Pitavastatin, a Phase 0 lead-in trial in primary GBM and recurrent GBM patients

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d7218349e106">Background: Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options. Pitavastatin, a statin approved for hypercholesterolemia, has demonstrated cytotoxic effects against patient-derived GBM cells and its physico-chemical properties suggest possible the blood-brain barrier (BBB) permeability. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7218349e108">Methods: In this Phase 0 lead-in trial, 8 patients with primary or recurrent GBM received pitavastatin for six days prior to surgery. A 3+3 dose-escalation design (16 mg, 32 mg, 48 mg) was used. Plasma and tissue samples from gadolinium-enhanced and tumor-infiltrating brain (TIB) regions were analyzed using LC-MS for pitavastatin concentration. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7218349e110">Results: Pitavastatin was well-tolerated with mild, self-limiting side effects. Clinically relevant concentrations were detected in both gadolinium-enhanced and TIB regions, achieving levels consistent with synergy with temozolomide. Mean concentrations at 16 mg, 32 mg, and 48 mg were 0.125 μM, 0.144 μM, and 0.168 μM in the gadolinium-enhanced, and 0.136 μM, 0.148 μM, and 0.204 μM in TIB. Plasma-to-tumor ratios ranged from 3.1 to 0.4. Effective concentrations for synergy with temozolomide were achieved in TIB tissue, suggesting potential therapeutic impact beyond areas with BBB disruption. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7218349e112">Conclusion: Short-term high-dose pitavastatin achieves therapeutic concentrations in GBM infiltrated tissue, supporting its potential as an adjunct therapy. Further investigation in Phase I/II trials is warranted. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d7218349e114"/>