Losartan + Pembrolizumab + SBRT for Head and Neck Cancer

Recruiting at 1 trial location

Overseen By Selina Laqui

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Shyam S.D. Rao

Must not be taking: ARBs, ACE inhibitors

Disqualifiers: Nasopharyngeal carcinoma, Diabetes, Autoimmune disorders, others

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

Compensation: Varies

Number of Visits: 3

Duration: Up to 1 year

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with a type of head and neck cancer that has returned or spread after initial improvement. The trial examines the safety and effectiveness of three combined treatments: losartan (a blood pressure drug that may enhance cancer treatment effects), pembrolizumab (a cancer immunotherapy that aids the immune system in attacking cancer cells), and SBRT (Stereotactic Body Radiation Therapy, a precise form of radiation therapy). It suits individuals whose cancer hasn't responded to previous treatments, affects up to four sites, and who are open to undergoing regular biopsies. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative combination therapy.

Do I need to stop my current medications to join the trial?

The trial requires that you stop using certain medications, such as angiotensin receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors for managing high blood pressure, and systemic corticosteroids over a certain dose. If you are on these medications, you may need to discuss alternatives with your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is investigating the safety of combining losartan, pembrolizumab, and stereotactic body radiation therapy (SBRT) for head and neck cancer patients. Losartan, commonly used to lower high blood pressure, might enhance the effectiveness of other cancer treatments. Pembrolizumab, an immunotherapy drug, helps the body's immune system combat cancer. SBRT is a precise radiation therapy that targets tumors while sparing healthy tissue.

Studies have shown that pembrolizumab combined with SBRT can be effective. In some research involving various cancer types, pembrolizumab achieved an 18% response rate, meaning 18 out of 100 people had a positive reaction. Although this research focused on a different cancer type, it provides insight into pembrolizumab's potential effectiveness in other cases.

As this trial is in an early stage, the primary goal is to assess the safety of these treatments when used together. Detailed safety information may be limited. However, losartan is approved for high blood pressure, and pembrolizumab is an approved cancer treatment, indicating known safety profiles.

While the combination is still under safety evaluation, previous research on the individual treatments offers some reassurance. Participants should remain aware that the study's main aim is to explore safety and side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Losartan, Pembrolizumab, and Stereotactic Body Radiation Therapy (SBRT) for head and neck cancer because it offers a novel approach to treatment. Unlike traditional therapies that often rely on surgery, chemotherapy, or standard radiation, this combination leverages Losartan, which may enhance blood flow to tumors, potentially making them more responsive to treatment. Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells, which is a newer approach compared to older chemotherapy methods. Additionally, SBRT provides highly targeted radiation, minimizing damage to surrounding healthy tissues and potentially reducing side effects. Together, these treatments aim to enhance effectiveness and reduce toxicity, offering hope for improved outcomes.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

This trial will evaluate the combination of losartan, pembrolizumab, and stereotactic body radiation therapy (SBRT) for treating head and neck cancer. Research has shown that using these treatments together may help treat certain cancers. Studies have found that SBRT with pembrolizumab effectively manages tumors by targeting them with precise radiation and boosting the body's immune system to fight cancer cells. Losartan, a medication typically used for high blood pressure, might enhance the effectiveness of these treatments. Early research has demonstrated that combining immunotherapy and radiation can be effective for cancers in the digestive system, and it might also work for head and neck cancer. Although detailed information about this combination for head and neck cancer remains limited, the individual treatments have shown positive results, and early findings are promising. ^{1 2 4 5 6}

Who Is on the Research Team?

Shyam S.D. Rao, MD, PhD

Principal Investigator

University of California, Davis

Are You a Good Fit for This Trial?

This trial is for adults with head and neck squamous cell carcinoma that has returned, resisted treatment, or spread to a few other places. Participants should have tried previous therapies without success and must be able to handle radiation therapy.

Inclusion Criteria

Leukocytes ≥ 3 × 10^9/L

My cancer can be measured and tracked using CT or MRI scans.

My cancer in the head or neck area cannot be surgically removed and has returned or spread, but only to a few places.

Exclusion Criteria

Hypersensitivity to losartan or any component of the formulation

I haven't needed IV antibiotics for an infection in the last 4 weeks.

I am taking more than 10 mg of prednisone or similar medication daily.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive losartan orally once daily. One week later, they receive SBRT 2-3 times per week for approximately 2 weeks. Within 1 week of completing SBRT, participants receive pembrolizumab intravenously every 3 weeks. Treatment continues for up to 1 year in the absence of disease progression or unacceptable toxicity.

Up to 1 year

Regular visits for SBRT and pembrolizumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 3 months for up to 1 year.

1 year

Follow-up visits every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Losartan
• Pembrolizumab
• Stereotactic Body Radiation Therapy

Trial Overview The trial tests combining losartan (a blood pressure medication), pembrolizumab (an immunotherapy drug), and precise radiation therapy. It aims to see if this mix can better treat cancer by enhancing the immune system's response and targeting tumors while sparing healthy tissue.

How Is the Trial Designed?

Group I: Treatment (losartan, SBRT, pembrolizumab) Experimental Treatment 3 Interventions

Patients receive losartan PO QD. One week later patients receive SBRT 2-3 times per week for approximately 2 weeks. Within 1 week of completing SBRT, patients receive pembrolizumab IV and repeat every 3 weeks. Treatment continues for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo PET, tumor biopsy, and blood sample collection throughout the study.

Losartan is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Stroke prevention in hypertension and left ventricular hypertrophy

Approved in European Union as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Approved in Canada as Cozaar for:

• Hypertension
• Diabetic nephropathy
• Heart failure

Who Is Running the Clinical Trial?

Shyam S.D. Rao

Lead Sponsor

Trials

1

Recruited

20+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

Losartan, when combined with anti-PD-L1 monoclonal antibodies, significantly enhances the antitumor effects in a mouse model of breast cancer by modulating the tumor microenvironment, leading to increased infiltration of CD8+ T cells and granzyme B production.

While losartan alone did not show efficacy, its combination with anti-PD-L1 mAb reduced tumor metastasis to the lungs and improved overall therapeutic outcomes, suggesting a potential strategy to enhance the effectiveness of immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulating the tumor microenvironment improves antitumor effect of anti-PD-L1 mAb in breast cancer. Li, X., Luo, X., Hu, S.[2023]

In a phase II study involving 29 patients with locally advanced head and neck squamous cell carcinoma who were ineligible for cisplatin, the combination of pembrolizumab and radiotherapy showed promising efficacy, with a 24-month progression-free survival rate of 71%.

The treatment was generally well-tolerated, although a significant number of patients experienced grade 3/4 lymphopenia (58.6%), indicating the need for monitoring immune cell changes during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. Weiss, J., Sheth, S., Deal, AM., et al.[2023]

In a study of over 5000 head and neck cancer patients, those with chronic kidney disease or hypertension who used angiotensin II receptor blockers (ARBs) showed improved overall survival (OS) and cancer-specific survival (CSS) compared to those not using ARBs.

No significant survival benefits were found for patients using angiotensin-converting enzyme inhibitors (ACEi), indicating that ARBs may be more beneficial for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in head and neck cancer. Stokes, WA., Molina, E., McDermott, JD., et al.[2022]

In a study using a murine model of metastatic HER2/neu-positive breast cancer, combining losartan with radiation therapy significantly increased tumor growth delay by an additional 5 to 8 days compared to radiation alone, indicating enhanced treatment efficacy.

Losartan treatment also reduced lung metastasis and improved animal survival, likely by increasing tumor vascularity and decreasing hypoxia, suggesting it could be a promising strategy for improving outcomes in HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model. Li, W., Li, S., Chen, IX., et al.[2021]

Losartan, an angiotensin II receptor blocker, effectively reduces the survival of prostate cancer cells, showing a significant antitumor effect at a concentration of 1 µM.

When combined with ionizing radiation, losartan enhances the treatment's effectiveness, further reducing prostate cancer cell proliferation without causing toxicity to non-malignant fibroblast cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan sensitizes selectively prostate cancer cell to ionizing radiation. Yazdannejat, H., Hosseinimehr, SJ., Ghasemi, A., et al.[2016]

In a study of 114 patients with metastatic pancreatic ductal adenocarcinoma, the use of losartan during chemotherapy did not show significant differences in overall survival (OS) or progression-free survival (PFS) compared to patients not using losartan.

While there was a trend towards longer PFS in patients treated with losartan and FOLFIRINOX, this did not reach statistical significance, suggesting that further research is needed to explore the potential benefits of losartan in metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy. Kasi, A., Allen, J., Mehta, K., et al.[2022]

The Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

Losartan is a safe and effective antihypertensive medication that blocks the angiotensin II type 1 receptor, showing similar overall adverse event rates compared to placebo in a large study of approximately 3800 patients with various conditions, including diabetes and heart failure.

The most common side effects of losartan were headache and dizziness, with dizziness being the only side effect reported more frequently than in the placebo group, indicating that losartan can be a suitable first-line treatment for hypertension, especially for patients who may not tolerate other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety and tolerability of losartan. Weber, M.[2019]

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

A 69-year-old patient with relapsed squamous cell carcinoma showed significant improvement after 14 cycles of pembrolizumab, indicating its efficacy as a second-line treatment for metastatic head and neck cancer.

The patient developed severe immune-related adverse effects, specifically grade 4 mucositis and esophagitis, highlighting the importance of monitoring for such complications in patients receiving PD-1 inhibitors like pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab. Acero Brand, FZ., Suter, N., Adam, JP., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06211335

Study Details | NCT06211335 | Losartan, Pembrolizumab ... This phase Ib trial tests the safety, side effects and how well losartan, pembrolizumab and stereotactic body radiation therapy (SBRT) for the treatment of ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03924869

NCT03924869 | Efficacy and Safety Study of Stereotactic ... The purpose of this study is to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus pembrolizumab (MK-3475) in the treatment of adult ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10378032/

Combination of Immunotherapy and Radiation Therapy in ... Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer.

4. clinicaltrials.ucbraid.org clinicaltrials.ucbraid.org/head-and-neck-cancer

Head and Neck Cancer clinical trials at University of California ... This phase Ib trial tests the safety, side effects and how well losartan, pembrolizumab and stereotactic body radiation therapy (SBRT) for the ...

5. clin.larvol.com clin.larvol.com/trial-detail/NCT06211335

Losartan, Pembrolizumab and Stereotactic Body Radiation ... According to RECIST 1.1. Will be summarized using Kaplan-Meier curves and 95% CI. From start of stereotactic body radiation therapy (SBRT) to local or distant ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10919132/

A Pilot Study of Pembrolizumab Combined With Stereotactic ... In the SARC028 study of pembrolizumab, there was an 18% response rate and median PFS of 18 weeks for the 40 patients with soft tissue sarcoma.