Targeting glioma-initiating cells in GBM: ABTC-0904, a randomized phase 0/II study targeting the Sonic Hedgehog-signaling pathway.

2026 Background: The prognosis for GBM, which appears to be driven by glioma initiating cells (GIC), remains poor. Our hypothesis was that interrupting sonic hedgehog signaling (SHh) would inhibit GIC activity and improve PFS (PFS6). Methods: A two armed, randomized phase 0/II study of Vismodegib, an inhibitor of SMO, was performed in 40 patients undergoing resection for recurrent GBM (rGBM). The trial hypothesis was to achieve 25% PFS6 rate compared to a null of 10 % with a 90% power and a 10% type I error rate (1-sided). Arm I received Vismodegib for 7 days pre-operatively; Arm II was not treated pre-operatively. All patients were treated with Vismodegib post-operatively. Primary objective was to assess PFS6, with secondary endpoints of median overall survival, response and toxicity. Secondary objectives included determination of: intra-tumoral PK and PD; inhibition of SHh signaling by RT-PCR and immunohistochemistry; and inhibition of GIC proliferation and self-renewal by neurosphere proliferation and ...