of cpt-11 when administered following temodar plus o6-benzylguanine to characterize any toxicity associated w combo of cpt-11 + temodar plus o6-bg to observe pts for clinical antitumor response when treated w combo of cpt-11 + temodar + o6-bg

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.

Eligibility criteria:
inclusion criteria: * pts have histologically confirmed diagnosis of recurrent primary malignant glioma * age \>18yrs * evidence of measurable recurrent/residual primary cns neoplasm on contrast-enhanced mri, unless medically contraindicated * an interval of \>2 wks between prior surgical resection/6 wks between prior xrt/chemo, \& enrollment on protocol, unless there is unequivocal evidence of tumor progression after surgery, xrt/chemo * kps\>60 percent * adequate hematologic, renal \& liver function as demonstrated by lab values performed within 14 days, inclusive, prior to administration of chemo: * anc \>1500/mm3 * platelet count \> 00,000/mm3 * hemoglobin \> 10gm/dl * bun \& serum creatinine \<1.5 x uln * total serum bilirubin \<1.5 x uln * sgot \& sgpt \< 2.5 x uln * alkaline phosphatase of\< 2 x uln * pts must have recovered from any effects of major surgery.= * pts must have life expectancy of \>12wks * pts/legal guardian must give written, informed consent exclusion criteria: * pts requiring immediate xrt * pts have not recovered from surgery * pts are not neurologically stable for 2wks prior to study entry * pts are poor medical risks because of non-malignant systemic disease as well as those w acute infection treated w intravenous antibiotics * frequent vomiting/medical condition that could interfere w oral medication intake * previous active malignancy treated in past year except for localized in-situ carcinomas \& basal/squamous cell carcinoma of skin * known hiv positivity/aids-related illness * pregnant/nursing women * women of childbearing potential who are not using effective method of contraception. women of childbearing potential must have negative serum pregnancy test 24 hrs prior to administration of study drug \& be practicing medically approved contraceptive precautions * men who are not advised to use effective method of contraception * prior failure of cpt-11 * pts taking immuno-suppressive agents other than prescribed corticosteroids

Keywords: temodar temozolomide o6-benzylguanine o6-bg nsc 637037 irinotecan cpt-11 recurrent cerebral anaplastic glioma progressive cerebral anaplastic glioma malignant glioma