Samantha Hammond

Phase 2 study of dose-intense temozolomide in recurrent glioblastoma

BACKGROUND Among patients with glioblastoma (GBM) who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by O(6)-methylguanine-DNA methyltransferase (MGMT). Because MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance. METHODS This was a multicenter, phase 2, single-arm study of temozolomide (75-100 mg/m(2)/day) for 21 days of each 28-day cycle. Patients had GBM in first recurrence after standard therapy. The primary end point was 6-month progression-free survival (PFS6). RESULTS Fifty-eight participants were accrued, 3 of whom were ineligible for analysis; one withdrew before response assessment. There were 33 men (61%), with a median age of 57 years (range, 25-79 years) and a median Karnofsky performance score of 90 (range, 60-100). Of 47 patients with MGMT methylation results, 36 (65%) had methylated tumors. There were 7 (13%) partial responses, and PFS6 was only 11%. Response and PFS did not depend on MGMT status; MSH2, MLH1, or ERCC1 expression; the number of prior temozolomide cycles; or the time off temozolomide. Treatment was well tolerated, with limited grade 3 neutropenia (n = 2) or thrombocytopenia (n = 2). CONCLUSIONS Dose-intense temozolomide on this schedule is safe in recurrent GBM. However, efficacy is marginal and predictive biomarkers are needed.

Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma

Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.