Phase I study of zeaxanthin alone or in combination with pembrolizumab in metastatic solid tumors.

Abstract

TPS2696 Background: Zeaxanthin is a carotinoid synthesized by plants that accumulates via dietary intake in the macula. Preclinical studies demonstrated anti-proliferative properties in cancer cell lines in vitro. In uveal melanoma cell lines SP6.5 and C918, zeaxanthin reduced cell viability in a dose dependent manner while not doing so in normal ocular melanocytes. Decreased cell viability associated with decreased expression of anti-apoptotic proteins bcl-2 and bcl-xL and increased expression of pro-apoptotic bak and bax (1). Anti-proliferative effects were demonstrated in nude mice inoculated in the choroid with uveal melanoma cells (2). Zeaxanthin enhances anti-tumor immunity. Screening a blood nutrient compound library found zeaxanthin to augment CD8+ T-cell activity through direct engagement with the T-cell receptor (3). Murine models showed zeaxanthin enhanced anti-cancer efficacy of anti-PD-1 immunotherapy (3). Pro-apoptotic and immunomodulatory properties of zeaxanthin suggest potential for efficacy in treating cancer patients warranting clinical investigation. The primary objectives of this phase I study are to determine safety and tolerability of escalating doses of zeaxanthin monotherapy or combination of zeaxanthin plus pembrolizumab in patients with metastatic solid tumor malignancies and to determine MTD and recommended phase 2 dose. Secondary objectives assess pharmacokinetics and efficacy. Exploratory endpoints assess blood based biomarkers, transcriptome changes, and immunologic effects. Pre- and on-treatment tumor biopsies assess tumor microenvironment change. Methods: This 2 cohort study treats standard therapy refractory metastatic solid tumor patients with zeaxanthin (monotherapy cohort) or zeaxanthin and pembrolizumab (combination cohort). Combination cohort inclusion requires prior progression on a PD-1/L1 inhibitor. Oral zeaxanthin is administered daily with escalating doses (2 mg/kg to 10 mg/kg). The combination cohort escalates doses of zeaxanthin with a fixed dose of pembrolizumab (400 mg) infused every 6 weeks. Dose escalation utilizes a 3+3 design. Combination cohort dose level enrollment occurs after a zeaxanthin dose demonstrates no monotherapy DLT. Pharmacokinetic assessments occur at specified time points, Required large volume blood draws for pharmacodynamic analysis and optional tumor biopsies are obtained within 15 days prior to treatment initiation and at 6 weeks on treatment. Cohort 1 of zeaxanthin monotherapy (2 mg/kg daily) completed without DLT. Enrollment to monotherapy cohort 2 (zeaxanthin 4 mg/kg daily) and combination cohort 1 (zeaxanthin 2 mg/kg plus pembrolizumab 400 mg IV every 6 weeks) began November 2025 and are actively accruing patients. Clinical trial registry number: NCT05232409. (1) Bi et al. Evid. Based Compl. Alt. Med. (2013)12; (2) Xu et al. J Opthal (2015)10; (3) Zhang et.al. Cell Rep. Med. (2025)6. Clinical trial information: NCT05232409 .