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.

Inclusion Criteria:

• Histologically or cytologically confirmed, locally advanced (Stage III-IV) head and neck squamous cell carcinoma (HNSCC) undergoing surgical-based treatment with curative intent that is HPV-unrelated disease, defined as SCC of the oral cavity, larynx, or hypopharynx, p16 negative SCC of the oropharynx.

• At least 18 years of age.

• ECOG performance status ≤ 1

• Normal bone marrow and organ function as defined below:

  • Leukocytes ≥ 3.0 K/cumm
  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Creatinine clearance > 50 mL/min by Cockcroft-Gault

• Able to swallow study drug

• The effects of pyrimethamine on the developing human fetus are unknown. For this reason and because it is in Pregnancy Category C, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document.

• Patient must be able to undergo a research biopsy prior to starting treatment, or have previously banked baseline tumor biopsy of at least 20 mg of frozen tissue collected under Tissue Acquisition Protocol (IRB 201102323).

Exclusion Criteria:

• Prior therapy for this cancer.
• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease.
• Prior treatment with pyrimethamine in the year prior to HNSCC diagnosis.
• Currently receiving any other investigational agents.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pyrimethamine or other agents used in the study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, current use of systemic immunosuppressive medications, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Documented megaloblastic anemia due to folate deficiency.
• Treatment with anticoagulant or antiplatelet therapy in the year prior to HNSCC diagnosis.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of Day 1.
• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.
• Active alcohol abuse in the opinion of the treating physician.
• Currently taking phenytoin