P12.06.a a Phase 1 Study of Tinostamustine, a Novel Alkylating Deacetylase Inhibitor, as Adjuvant Treatment in Newly Diagnosed MGMT Promoter-Unmethylated Glioblastoma

BACKGROUND Treatment with temozolomide (TMZ) offers limited benefit in patients with MGMT promoter-unmethylated (uMGMT) glioblastoma (GBM). Tinostamustine, a novel multi-action alkylating deacetylase inhibitor, improves DNA accessibility and impairs repair mechanisms. Tinostamustine following chemoradiation with TMZ (RT/TMZ) in 5 uMGMT GBM patients has shown promising results. METHODS We conducted a Phase 1, open-label, dose-escalation study to determine the MTD and RP2D of tinostamustine following RT/TMZ in newly diagnosed uMGMT GBM patients (NCT05432375). Secondary objectives included tolerability, PFS and OS. Adults aged >18 years with uMGMT GBM were enrolled within 5 weeks of completing RT/TMZ without tumor progression. Tinostamustine was administered intravenously over 60 min on Day 1 of each 21-Day cycle starting at 80 mg/m2 escalating to 100 mg/m2 using a “3 + 3” design. Tumor response was assessed by MRI using mRANO criteria every two cycles. RESULTS Of the 10 patients enrolled, nine were evaluable. Median age was 63 years, 77.8% were male, median time from diagnosis to screening was 108 days. Three patients completed the 80 mg/m2 dose without DLT. Six patients were enrolled at 100mg/m2; one DLT (low-grade thrombocytopenia with prolonged recovery) was noted. Ten grade ≥3 related TEAEs occurred in 2 patients at 80 mg/m2 and five in 4 patients at 100 mg/m2, including one severe anemia case in each group. When measured from tinostamustine initiation (per-protocol), mPFS and mOS were 4.9 and 13.5 months at 80 mg/m2 and 2.9 and 9.5 months at 100 mg/m2. Measured from diagnosis, mPFS and mOS were 8.5 and 18 months at 80 mg/m2 and 7 and 12.8 months at 100 mg/m2. CONCLUSION Tinostamustine following RT/TMZ was associated with manageable toxicities in newly diagnosed uMGMT GBM patients at a MTD of 100 mg/m2 with encouraging efficacy signals. A planned future trial will further evaluate the RP2D of tinostamustine and impact on survival outcomes.