NCT05678348

Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma

Early Phase I Window of Opportunity Biomarker and Safety Trial to Test Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated, Locally Advanced Head and Neck Squamous Cell Carcinoma

• Status: Completed
• Phase: EARLY_Phase 1
• Study type: Interventional
• Enrollment: 22 (actual)
• Sponsor: Washington University School of Medicine · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

NRF2 activation, observed in up to 40% of head and neck squamous cell carcinoma (HNSCC) tumors, plays a critical role in tumor progression, metastasis, and radiation therapy resistance. The investigators have recently discovered that pyrimethamine (PYR) and its analogs have an inhibitory effect on NRF2 activity in vitro and in mouse models via inhibition of dihydrofolate reductase (DHFR). Pyrimethamine is an established drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however its activity on growing human tumors has not been previously studied. The primary efficacy goal of this study is to evaluate the activity of pyrimethamine on human tumors as demonstrated by inhibition of DHFR and downregulation of NRF2 pathway activity. On-target inhibition of DHFR by pyrimethamine results in the stabilization and increased protein expression of human DHFR. The primary efficacy hypothesis of this study is that treatment with pyrimethamine will result in a 50% increase in DHFR protein within the tumor cells as measured by quantitative western blot analysis. Secondarily, among those tumors classified as NRF2-active on pre-treatment biopsy, the investigators hypothesize there will be a 50% reduction in NRF2 activity as measured by SureQuant targeted proteomic analysis.

Conditions

• Head and Neck Cancer
• Cancer of the Head and Neck

Interventions

Type	Name	Description
DRUG	Pyrimethamine	Patients will be instructed to take their dose at approximately the same time each day.

Timeline

• Start date: 2023-08-03
• Primary completion: 2025-07-11
• Completion: 2025-08-04
• First posted: 2023-01-10
• Last updated: 2025-08-17

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study