Head and Neck CancerEarly Phase 1NCT05678348
Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma
A Early Phase 1 study testing Pyrimethamine in people with Head and Neck Cancer and Cancer of the Head and Neck, run by Washington University School of Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Head and Neck Cancer, Cancer of the Head and Neck
- What is being tested?
- Pyrimethamine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Aug 2023to 4 Aug 2025
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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).
Who cannot join
- 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.
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
Official title: 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
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
- Being tested
- Pyrimethamine
- Keywords
- head and neck cancer, squamous cell carcinoma, NRF2, pyrimethamine, treatment resistance
- Medical subject headings
- Head and Neck Neoplasms, Carcinoma, Squamous Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyrimethamineDrug
Also called Daraprim
Patients will be instructed to take their dose at approximately the same time each day.
| Study group | Role | What they receive |
|---|---|---|
| Pyrimethamine | Experimental | 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. Receives: Drug: Pyrimethamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Log2 of tumor DHFR expression as measured by western blot analysis
Measured: Pre-treatment and post-treatment (estimated to be 14 days)
Secondary outcomes (4)
Safety and tolerability of pyrimethamine as measured by number of adverse events
Measured: From start of treatment through Day 43 (estimated to be 6 weeks)
Change in Log2 of NRF2 activity score as measured using the NRF2 SureQuant proteomic assay
Measured: Pre-treatment and post-treatment (estimated to be 14 days)
Number of grade 3 or higher adverse events due to pyrimethamine
Measured: 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
Measured: Through completion of follow-up (estimated to be 6 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jan 2023
- Study start3 Aug 2023
- Primary completion11 Jul 2025
- Study completion4 Aug 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Head and Neck CancerStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Tilde Sciences LLC
- Responsible party
- Sponsor
- Investigators
- Paul Zolkind, M.D., Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05678348
- Sponsor's protocol ID
- 202302068
- Status last verified
- Aug 2025
- First submitted
- 20 Dec 2022
- Last updated
- 17 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05678348
- Acronym / sponsor ID
- 202302068
- Conditions
- Head and Neck Cancer, Cancer of the Head and Neck
- Keywords
- head and neck cancer, squamous cell carcinoma, NRF2, pyrimethamine, treatment resistance
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- Tilde Sciences LLC
- Study start
- 3 Aug 2023 (actual)
- Primary completion
- 11 Jul 2025 (actual)
- Study completion
- 4 Aug 2025 (actual)
- First posted
- 10 Jan 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pyrimethamine | Experimental | Drug: PyrimethaminePyrimethamine 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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:
- Able to swallow study drug
Key exclusion criteria (12 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PyrimethamineAlso: DaraprimPatients will be instructed to take their dose at approximately the same time each day. | Drug | Pyrimethamine |
Primary outcome
Change in Log2 of tumor DHFR expression as measured by western blot analysis
Time frame: Pre-treatment and post-treatment (estimated to be 14 days)
4 secondary outcomes
Safety and tolerability of pyrimethamine as measured by number of adverse events
Time frame: From start of treatment through Day 43 (estimated to be 6 weeks)
Change in Log2 of NRF2 activity score as measured using the NRF2 SureQuant proteomic assay
Time frame: Pre-treatment and post-treatment (estimated to be 14 days)
Number of grade 3 or higher adverse events due to pyrimethamine
Time frame: 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
Time frame: Through completion of follow-up (estimated to be 6 weeks)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Aug 2025.
- Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of MedicineLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul Zolkind, M.D. principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Pyrimethamine in people with Head and Neck Cancer and Cancer of the Head and Neck, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Log2 of tumor DHFR expression as measured by western blot analysis (time frame: Pre-treatment and post-treatment (estimated to be 14 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Aug 2025.