A Phase III study of radiation therapy (RT) and O6-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma: Southwest Oncology Group (SWOG) study S0001

Abstract

Aims To determine the efficacy of MGMT depletion plus BCNU (carmustine) therapy and the impact of methylation status in adults with glioblastoma (GBM) and gliosarcoma. Methods Methylation analysis was performed on GBM patients with adequate tissue samples. Patients with newly-diagnosed GBM or gliosarcoma were eligible for this Phase III open-label clinical trial. At registration patients were randomized to Arm 1: O6-BG + BCNU (reduced dose) plus radiation therapy (RT) or Arm 2: BCNU plus radiation therapy. Results One hundred eighty-three patients with newly diagnosed GBM or gliosarcoma were enrolled from 42 United States institutions; 90 eligible patients received O6-BG + BCNU plus radiation therapy (RT), and 89 received BCNU plus RT. The trial was halted at first interim analysis per stopping guidelines due to futility (less than 40% improvement on O6BG + BCNU arm). Following adjustment for stratification factors, there was no significant difference in overall (OS) or progression-free survival (PFS) between the two groups (one sided p=0.94 and p=0.88 respectively). Median OS was 11 months (95% c.i. 8 – 13 months) for patients on the O6BG+BCNU arm and 10 months (95% c.i. 8 – 12) for the BCNU arm. PFS was 4 months for patients in each arm. Adverse events were reported in both arms, with significantly more grade 4 and 5 events in the experimental arm. Conclusions The addition of O6-BG to the standard regimen of radiation and BCNU for treatment of newly-diagnosed glioblastoma and gliosarcoma did not offer added benefit and in fact caused additional toxicity.

Synergistic Activity of PARP Inhibition by Talazoparib (BMN 673) with Temozolomide in Pediatric Cancer Models in the Pediatric Preclinical Testing Program

“…Experience to date with potentiating agents has highlighted this risk, as exemplified by experience with MGMT inhibitors (e.g., O 6 -benzylguanine and lomeguatrib) (40–42). For both O 6 -benzylguanine and lomeguatrib, their addition to alkylating agents (e.g., nitrosoureas and temozolomide) leads to increased toxicity requiring dose reductions, such that the combination is no more effective than the chemotherapy agent given alone at its single agent dose.…”

Optimized Image-Based Surrogate Endpoints in Targeted Therapies for Glioblastoma: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

“…There was no statistical difference in the use of ITT-based analysis over time (OR, 0.935 [95% CI, 0.728-1.200]; p = 0.598). Sponsorship was reported in 21 trials (91%), among which 11 (48%) were sponsored by industry (3,5,8,10,17,(19)(20)(21)(22)(23)25), 6 (26%) were sponsored by a cooperative group or an institution (4,7,9,11,14,16), and 4 received combined funding (12,13,18,24). Compared with trials published between 2000 and 2011, those published between 2012 and 2017 were more likely to be supported by industry (29% versus 81%; OR, 10.833 [95% CI, 1.374-85.440]; p = 0.024).…”

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

“…This trial, conducted in the pre-TMZ era, was negative both with lack of OS benefit and additional toxicity in the experimental arm [55]. with high-grade glioma [57].…”