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

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects and how well losartan, pembrolizumab and stereotactic body radiation therapy (SBRT) for the treatment of patients with head and neck squamous cell carcinoma that has come back to nearby tissue or lymph node after a period of improvement (locally recurrent), that has not responded to previous treatment (refractory) or that has spread from where it first started to multiple other placed in the body (oligometastatic). Losartan is a drug used to treat high blood pressure that may enhance the effects of other cancer treatments such as immunotherapy and radiation. Immunotherapy with pembrolizumab may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Giving losartan, pembrolizumab and SBRT may work better in treating patients with locally recurrent, refractory or oligometastatic head and neck squamous cell carcinoma.

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.

What data supports the effectiveness of the drug combination Losartan, Pembrolizumab, and SBRT for treating head and neck cancer?

Research shows that Losartan can enhance the effectiveness of radiation therapy in prostate and breast cancer by improving tumor oxygenation, which may help in head and neck cancer treatment. Additionally, combining Losartan with immune therapies like Pembrolizumab has shown improved antitumor effects in breast cancer models. ^{1 2 3 4 5}

Is the combination of Losartan, Pembrolizumab, and SBRT generally safe for humans?

Losartan is generally safe for humans, with common side effects like headache and dizziness, and it has been used safely in patients with conditions like hypertension and diabetes. Pembrolizumab (KEYTRUDA) is an immune therapy used in various cancers and is generally well-tolerated, though it can cause immune-related side effects. Stereotactic Body Radiation Therapy (SBRT) is a precise form of radiation therapy that is generally safe but can cause localized side effects depending on the treatment area. ^{1 2 3 5 6}

What makes the Losartan + Pembrolizumab + SBRT treatment unique for head and neck cancer?

This treatment is unique because it combines Losartan, a blood pressure medication, with Pembrolizumab, an immune therapy drug, and Stereotactic Body Radiation Therapy (SBRT), a precise form of radiation, to potentially enhance the immune response against head and neck cancer, which is different from the standard chemoradiation approaches. ^{7 8 9 10 11}

Research Team

Shyam S.D. Rao, MD, PhD

Principal Investigator

University of California, Davis

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

Losartan sensitizes selectively prostate cancer cell to ionizing radiation. [2016]

2. Singapore pubmed.ncbi.nlm.nih.gov

Association of losartan with outcomes in metastatic pancreatic cancer patients treated with chemotherapy. [2022]

3. England 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. [2021]

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

Survival impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in head and neck cancer. [2022]

5. Iran pubmed.ncbi.nlm.nih.gov

Modulating the tumor microenvironment improves antitumor effect of anti-PD-L1 mAb in breast cancer. [2023]

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

Clinical safety and tolerability of losartan. [2019]

7. United States 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. [2022]

8. United States 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. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab. [2019]

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

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. [2023]

11. England 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. [2021]