Clinical trial NCT00612638: Ph. I Temozolomide + O6-BG + Irinotecan in Treatment of Pts w Recurrent / Progressive Cerebral Anaplastic Gliomas
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioblastoma
Gliosarcoma
Keywords: Temodar
Temozolomide
O6-Benzylguanine
O6-BG
NSC 637037
Irinotecan
CPT-11
Recurrent cerebral anaplastic glioma
Progressive cerebral anaplastic glioma
Malignant glioma
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Keryx / AOI Pharmaceuticals, Inc.
name: Pharmacia
First posted: 2008-02-12
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Incidence of toxicities
timeFrame: 6 months
Secondary outcomes:
measure: Response rate & progression-free survival
timeFrame: 6 months
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
Study officials:
affiliation: Duke Health
name: David A. Reardon, MD
role: PRINCIPAL_INVESTIGATOR
References: