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

Phase II Trial of Temodar Plus O6-Benzylguanine (O6-BG) (NSC 637037) in the Treatment of Patients With Temodar-Resistant Malignant Glioma

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Anaplastic Glioma
• Intervention / Treatment: Drug: Temodar and O6-Benzylguanine (BG)

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 Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Radiographic evidence of tumor response	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
6 month progression-free survival	6 months
Relationship between tumor AGT at original diagnosis & response to Temozolomide + O6-BG	6 months

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institutes of Health (NIH); Keryx / AOI Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• The Preston Robert Tisch Brain Tumor Center at Duke

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (Actual): March 1, 2006
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: January 29, 2008
• First Submitted That Met QC Criteria: February 11, 2008
• First Posted (Estimate): February 12, 2008

Study Record Updates

• Last Update Posted (Estimate): July 9, 2014
• Last Update Submitted That Met QC Criteria: July 8, 2014
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: Glioma; Temozolomide; Temodar; Brain tumor; O6-BG; O6-Benzylguanine; NSC 637037; Temodar-Resistant Malignant Glioma; CNS tumor; Cerebral glioblastoma; Anaplastic astrocytomas
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Glioma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; O(6)-benzylguanine
• Other Study ID Numbers: 4260