Phase I/II study of liposomal curcumin in combination with standard radiation and temozolomide in patients with newly diagnosed high-grade gliomas.

Abstract

2069 Background: Liposomal curcumin (LC) is an intravenous formulation designed to enhance curcumin delivery and modulate inflammatory, oxidative, and oncogenic pathways relevant to high-grade glioma (HGG), including dysregulated kynurenine metabolism. Preclinical studies demonstrate synergy between LC and chemoradiation. This Phase I/II study was designed to determine the recommended Phase II dose (RP2D) of weekly IV LC with radiotherapy and temozolomide (RT/TMZ) in newly diagnosed HGG (primary objective), assess safety and feasibility (secondary objective), and preliminary efficacy (exploratory objective). Methods: This open-label, sequential dose-escalation study used the TITE-BOIN Bayesian design to evaluate LC at 300, 350, and 400 mg/m². Patients received standard chemoradiation (2 Gy × 5 days/week × 6 weeks with concomitant TMZ 75 mg/m²/day), followed by standard adjuvant TMZ and weekly LC infusions over 3 hours for a target of 34 doses, with optional continuation. Eligible patients had newly diagnosed HGG (WHO grade 3 or 4) and KPS ≥70%. Patients were evaluable if they received ≥80% of planned LC infusions and ≥60% of planned TMZ dosing during the 10-week toxicity evaluation period. Radiographic response was assessed per RANO 2.0. Results: Twenty-five patients were treated: 300 mg/m² (n=6), 350 mg/m² (n=12), and 400 mg/m² (n=7); all patients assigned to 400 mg/m² were treated at 350 mg/m² per Safety Review Committee recommendation. All patients had glioblastoma or molecular glioblastoma, IDH-wildtype, WHO grade 4 per 2021 WHO classification (MGMT promoter methylation status: 7 methylated, 1 indeterminate, 17 unmethylated). Median age was 56 years (range, 43–75); median KPS was 90 (range, 70–100). Two protocol-defined dose-limiting toxicities occurred at 400 mg/m²: grade 4 pancytopenia and grade 1 hemolysis. LC-related grade ≥3 toxicities occurred in 4 patients (16%) and included confusion, seizure, thromboembolic event, cerebral edema, lymphopenia, thrombocytopenia, fatigue (all grade 3), and pancytopenia (grade 4). There were no LC-related deaths. Based on the TITE-BOIN design and cumulative safety data, 350 mg/m² was identified as the RP2D. With a median follow-up of 12.9 months (range, 2.4-27.3 months) as of 1/23/2026, median progression-free and overall survival have not been reached. At 6 and 12 months from first LC infusion, 95% and 87% of uncensored patients (n=18, n=13), respectively, remained alive. Conclusions: LC combined with standard chemoradiation was safe and well tolerated, with encouraging exploratory signals of disease control in newly diagnosed glioblastoma. Further evaluation in an expanded Phase II/III study is planned. Clinical trial information: NCT05768919 .