Itraconazole (ITRA) with Standard Radiotherapy (RT) and Temozolomide (TMZ) in Patients with Newly Diagnosed Glioblastoma Multiforme (GBM) ITRA-RAD: Phase I Clinical Study

Preclinical studies and data from other cancers suggest that inhibition of the Hedgehog (Hh) pathway also has antiproliferative effects on glioma cells. A key component of this pathway is the Smoothened (SMO) protein, which is expressed in high-grade gliomas. Itraconazole (ITRA), a widely used antifungal agent, inhibits SMO, the PI3K/AKT/mTOR pathway, and the VEGF/VEGFR-2 axis—both of which are critical for GBM progression and angiogenesis. This protocol describes a prospective, single-center, dose-escalation phase I study with the classical 3 + 3 design in order to determine the MTD of ITRA. The study enrolls patients with a newly histologically confirmed diagnosis of GBM, without previous treatment except surgery. They will be treated with standard RT schedule (60 Gy in 30 fractions) with concurrent TMZ 75 mg/m2 and ITRA 2 × 100 mg, 200 mg, or 300 mg daily. The primary endpoint is to determine the MTD of ITRA given concurrently with RT + TMZ. Secondary endpoints include safety and tolerability of ITRA, overall survival (OS), progression-free survival (PFS), overall objective response rate, use of corticosteroids, treatment compliance, and health-related quality of life (EORTC QLQ-C30 and BN20). Participants will be monitored for one week post-treatment. All relevant statistics will be primarily descriptive.