Pyrimethamine for Head and Neck Cancer

Overseen by Paul Zolkind, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: Washington University School of Medicine

Must not be taking: Phenytoin, Anticoagulants

Disqualifiers: Prior cancer therapy, Other malignancy, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking phenytoin or have used anticoagulant or antiplatelet therapy in the year prior to diagnosis. It's best to discuss your current medications with the trial team.

Is Pyrimethamine (Daraprim) generally safe for humans?

Pyrimethamine, also known as Daraprim, has been used safely in humans for other conditions, such as malaria, but specific safety data for its use in head and neck cancer is not available in the provided research articles. ^{1 2 3 4 5}

How is the drug Pyrimethamine unique for treating head and neck cancer?

Pyrimethamine is unique for treating head and neck cancer because it is traditionally used to treat parasitic infections like malaria, and its use in cancer treatment is novel. Unlike standard chemotherapy drugs for head and neck cancer, which often include combinations of cisplatin, 5-fluorouracil, and other agents, Pyrimethamine's mechanism of action involves inhibiting an enzyme called dihydrofolate reductase, which is different from the typical mechanisms of existing cancer treatments. ^{2 4 6 7 8}

Research Team

Paul Zolkind, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with HPV-negative, locally advanced head and neck squamous cell carcinoma (HNSCC) who are fit for surgery can join. They must have good organ function, be able to swallow pills, and agree to use contraception. Excluded are those with recent anticoagulant use, allergies to similar drugs, active alcohol abuse, uncontrolled illnesses like heart disease or infections, certain blood disorders or other cancers treated within the last 2 years.

Inclusion Criteria

I am 18 years old or older.

I am fully active and can carry on all my pre-disease activities without restriction.

I agree to use birth control or abstain from sex during the study.

Exclusion Criteria

Currently receiving any other investigational agents

Active alcohol abuse in the opinion of the treating physician

I have been on blood thinners within a year before my head or neck cancer diagnosis.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pyrimethamine at a dose of 50 mg once daily for 14 days

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pyrimethamine (DHFR Inhibitor)

Trial Overview The trial is testing Pyrimethamine's effect on tumors by inhibiting a protein called DHFR and reducing NRF2 activity which could help in treating cancer. The goal is to see if it increases DHFR levels in tumor cells by 50% and cuts down NRF2 activity by half in tumors that were already active before treatment.

Participant Groups

Group I: Pyrimethamine Experimental Treatment 1 Intervention

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.

Pyrimethamine is already approved in Canada for the following indications:

Approved in Canada as Pyrimethamine for:

• Malaria
• Toxoplasmosis

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

David H. Perlmutter

Washington University School of Medicine

Chief Executive Officer since 2015

MD from Washington University School of Medicine

Paul Scheel

Washington University School of Medicine

Chief Medical Officer since 2022

MD from Washington University School of Medicine

Tilde Sciences

Collaborator

Trials

1

Recruited

20+

Vyera Pharmaceuticals

Collaborator

Trials

1

Recruited

20+

Findings from Research

In a phase Ia clinical trial involving 32 patients with advanced head and neck cancer, atezolizumab demonstrated a tolerable safety profile, with 66% of patients experiencing treatment-related adverse events, but no grade 5 events reported.

The treatment showed promising efficacy, with 22% of patients achieving objective responses and a median overall survival of 6.0 months, indicating potential benefits regardless of HPV status or PD-L1 expression levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial. Colevas, AD., Bahleda, R., Braiteh, F., et al.[2022]

In a phase II study of 35 patients with advanced head and neck cancer, pemetrexed disodium showed an objective response rate of 26.5%, with a median response duration of 5.6 months, indicating its efficacy as a treatment option.

While pemetrexed treatment led to significant hematological toxicities, including grade 3/4 neutropenia in 68.6% of patients, these side effects can be managed with folic acid and vitamin B12 supplementation, enhancing the safety profile of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Pivot, X., Raymond, E., Laguerre, B., et al.[2018]

PD-1 inhibitors, used for treating recurrent or metastatic squamous cell carcinoma of the head and neck, can lead to immune-mediated adverse reactions (IMARs), highlighting the importance of monitoring patients closely.

Nurses play a crucial role in mapping patients' baseline profiles and educating them about IMARs, which helps in the timely diagnosis and management of these reactions, ultimately supporting the continuation of effective PD-1 immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 Inhibitors: Safety of Use and Management of Immune-Mediated Adverse Reactions in Patients With Head and Neck Cancer. Lewis, RL., Miller, KL.[2020]

In a phase 3 trial involving 501 patients with advanced squamous-cell carcinoma of the head and neck, those treated with the TPF regimen (docetaxel, cisplatin, and fluorouracil) had a significantly longer overall survival compared to those receiving the PF regimen (cisplatin and fluorouracil), with a 3-year survival rate of 62% versus 48%.

While the TPF group showed better locoregional control of the disease, they also experienced higher rates of neutropenia and febrile neutropenia, indicating a trade-off between improved survival and increased hematologic side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. Posner, MR., Hershock, DM., Blajman, CR., et al.[2022]

In a study of 52 patients with advanced squamous cell cancer of the head and neck treated with weekly edatrexate, only 6% showed a complete or partial response, indicating limited efficacy of the drug in this setting.

The most common side effects included myelosuppression and mucositis, with 25% of patients experiencing dermatologic toxicity, highlighting the need for careful monitoring of adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of edatrexate in advanced head and neck cancer. A Southwest Oncology Group study. Kuebler, JP., Benedetti, J., Schuller, DE., et al.[2019]

The MVAC chemotherapy regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) demonstrated a 46% overall objective response rate in 36 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, indicating its effectiveness in this patient population.

Despite its efficacy, the treatment was associated with significant toxicity, with severe leukopenia occurring in 55% of patients during the first cycle and 81% overall, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of methotrexate, vinblastine, doxorubicin, and cisplatin in patients with squamous cell carcinoma of the upper respiratory or alimentary passages of the head and neck. Okuno, SH., Mailliard, JA., Suman, VJ., et al.[2013]

In a study of 77 patients with locally advanced squamous cell carcinoma of the head and neck, the concurrent chemoradiotherapy regimen using cisplatin, 5-fluorouracil, methotrexate, and leucovorin resulted in a high overall clinical response rate of 94% and a pathological complete response rate of 71%.

The treatment was generally safe and well tolerated, with significant toxicities including mucositis (39%), leukocytopenia (34%), and neutropenia (30%), indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. Katori, H., Tsukuda, M., Taguchi, T.[2013]

In a study of 63 patients with recurrent/metastatic squamous cell carcinoma of the head and neck, the combination of carboplatin and pemetrexed demonstrated a median progression-free survival (PFS) of 5.1 months and a median overall survival (OS) of 9.4 months, indicating its efficacy as a treatment option.

Among patients with oropharyngeal cancer, particularly those with HPV-positive disease, the treatment showed even better outcomes, with a median PFS of 7.0 months and median OS of 17.1 months, highlighting the potential for improved survival in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin-pemetrexed in treatment of patients with recurrent/metastatic cancers of the head and neck; superior outcomes in oropharyngeal primaries. Malhotra, B., Bellile, EL., Nguyen, NP., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

PD-1 Inhibitors: Safety of Use and Management of Immune-Mediated Adverse Reactions in Patients With Head and Neck Cancer. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II study of edatrexate in advanced head and neck cancer. A Southwest Oncology Group study. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Phase II study of methotrexate, vinblastine, doxorubicin, and cisplatin in patients with squamous cell carcinoma of the upper respiratory or alimentary passages of the head and neck. [2013]

7. Germany pubmed.ncbi.nlm.nih.gov

Analysis of efficacy and toxicity of chemotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin (PFML) and radiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. [2013]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Carboplatin-pemetrexed in treatment of patients with recurrent/metastatic cancers of the head and neck; superior outcomes in oropharyngeal primaries. [2020]