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

Phase 1

Completed

• Conditions: Glioblastoma; Gliosarcoma
• Interventions: Drug: Temodar, O6-BG, and Irinotecan

• Registration Number: NCT00612638
• Lead Sponsor: Duke University

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.

Study Timeline

• Study Start: 2005-01
• Primary Completion: 2007-01
• Study First Submitted: 2008-01-29
• Study First Submitted QC: 2008-02-11
• Study First Posted: 2008-02-12
• Study Completion: 2008-07
• Status Verified: 2009-01
• Last Update Submitted: 2013-06-18
• Last Update Posted: 2013-06-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 96

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1	Temodar, O6-BG, and Irinotecan	Pts receiving Dilantin, Tegretol or Phenobarbital
2	Temodar, O6-BG, and Irinotecan	Pts on anti-convulsants other than Dilantin, Tegretol / Phenobarbital / pts not on any anti-convulsants

Primary Outcome Measures

Name	Time	Method
Incidence of toxicities	6 months

Secondary Outcome Measures

Name	Time	Method
Response rate & progression-free survival	6 months

Trial Locations

Locations (1)

Duke University Health System; 🇺🇸 Durham, North Carolina, United States