Pembrolizumab + N-803 + PD-L1 t-haNK Cells for Head and Neck Cancer

Overseen By Jason M Redman, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Autoimmune disease, Hepatitis B, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 50

Duration: 3 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for head and neck squamous cell carcinoma (HNSCC), a cancer that forms tumors in the head and neck area. The study tests the effectiveness of a drug combination, including N-803 (an IL-15 superagonist complex) and pembrolizumab, with or without PD-L1 t-haNK cells, in aiding the immune system to combat this cancer. The trial seeks participants with HNSCC who have not yet received treatment and are scheduled for tumor-removal surgery. Participants will receive the treatments and attend follow-up visits to monitor progress. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on active immunosuppressive treatment or have had prior therapy with an investigational drug within 2 weeks before starting the trial, you may not be eligible to participate.

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

Research has shown that both N-803 and pembrolizumab have been tested in cancer patients and are generally safe. Studies have found that N-803, when combined with other treatments, is well-tolerated. For example, a study combining N-803 with ipilimumab for head and neck cancer patients found it to be safe and increased certain immune cells.

Pembrolizumab is already approved by the FDA for several cancers and has a known safety record. It is widely used and considered safe, although it can have side effects like any treatment.

For the combination of N-803, pembrolizumab, and PD-L1 t-haNK cells, less data is available, but research is ongoing to understand its safety. This combination has been used in special cases for other cancers, and while detailed safety data is still being gathered, its use suggests it is reasonably safe to explore further.

Overall, these treatments are generally well-tolerated, and studies continue to explore their safety in different combinations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of pembrolizumab, N-803, and PD-L1 t-haNK cells for treating head and neck cancer because this approach offers a unique mechanism of action. Most treatments for head and neck cancer, like chemotherapy and radiation, aim to kill cancer cells directly. However, this investigational therapy uses immunotherapy to boost the body's own immune system. Pembrolizumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells, while N-803 enhances the activity of natural killer cells. The addition of PD-L1 t-haNK cells, which are genetically modified natural killer cells, provides a targeted attack against cancer cells expressing PD-L1, a protein that often helps tumors evade the immune system. This multi-faceted immune approach holds the promise of more effective and potentially longer-lasting cancer control.

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

Research shows that pembrolizumab, a treatment in this trial, can help treat certain head and neck cancers by enabling the immune system to identify and attack cancer cells. Studies have demonstrated that pembrolizumab can increase survival rates in these cases. N-803, another treatment option in this trial, strengthens the immune system's response to cancer. Previous trials tested N-803 with pembrolizumab, showing promising results in other cancers. In one arm of this trial, N-803 and pembrolizumab are combined with PD-L1 t-haNK cells. Early findings in other types of cancer suggest this method may further boost the body's ability to fight cancerous tumors. Initial data supports the idea that these treatments could work well together in treating head and neck cancers. ^{1 4 5 6 7}

Who Is on the Research Team?

Charalampos Floudas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with a specific type of head and neck cancer (HNSCC) that's not linked to HPV, who haven't been treated yet and are set for surgery. They should be in decent health, understand the study, and agree to use birth control. People with severe allergies to similar drugs, active immune suppression over a certain dose, some autoimmune diseases or recent cancers aren't eligible.

Inclusion Criteria

My blood clotting times are normal or only slightly above.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3.0 x upper limit of normal (ULN)

Total bilirubin <= 1 x ULN. Note: Participants with Gilbert's syndrome can have total bilirubin < 3.0 mg/dL

Exclusion Criteria

I am on a high dose of immunosuppressants, not including short-term or non-cancer related uses.

I have an autoimmune disease, but it's not severe and doesn't require medication.

I have a history of hepatitis B.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive pembrolizumab and N-803 on Day 1. Arm 2 participants also receive PD-L1 t-haNK cells on Days 1, 5, 8, 12, and 15.

3 weeks

Multiple visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up visits occur on Days 49 and 105, and continue every 9 weeks for 2 years.

2 years

Visits on Days 49, 105, and every 9 weeks

What Are the Treatments Tested in This Trial?

Interventions

• N-803
• PD-L1 t-haNK cells
• Pembrolizumab

Trial Overview The trial is testing if adding N-803 and pembrolizumab, alone or combined with PD-L1 t-haNK cells (which attack cancer), can help treat HNSCC better. Participants will get these treatments through injections or infusions before their surgery and will have follow-ups including biopsies.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 3 Interventions

N-803 + pembrolizumab + PD-L1 t-haNK cells

Group II: Arm 1 Experimental Treatment 2 Interventions

N-803 + pembrolizumab

N-803 is already approved in United States for the following indications:

Approved in United States as N-803 for:

• Non-muscle invasive bladder cancer (NMIBC) in combination with BCG

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), offering a new option with potentially improved efficacy compared to traditional chemotherapy and EGFR inhibitors.

This review discusses the pharmacology and tolerability of pembrolizumab, emphasizing its mechanism of action by blocking the PD-1 receptor, which may enhance the immune response against HNSCC tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. Sheth, S., Weiss, J.[2019]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[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]

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]

In a study of 78 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, treatment with immune checkpoint inhibitors (CPI), either alone or combined with chemotherapy, showed a median progression-free survival (PFS) of 4 months and a median overall survival (OS) of 11 months, indicating the treatment's effectiveness.

The overall response rate was 20.5% and the disease control rate was 46.1%, with the safety profile of immune-related adverse events being consistent with existing data, supporting the use of CPI therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Data of Palliative First-line Checkpoint Inhibitor Therapy for Head and Neck Cancer. Wagner, SM., Magnes, T., Melchardt, T., et al.[2023]

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 involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

In a study with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., et al.[2023]

In a phase III trial, pembrolizumab, a single-agent treatment, showed significant effectiveness in patients with head and neck tumors that had high PD-L1 expression, leading to deep and lasting responses.

This study highlights the potential of pembrolizumab as a first-line therapy for this specific group of cancer patients, suggesting a targeted approach based on PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembro Ups Survival in PD-L1-positive HNSCC. [2019]

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

Citations

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Safety, Tolerability, and Long-Term Clinical Outcomes of an IL ... This phase 1b trial found the combination of intravesical N-803 and BCG to be associated with modest toxic effects, low immunogenicity, and substantial ...

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Recurrent pancreatic cancer treated with N-803 and PD-L1 t ... Here, we report the compassionate use treatment of this combination in a patient with recurrent, metastatic pancreatic cancer (mPC) after 3 lines of therapy.

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Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for ... In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the ...

7. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-025-01669-3

First-in-human evaluation of memory-like NK cells with an IL ... CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype.