Glioblastoma, Gliosarcoma
Conditions
Keywords
Temodar, Temozolomide, O6-Benzylguanine, O6-BG, NSC 637037, Irinotecan, CPT-11, Recurrent cerebral anaplastic glioma, Progressive cerebral anaplastic glioma, Malignant glioma
Brief 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
Detailed 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.
Interventions
DRUGTemodar, O6-BG, and Irinotecan
2 separate strata accrued independently: Stratum 1-pts receiving Dilantin, Tegretol or phenobarbital. Stratum 2-pts on anti-convulsants other than Dilantin, Tegretol/phenobarbital/pts not on any anti-convulsants. O6-BG administered intravenously 120mg/m2, over 1hr, prior to administration of Temozolomide on day 1 of 21day cycle. O6-BG administered intravenously 30mg/m2/day, over 48hrs, immediately after completion of CPT-11 infusion on day 1 of 21-day cycle. Temozolomide administered orally 355mg/m2 within 60 mins of end of 1hr O6-BG infusion. Treatment cycles may be repeated every 3wks following dose of Temozolomide from previous cycle. CPT-11 administered intravenously in fasting state over 90mins. CPT-11 infusion will begin 1hr after Temozolomide administration. Initial doses 60mg/m2 for stratum 1 & 40mg/m2 for stratum2. Treatment cycles repeated every 3 wks following dose of CPT-11 from previous cycle.
Sponsors
Keryx / AOI Pharmaceuticals, Inc.
Pharmacia
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of toxicities | 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Response rate & progression-free survival | 6 months |
Countries
United States
Outcome results
None listed