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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

Phase 1
18 Years
Not Enrolling
Glioblastoma, Gliosarcoma

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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.

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

- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Incidence of toxicities

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

David A. Reardon, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Food and Drug Administration

Study ID:




Start Date:

January 2005

Completion Date:

July 2008

Related Keywords:

  • Glioblastoma
  • Gliosarcoma
  • Temodar
  • Temozolomide
  • O6-Benzylguanine
  • O6-BG
  • NSC 637037
  • Irinotecan
  • CPT-11
  • Recurrent cerebral anaplastic glioma
  • Progressive cerebral anaplastic glioma
  • Malignant glioma
  • Glioblastoma
  • Glioma
  • Gliosarcoma



Duke University Health System Durham, North Carolina  27705