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

Sponsor

Washington University School of Medicine (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05678348

Collaborator

(none)

Enrollment

Location

Arm

31.5

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Cancer Cancer of the Head and Neck	Drug: Pyrimethamine	Early Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Apr 30, 2023

Anticipated Primary Completion Date :

Dec 15, 2025

Anticipated Study Completion Date :

Dec 15, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pyrimethamine Pyrimethamine will be taken by mouth at a dose of 50 mg once daily for 14 days (+/-2 days) with the last dose the day prior to surgery.	Drug: Pyrimethamine Patients will be instructed to take their dose at approximately the same time each day. Other Names: Daraprim

Arm

Intervention/Treatment

Experimental: Pyrimethamine

Pyrimethamine will be taken by mouth at a dose of 50 mg once daily for 14 days (+/-2 days) with the last dose the day prior to surgery.

Drug: Pyrimethamine

Patients will be instructed to take their dose at approximately the same time each day.

Other Names:

Daraprim

Outcome Measures

Primary Outcome Measures

Change in tumor DHFR expression as measured by western blot analysis [Pre-treatment and post-treatment (estimated to be 14 days)]
Number of grade 3 or higher adverse events due to pyrimethamine [From start of treatment through Day 43 (estimated to be 6 weeks)]
Number of participants with a delay in surgery by ≥ 10 days due to pyrimethamine [Through completion of follow-up (estimated to be 6 weeks)]

Secondary Outcome Measures

Safety and tolerability of pyrimethamine as measured by number of adverse events [From start of treatment through Day 43 (estimated to be 6 weeks)]
Change in tumor NRF2 activation as measured using the NRF2 SureQuant proteomic assay [Pre-treatment and post-treatment (estimated to be 14 days)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed HPV-negative, locally advanced (Stage III-IV) head and neck squamous cell carcinoma (HNSCC) undergoing surgical-based treatment with curative intent.
At least 18 years of age.
ECOG performance status ≤ 1
Normal bone marrow and organ function as defined below:
Leukocytes ≥ 3,000/mcL
Absolute neutrophil count ≥ 1,500/mcL
Platelets ≥ 100,000/mcL
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 (or that of legally authorized representative, if applicable).

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 study entry.
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.
Unable to swallow study drug
Active alcohol abuse
Receiving phenytoin