Ph. I Temozolomide + O6-BG + Irinotecan in Treatment of Pts w Recurrent / Progressive Cerebral Anaplastic Gliomas

Duke University

Status and phase

Completed

Phase 1

Conditions

Glioblastoma

Gliosarcoma

Treatments

Drug: Temodar, O6-BG, and Irinotecan

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00612638

Pro00007681

Details and patient eligibility

About

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

Full description

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.

Enrollment

96 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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