Pyrimethamine for Head and Neck Cancer

No longer recruiting at 1 trial location

Overseen By Paul Zolkind, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Washington University School of Medicine

Must not be taking: Phenytoin, Anticoagulants

Disqualifiers: Prior cancer therapy, Other malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the drug pyrimethamine can help treat head and neck cancer by targeting a protein called NRF2, which often worsens tumors and makes them harder to treat. Originally used for malaria, pyrimethamine may reduce NRF2 activity in tumors, making them less aggressive. Individuals with advanced head and neck cancer, specifically non-HPV-related types, who are planning surgery, might be suitable for this trial. As an Early Phase 1 trial, the research focuses on understanding how pyrimethamine works in people, offering participants the chance to contribute to groundbreaking cancer treatment research.

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 there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that pyrimethamine has been safely used for many years to treat infections like malaria. While its effects on human tumors remain under investigation, it has shown promise in slowing tumor growth in mice.

In this early-stage trial, researchers are primarily focused on ensuring pyrimethamine's safety for people with head and neck cancer. They are still learning about its safety in this new context. However, since pyrimethamine is already approved for other uses, there is some confidence in its general tolerability.

As the trial progresses, researchers will gather more information about any side effects and how patients respond to the treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for head and neck cancer, which often involve surgery, radiation, and chemotherapy, pyrimethamine presents a novel approach. This drug, commonly known for its use in treating malaria, works by blocking the enzyme dihydrofolate reductase, which is essential for cancer cell growth. Researchers are excited about pyrimethamine because it targets cancer cells in a unique way, potentially offering a new and effective treatment option with fewer side effects. Additionally, its oral administration makes it convenient and potentially less invasive compared to traditional cancer therapies.

What evidence suggests that pyrimethamine might be an effective treatment for head and neck cancer?

Research has shown that pyrimethamine might help fight cancer. In studies with mice, pyrimethamine shrank tumors by blocking a protein called NRF2, which aids tumor growth and resistance to treatment. Lab tests demonstrated that pyrimethamine stopped NRF2 from functioning, suggesting it might have a similar effect in humans. In this trial, participants with head and neck cancer will receive pyrimethamine. Specifically, some patients in previous studies showed promising results, with 22% responding positively to the treatment. While more research is needed, these early findings suggest pyrimethamine could be effective against certain cancers by targeting NRF2. ^{1 2 3 4 6}

Who Is on the Research Team?

Paul Zolkind, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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

Ability to understand and willingness to sign an IRB approved written informed consent document

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Pyrimethamine

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Daraprim for:

• Malaria
• Toxoplasmosis

Approved in European Union as Pyrimethamine for:

• Malaria
• Toxoplasmosis

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+

Tilde Sciences

Collaborator

Trials

1

Recruited

20+

Vyera Pharmaceuticals

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

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 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]

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]

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 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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05678348?term=DHFR+inhibitor+clinical+trials&draw=2&rank=1

Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11014785/

Pyrimethamine reduced tumour growth in pre-clinical ... Pyrimethamine (PYR), a STAT3 inhibitor, has been shown to reduce tumour burden in mouse cancer models. It is unclear how much of a reduction occurred.

3. withpower.com withpower.com/trial/early-phase-1-carcinoma-3-2023-99808

Pyrimethamine for Head and Neck Cancer The treatment showed promising efficacy, with 22% of patients achieving objective responses and a median overall survival of 6.0 months, indicating potential ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0021925825025116

Pyrimethamine and a potent analogue inhibit NRF2 by ... Our recent discovery that PYR inhibits NRF2 in cells and mice led to an ongoing phase 1 trial in HPV-negative head and neck squamous cell ...

5. academic.oup.com academic.oup.com/biomethods/article-pdf/doi/10.1093/biomethods/bpae021/57226997/bpae021.pdf

Pyrimethamine reduced tumour growth in pre-clinical cancer ... Pyrimethamine (PYR), a STAT3 inhibitor, has been shown to reduce tumour burden in mouse cancer models. It is unclear how much of a reduction ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-02255

Pyrimethamine for the Treatment of Patients with HPV ... This early phase I trial tests the safety, side effects, and biological activity of a drug called pyrimethamine in patients with human papillomavirus ...