Ph. II Temozolomide + O6-BG in Treatment of Pts w Temozolomide-Resistant Malignant Glioma

• ClinicalTrials.gov Identifier: NCT00613093
• Recruitment Status: Completed
• First Posted: February 12, 2008
• Last Update Posted: July 9, 2014
• Sponsor: Duke University
• Collaborators: Keryx / AOI Pharmaceuticals, Inc.; National Institutes of Health (NIH)
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

Objectives:

To define role of O6-Benzylguanine (BG) in restoring Temodar (temozolomide) sensitivity in patients with Temodar-resistant malignant glioma.

To further define toxicity of combo therapy using Temodar + BG.

Condition or disease	Intervention/treatment	Phase
Glioblastoma Multiforme; Anaplastic Glioma	Drug: Temodar and O6-Benzylguanine (BG)	Phase 2

Detailed Description:

2 separate strata accrued independently of each other: Stratum 1-patients with Glioblastoma Multiforme (GBM). Stratum 2-patients with Anaplastic Glioma [anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed (AA and AO)] .

BG at 120mg/m2 administered intravenously over 1 hour followed immediately by 48-hour infusion at 30mg/m2/24hrs. Temozolomide 472mg/m2 administered orally, in fasting state, within 60 minutes of end of the 1-hour administration of BG infusion. Treatment cycles may be repeated every 28 days following dose of Temodar from previous cycle.

Temodar has been well tolerated by both adults and children with most common toxicity being mild myelosuppression. Other, less likely, potential toxicities include nausea and vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, hepatotoxicity, anorexia, fatigue and hyperglycemia. Hypersensitivity reactions have not yet been noted with Temodar. As in the case with many anti-cancer drugs, Temodar may be carcinogenic. BG toxicities include agitation, lethargy, nausea, vomiting, rapid heart rate, elevated liver functions, & leukemia; but, not with BG as single agent. Transient lymphopenia has been seen with BG as single agent.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 67 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Temodar Plus O6-Benzylguanine (O6-BG) (NSC 637037) in the Treatment of Patients With Temodar-Resistant Malignant Glioma
• Study Start Date: October 2002
• Actual Primary Completion Date: March 2006
• Actual Study Completion Date: August 2008

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Patients with glioblastoma multiforme	Drug: Temodar and O6-Benzylguanine (BG); Objectives of study are to define role of BG in restoring Temodar sensitivity in patients with Temodar-resistant malignant glioma and to further define the toxicity of combination therapy using Temodar + BG. 2 separate strata accrued independently of each other: Stratum 1-patients with glioblastoma multiforme (GBM). Stratum 2-patients with anaplastic glioma (AG). BG at 120mg/m2 administered intravenously over 1 hour followed immediately by 48-hour infusion at 30mg/m2/24 hours. Temodar 472mg/m2 administered orally, in fasting state, within 60 minutes of end of the 1-hour administration of BG infusion. Treatment cycles may be repeated every 28 days following dose of Temodar from previous cycle.; Other Names: Temodar - Temozolomide; O6-Benzylguanine - O6-BG
Active Comparator: Patients with Anaplastic Glioma	Drug: Temodar and O6-Benzylguanine (BG); Objectives of study are to define role of BG in restoring Temodar sensitivity in patients with Temodar-resistant malignant glioma and to further define the toxicity of combination therapy using Temodar + BG. 2 separate strata accrued independently of each other: Stratum 1-patients with glioblastoma multiforme (GBM). Stratum 2-patients with anaplastic glioma (AG). BG at 120mg/m2 administered intravenously over 1 hour followed immediately by 48-hour infusion at 30mg/m2/24 hours. Temodar 472mg/m2 administered orally, in fasting state, within 60 minutes of end of the 1-hour administration of BG infusion. Treatment cycles may be repeated every 28 days following dose of Temodar from previous cycle.; Other Names: Temodar - Temozolomide; O6-Benzylguanine - O6-BG

Outcome Measures

Primary Outcome Measures :

1. Radiographic evidence of tumor response [ Time Frame: 6 months ]

Secondary Outcome Measures :

1. 6 month progression-free survival [ Time Frame: 6 months ]
2. Relationship between tumor AGT at original diagnosis & response to Temozolomide + O6-BG [ 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:

• Patients have recurrent/progressive Malignant Glioma (MG). Stereotactic biopsy at time of recurrence/progression is only required if radiation-induced necrosis is suspected
• Patients have MG resistant to Temodar, which is defined as > or = to 25 percent increase in tumor growth on contrast enhanced MRI/CT within 8 weeks of last dose of Temodar
• Age > or = to 18 years
• Evidence of measurable enhancing disease on contrast-enhanced MRI, unless medically contraindicated.
• Interval of at least 2 weeks between prior surgical resection/ 4 weeks between prior radiotherapy/chemotherapy, and enrollment on protocol unless there is unequivocal evidence of tumor progression. However, patients treated with chemotherapy agents such as VP-16 who would normally be retreated after shorter intervals may be treated at usual starting time even if less than 4 weeks from last prior dose of chemotherapy
• Karnofsky performance score > or = to 60 percent
• Hematocrit > 29 percent, absolute neutrophil count (ANC) > 1,500 cells/microliter, platelets > 100,000 cells/microliter
• Serum creatinine <1.5 mg/dl, Blood Urea Nitrogen (BUN) <25 mg/dl, Serum Glutamic Oxaloacetic Transaminase (SGOT) & bilirubin <1.5 x upper limit of normal (ULN)
• For patients on corticosteroids, they must have been on stable dose for 1 week prior to entry, if clinically possible, and dose should not be escalated over entry dose level
• Signed informed consent approved by Institutional Review Board (IRB) prior to patient entry
• If sexually active, patients will take contraceptive measures for duration of treatments

Exclusion criteria:

• Pregnancy
• Co-medication that may interfere with study results

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.

National Institutes of Health (NIH)

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: Duke University
• ClinicalTrials.gov Identifier: NCT00613093
• Other Study ID Numbers: 4260
• First Posted: February 12, 2008
• Last Update Posted: July 9, 2014
• Last Verified: November 2012

Keywords provided by Duke University:

Temodar; Temozolomide; O6-BG; O6-Benzylguanine; NSC 637037; Temodar-Resistant Malignant Glioma; Brain tumor; CNS tumor; Cerebral glioblastoma; Anaplastic astrocytomas; Glioma

Additional relevant MeSH terms:

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