Trial Title:
Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma
NCT ID:
NCT05678348
Condition:
Head and Neck Cancer
Cancer of the Head and Neck
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Squamous Cell Carcinoma of Head and Neck
Pyrimethamine
Conditions: Keywords:
head and neck cancer
squamous cell carcinoma
NRF2
pyrimethamine
treatment resistance
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Pyrimethamine
Description:
Patients will be instructed to take their dose at approximately the same time each day.
Arm group label:
Pyrimethamine
Other name:
Daraprim
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.
Criteria for eligibility:
Criteria:
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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Washington University School of Medicine
Address:
City:
Saint Louis
Zip:
63110
Country:
United States
Status:
Recruiting
Contact:
Last name:
Paul Zolkind, M.D.
Phone:
314-362-7395
Email:
pzolkind@wustl.edu
Investigator:
Last name:
Paul Zolkind, M.D.
Email:
Principal Investigator
Investigator:
Last name:
Ben Major, Ph.D.
Email:
Sub-Investigator
Investigator:
Last name:
Douglas Adkins, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Sidharth Puram, M.D., Ph.D.
Email:
Sub-Investigator
Investigator:
Last name:
Ryan Jackson, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Patrik Pipkorn, M.D., MSCI
Email:
Sub-Investigator
Investigator:
Last name:
Jason Rich, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Randal Paniello, M.D., Ph.D.
Email:
Sub-Investigator
Investigator:
Last name:
Wade Thorstad, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Hiram Gay, M.D.
Email:
Sub-Investigator
Investigator:
Last name:
Esther Lu, M.S., Ph.D.
Email:
Sub-Investigator
Investigator:
Last name:
Peter Oppelt, M.D.
Email:
Sub-Investigator
Start date:
August 3, 2023
Completion date:
April 15, 2026
Lead sponsor:
Agency:
Washington University School of Medicine
Agency class:
Other
Collaborator:
Agency:
Tilde Sciences
Agency class:
Other
Source:
Washington University School of Medicine
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05678348
http://www.siteman.wustl.edu
