The temozolomide RESCUE study: A phase II trial of continuous (28/28) dose-intense temozolomide (TMZ) after progression on conventional 5/28 day TMZ in patients with recurrent malignant glioma

Abstract

2010 Background: The combination of radiation with temozolomide (TMZ) 75 mg/m2 x 6 weeks + adjuvant TMZ 150-200 mg/m2 given 5 days out of 28 (5/28) is the standard of care for glioblastoma multiforme (GBM). However, many patients (pts) progress during or after first-line therapy and second-line regimens are only modestly active. Continuous dosing and dose intensification decrease levels of O-6-methylguanine-DNA methyltransferase (MGMT), which has been associated with TMZ resistance. Altering the schedule of TMZ and dose intensification may re-induce chemosensitivity. Methods: After REB-approved informed consent, pts with high-grade glioma who failed the standard TMZ 5/28 adjuvant regimen received continuous dose-intense TMZ 50 mg/m2 for 28 days out of 28 (28/28) for up to one year. The primary endpoint was 6-mo progression-free survival (PFS). The trial used a two-stage design in which at least 1 of the first 15 pts enrolled in each group needed to achieve 6-mo PFS before the next stage was initiated Results: 120 pts were enrolled at 11 centers. Patients were divided into four cohorts: GBM patients failing during the first 3–6 months of adjuvant therapy (B1); GBM patients failing after more than 6 months of therapy (B2); GBM patients who recurred after stopping treatment (B3); and anaplastic glioma pts (A). Median age overall was 52 yrs (25–73 yrs). The majority (66%) were male. ECOG performance status was 0 in 47%, and 1 in 53%. An interim analysis was performed on the first 60 patients. The 6-mo PFS rates were 23% (B1), 7% (B2), 35% (B3), and 53% (A). Nausea and vomiting was observed in less than 5% of patients. Other toxicities were rare. Progressive lymphopenia was observed in some pts but no related clinically significant events have been reported. Prophylaxis for Pneumocystis carinii pneumonia was not required. Conclusions: Continuous dose-intense TMZ 50 mg/m2 given on a 28/28 day schedule is active and well tolerated after failure of the conventional 5/28 day regimen. Efficacy compares favorably to other commonly used second-line agents. Continuous dose-intense TMZ may represent an ideal regimen for use in combination with other agents such as the new targeted therapies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough Canada Schering-Plough Schering-Plough Schering-Plough