Ignite Creation Date:
2024-05-06 @ 6:28 PM
Last Modification Date:
2024-10-26 @ 2:49 PM
Study NCT ID:
NCT05678348
Status:
RECRUITING
Last Update Posted:
2024-04-22
First Post:
2022-12-20
Brief Title:
Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma
Sponsor:
Washington University School of Medicine
Organization:
Washington University School of Medicine
Study Overview
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
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None