A Phase II Study of Temozolomide and O6-Benzylguanine (O6-BG) in Patients With Temozolomide-Resistant Anaplastic Glioma
A Phase II Study of Temozolomide and O6-Benzylguanine (O6-BG) in Patients With Temozolomide-Resistant Anaplastic Glioma
This is an open-label, multicenter, phase II trial, assessing the antitumor activity, and
 safety of temozolomide in combination with O6-BG in patients with temozolomide-resistant
 anaplastic glioma.
This open-label, multicenter, phase II trial will assess the antitumor activity and safety of
 temozolomide in combination with O6-BG in patients with temozolomide-resistant anaplastic
 glioma.

 Forty-one to 104 evaluable patients with temozolomide-resistant anaplastic glioma will be
 enrolled in this study. Total accrual on this study will not exceed 116 patients. The
 patients will receive daily temozolomide on 5 consecutive days (days 1-5) along with bolus
 infusions of O6-BG on days 1, 3, and 5 and a continuous infusion of O6-BG beginning
 immediately after the first bolus infusion and continuing until immediately prior to the last
 bolus injection. Patients will be evaluated for AEs during the course of therapy. Patients
 may receive treatment at the same dose level until appearance of significant
 treatment-related toxicities, disease progression or withdrawal of consent.

 Tumor response will be evaluated at the end of cycle 1, cycle 2 and then every two cycles for
 the duration of therapy, using physical and neurological examinations and diagnostic imaging.
Inclusion Criteria:

 1. Patients with histologically documented anaplastic glioma (anaplastic astrocytoma,
 anaplastic oligodendroglioma or mixed anaplastic oligoastrocytoma).

 2. Temozolomide-resistant defined as patients who have progressed while receiving or
 within 8 weeks of completing the last dose of temozolomide.

 3. Disease progression >= 12 weeks after the completion of any radiotherapy.

 4. If patient received chemotherapy or an investigational agent as part of their prior
 therapy, the patient must recover from all toxicities (<= Grade 1) prior to enrollment
 on this protocol.

 5. Bi-dimensionally measurable disease on contrast-enhanced magnetic resonance imaging
 study (MRI) performed within two weeks of study drug administration.

 6. If patient received intratumoral chemotherapy or immunotherapy as part of their prior
 therapy then histological confirmation of recurrence is mandated.

 7. KPS >= 70%.

 8. The following laboratory results:

 -  Absolute neutrophil count >= 1500 cells/microliter

 -  Platelet count >= 100,000 cells/microliter

 -  SGOT <= 2.5 x ULN

 -  Serum creatinine <= 1.5 x ULN

 9. Signed informed consent approved by Institutional Review Board.

 10. If sexually active, patients will take contraceptive measures for the duration of the
 treatment.

 11. For patients on corticosteroids, they must have been on a stable dose 1 week prior to
 baseline MRI and the dose should not be escalated over entry dose level, if clinically
 possible.

 Exclusion Criteria:

 1. Pregnant or breast feeding women.

 2. Prior treatment with O6-BG plus temozolomide in combination.

 3. Active infection requiring intravenous antibiotics.

 4. Known diagnosis of Human Immunodeficiency Virus (HIV) infection (HIV testing is not
 mandatory).

 5. Patients with a history of another primary malignancy that is currently clinically
 significant or currently requires active intervention.

 6. Patients unwilling or unable to comply with the protocol.

 7. Patients who have received stereotactic radiosurgery or brachytherapy as part of their
 prior therapy.

 8. Comedication that may interfere with study results; eg. immunosuppressive agents other
 than corticosteroids.