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

• ClinicalTrials.gov Identifier: NCT00612638
• Recruitment Status: Completed
• First Posted: February 12, 2008
• Last Update Posted: June 19, 2013
• Sponsor: Duke University
• Collaborators: Keryx / AOI Pharmaceuticals, Inc.; Pharmacia
• Information provided by: Duke University

Study Description

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

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Gliosarcoma	Drug: Temodar, O6-BG, and Irinotecan	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 96 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: January 2005
• Actual Primary Completion Date: January 2007
• Actual Study Completion Date: July 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Pts receiving Dilantin, Tegretol or Phenobarbital	Drug: Temodar, 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.; Other Names: Temodar-Temozolomide; O6-Benzylguanine-O6-BG; Irinotecan-Camptosar-CPT 11
Experimental: 2; Pts on anti-convulsants other than Dilantin, Tegretol / Phenobarbital / pts not on any anti-convulsants	Drug: Temodar, 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.; Other Names: Temodar-Temozolomide; O6-Benzylguanine-O6-BG; Irinotecan-Camptosar-CPT 11

Outcome Measures

Primary Outcome Measures :

1. Incidence of toxicities [ Time Frame: 6 months ]

Secondary Outcome Measures :

1. Response rate & progression-free survival [ Time Frame: 6 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, North Carolina

Duke University Health System

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

Keryx / AOI Pharmaceuticals, Inc.

Pharmacia

Investigators

• Principal Investigator: David A. Reardon, MD; Duke University Health System

More Information

Additional Information:

The Preston Robert Tisch Brain Tumor Center at DUKE 

• Responsible Party: David A. Reardon, MD, Duke University Health System
• ClinicalTrials.gov Identifier: NCT00612638
• Other Study ID Numbers: Pro00007681
• First Posted: February 12, 2008
• Last Update Posted: June 19, 2013
• Last Verified: January 2009

Keywords provided by Duke University:

Temodar; Temozolomide; O6-Benzylguanine; O6-BG; NSC 637037; Irinotecan; CPT-11; Recurrent cerebral anaplastic glioma; Progressive cerebral anaplastic glioma; Malignant glioma

Additional relevant MeSH terms:

Glioblastoma; Glioma; Gliosarcoma; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Irinotecan; Temozolomide; O(6)-benzylguanine; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents