This phase II trial was designed to define the role of O⁶-benzylguanine (O⁶-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O⁶-BG in combination with temozolomide.

Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O⁶-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O⁶-BG infusion at a dose of 120 mg/m² followed immediately by a 48-hour infusion at a dose of 30 mg/m²/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O⁶-BG infusion at a dose of 472 mg/m². The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety.

Sixty-six of 67 patients who enrolled were treated with temozolomide and O⁶-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients.

O⁶-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.