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

Recruiting at 1 trial location

Overseen By Glenn J Hanna, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Glenn J. Hanna

Must be taking: Anti-PD-1/L1 therapy

Must not be taking: Corticosteroids, others

Disqualifiers: CNS metastases, Autoimmune disease, 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: 12

Duration: 12 months

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for advanced head and neck cancer. It combines PD-L1 t-haNK, a therapy using modified immune cells; N-803, a protein that boosts the immune system; and cetuximab, a targeted antibody treatment. The trial aims to assess the safety and effectiveness of this combination for individuals whose cancer has returned or spread and cannot be surgically removed. Suitable candidates have head and neck squamous cell carcinoma and have undergone one or two previous treatments, including anti-PD-1/L1 therapy. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must wait at least 2 weeks after your last chemotherapy, biological agents, or investigational drugs before starting the trial.

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

Research has shown that PD-L1 t-haNK cell therapy is generally safe and well-tolerated. One study reported no cases of cytokine release syndrome (CRS), a common side effect of similar treatments, suggesting a good safety profile.

N-803 also shows promising safety data. Studies indicate it causes mild side effects and doesn't trigger a strong immune response. In one study, it was safe when combined with other treatments for head and neck cancer.

Cetuximab, the third treatment in this trial, has been used for a long time. It is often prescribed for head and neck cancers and has a manageable safety profile. Patients may experience side effects, but they are usually considered acceptable for this type of treatment.

Overall, these treatments have demonstrated a good safety record in previous studies. While all treatments can have side effects, evidence suggests they are generally well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of PD-L1 t-haNK, N-803, and Cetuximab for head and neck cancer because it offers a new approach to targeting the disease. Unlike standard treatments such as surgery, radiation, and chemotherapy, which can have broad effects on the body, this combination focuses on enhancing the immune system's ability to fight cancer. PD-L1 t-haNK and N-803 are designed to boost immune responses, while Cetuximab specifically targets cancer cell growth. This targeted strategy could lead to more effective treatments with potentially fewer side effects, providing hope for better outcomes for patients.

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

Research has shown that a combination of three treatments—PD-L1 t-haNK, N-803, and cetuximab—may help treat head and neck cancer. In this trial, participants will receive this combination therapy. Lab tests have demonstrated that PD-L1 t-haNK cells can kill cancer cells, including those from head and neck cancer. N-803 boosts these immune cells, enhancing their effectiveness against cancer. Cetuximab, an antibody already used for head and neck cancer, targets specific proteins on cancer cells to inhibit their growth. Together, these treatments are believed to strengthen the immune system's ability to fight cancer, with cetuximab adding its proven effectiveness. Early studies suggest this combination could be a powerful option for patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Glenn J. Hanna, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with advanced head and neck squamous cell carcinoma that has come back or spread. Participants should have tried other treatments without success. They must be in good physical condition, with no major organ dysfunction, and able to handle biopsies.

Inclusion Criteria

I can provide records of my tumor's PD-L1 and HPV status.

I am not pregnant or will use contraception during and 6 months after the study.

My organ and bone marrow functions are within normal ranges.

Exclusion Criteria

I have received an organ transplant from another person.

I have hepatitis B or C, or I am HIV positive but undetectable with treatment.

Subjects who are pregnant, or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Breastfeeding should be discontinued if the mother is treated on this protocol. Women who could potentially become pregnant while undergoing treatment on this protocol must be willing to use 2 methods of contraception.

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 PD-L1 t-haNK, N-803, and Cetuximab every 2 weeks for at least 1 year

12 months

Visits every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Follow-up every 3-4 months

Long-term follow-up

Participants are monitored for long-term safety and survival

15 years

Follow-up every 6-12 months

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• N-803
• PD-L1 t-haNK

Trial Overview The study tests a combination of three therapies: PD-L1 t-haNK (modified immune cells), N-803 (an immune system booster), and cetuximab (a targeted antibody). It aims to see if this mix can safely improve outcomes for patients with recurrent or metastatic head and neck cancer.

How Is the Trial Designed?

Group I: Dose Level 0: PD-L1 t-haNK + N-803 + Cetuximab Experimental Treatment 3 Interventions

Dose level modifications of PD-L1 t-haNK and N-803 due to toxicities will follow protocol specifications, starting at Dose Level 0 and de-escalating to Dose Level -1. Participants will complete: * Baseline visit. * Imaging scans every 8 weeks while on study. * Cycle 1 through End of Treatment: --Days 1 and 15 of 28 day cycle in the following order: Predetermined dose of PD-L1 t-haNK 1x daily, predetermined dose of N-803 1x daily, and predetermined dose of Cetuximab 1x daily. * End of Treatment visit with assessments. * Follow up: follow up every 3-4 months for up to 3 years after end of treatment. Longer-term follow-up every 6-12 months for up to 15 years.

Group II: Dose Level -1: PD-L1 t-haNK + N-803 + Cetuximab Experimental Treatment 3 Interventions

Dose level modifications of PD-L1 t-haNK and N-803 due to toxicities will follow protocol specifications. Participants will complete: * Baseline visit. * Imaging scans every 8 weeks while on study. * Cycle 1 through End of Treatment: --Days 1 and 15 of 28 day cycle in the following order: Predetermined dose of PD-L1 t-haNK 1x daily, predetermined dose of N-803 1x daily, and predetermined dose of Cetuximab 1x daily. * End of Treatment visit with assessments. * Follow up: follow up every 3-4 months for up to 3 years after end of treatment. Longer-term follow-up every 6-12 months for up to 15 years.

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

Approved in United States as Erbitux for:

• Locally or regionally advanced squamous cell carcinoma of the head and neck
• Recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer
• BRAF V600E mutation-positive metastatic colorectal cancer

Approved in European Union as Erbitux for:

• Squamous cell carcinoma of the head and neck
• K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer

Who Is Running the Clinical Trial?

Glenn J. Hanna

Lead Sponsor

Trials

6

Recruited

160+

ImmunityBio, Inc.

Industry Sponsor

Trials

75

Recruited

5,000+

Richard Adcock

ImmunityBio, Inc.

Chief Executive Officer since 2024

Information not available

Dr. Patrick Soon-Shiong

ImmunityBio, Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Cetuximab, a monoclonal antibody targeting the EGFR, significantly improves treatment outcomes for patients with squamous cell carcinomas of the head and neck (SCCHN), enhancing locoregional control when combined with radiotherapy and overall survival when paired with platinum-based chemotherapy, based on phase III clinical trials.

The combination therapies using cetuximab do not negatively impact patients' quality of life and have an acceptable safety profile, with most adverse events being mild to moderate, making it a valuable treatment option for SCCHN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: a review of its use in squamous cell carcinoma of the head and neck. Frampton, JE.[2021]

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]

Cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor, which plays a crucial role in the growth of various cancers.

It received accelerated approval from the US FDA in February 2004 for treating metastatic colorectal cancer based on positive tumor response rates observed in Phase II clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab. Goldberg, RM.[2020]

The combination of cetuximab, an antibody targeting EGFR, with ALT-803, a novel IL-15 compound, significantly enhances the cytotoxic activity of natural killer (NK) cells against head and neck squamous cell carcinoma (SCCHN) tumors, as shown in experiments with NK cells from healthy donors and in mouse models.

In mice with SCCHN tumors, the dual treatment led to a notable reduction in tumor volume compared to controls and single-agent treatments, indicating a promising strategy for improving anti-tumor responses in patients with EGFR-positive SCCHN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An IL-15-based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous cell carcinoma of the head and neck. Pinette, A., McMichael, E., Courtney, NB., et al.[2020]

Cetuximab, an anti-HER1 monoclonal antibody, effectively enhances the immune response against squamous cell carcinoma of the head and neck by activating natural killer (NK) cells, leading to significant tumor cell lysis.

The addition of interleukin-12 (IL-12) to cetuximab treatment markedly improves NK cell activity and cytokine production, resulting in reduced tumor burden in a murine model, suggesting that IL-12 could be a beneficial adjuvant in treating HER1-positive cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab therapy in head and neck cancer: immune modulation with interleukin-12 and other natural killer cell-activating cytokines. Luedke, E., Jaime-Ramirez, AC., Bhave, N., et al.[2021]

The recommended phase II dose (RP2D) of ipilimumab, when added to standard cetuximab and radiotherapy for high-risk head and neck squamous carcinoma, is established at 1 mg/kg, demonstrating a tolerable safety profile with manageable adverse effects.

The combination treatment resulted in a promising 3-year disease-free survival and overall survival rate of 72%, indicating its efficacy without the need for cytotoxic chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer. Ferris, RL., Moskovitz, J., Kunning, S., et al.[2023]

In head and neck cancer, PD-1 expression on natural killer (NK) cells indicates an activated state, and higher levels of PD-1+ NK cells in patients correlate with better clinical outcomes, suggesting their potential role in anti-tumor immunity.

Blocking the PD-1-PD-L1 interaction enhances NK cell activation and cytotoxicity against tumor cells, particularly those with high PD-L1 expression, indicating that combining PD-1 blockade with cetuximab therapy could improve treatment efficacy in resistant head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-L1 Mediates Dysfunction in Activated PD-1+ NK Cells in Head and Neck Cancer Patients. Concha-Benavente, F., Kansy, B., Moskovitz, J., et al.[2020]

High affinity natural killer cells (haNKs) can directly kill both HPV-positive and negative head and neck squamous cell carcinoma cells, showing potential as a cell therapy for tumors that evade T-cell immunity.

haNKs' effectiveness is significantly enhanced through antibody-dependent cell-mediated cytotoxicity (ADCC) when combined with treatments like cetuximab or avelumab, particularly in tumors with high EGFR or PD-L1 expression, suggesting a promising strategy for advanced head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct and antibody-dependent cell-mediated cytotoxicity of head and neck squamous cell carcinoma cells by high-affinity natural killer cells. Friedman, J., Padget, M., Lee, J., et al.[2021]

Cetuximab, an antibody targeting EGFR, enhances the immune response in head and neck cancer by activating natural killer (NK) cells and promoting their interaction with dendritic cells, which is crucial for antitumor immunity.

Combining cetuximab with the CD137 agonist urelumab significantly improves NK cell survival and dendritic cell maturation, leading to better tumor antigen presentation, suggesting that this combination therapy could enhance clinical outcomes in patients with head and neck cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer. Srivastava, RM., Trivedi, S., Concha-Benavente, F., et al.[2022]

Engineered NK cells (haNKs) expressing a PD-L1 chimeric antigen receptor effectively killed head and neck cancer cells and inhibited tumor growth in both syngeneic and xenograft models, demonstrating their potential as a treatment option.

The treatment not only targeted tumors but also reduced levels of immunosuppressive myeloid cells expressing high PD-L1, suggesting that PD-L1 CAR haNKs could overcome some limitations of T cell-based therapies in cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells. Robbins, Y., Greene, S., Friedman, J., et al.[2021]

The ERBITAX regimen (paclitaxel and cetuximab) demonstrated a response rate of 37.7% in 531 patients with recurrent/metastatic squamous cell carcinoma of the head and neck who were ineligible for cisplatin-based chemotherapy, indicating its efficacy as a first-line treatment.

Patients who received immunotherapy after ERBITAX treatment had significantly improved overall survival (OS) of 29.8 months compared to 13.8 months for those receiving other treatments, suggesting a beneficial sequential treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck. Rubió-Casadevall, J., Cirauqui Cirauqui, B., Martinez Trufero, J., et al.[2023]

Citations

1. dana-farber.org dana-farber.org/clinical-trials/23-583

A Phase 2 Trial of PD-L1 t-haNK, N-803 IL-15 superagonist ... The purpose of this research study is to test the safety and efficacy of the combination of PD-L1 t-haNK (modified immune cells), N-803 (a manufactured protein ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7247398/

PD-L1 targeting high-affinity NK (t-haNK) cells induce ... In vitro, we demonstrate the ability of irradiated PD-L1 t-haNK cells to lyse 20 of the 20 human cancer cell lines tested, including triple ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-01652

PD-L1 t-haNK with N-803 and Cetuximab for the Treatment ... This phase II trial tests the safety and effectiveness of PD-L1 t-haNK with N-803 and cetuximab in treating patients with head and neck squamous cell carcinoma.

4. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/456755

PD-L1 t-haNK, N-803 IL-15sa and Cetuximab for Recurrent ... The purpose of this research study is to test the safety and efficacy of the combination of PD-L1 t-haNK (modified immune cells), N-803 (a ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8453198/

Unlocking the Potential of the Anti-EGFR Antibody ... Cetuximab has an established role in the treatment of patients with recurrent/metastatic colorectal cancer and head and neck squamous cell cancer (HNSCC).

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33751752/

Safety and Efficacy of Cetuximab-Based Salvage ... Cetuximab-based salvage chemotherapy after PD(L)1 inhibitors associated with high response rates and deep tumor reductions with a manageable safety profile.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa0802656

Platinum-Based Chemotherapy plus Cetuximab in Head ... Cetuximab is effective in recurrent or metastatic squamous-cell carcinoma of the head and neck that progresses despite platinum-containing therapy.

8. news.bms.com news.bms.com/news/details/2008/ERBITUXR-Five-Year-Data-Show-Significant-Improvement-in-Overall-Survival-for-Patients-with-Locally-or-Regionally-Advanced-Head-and-Neck-Cancer/default.aspx

ERBITUX(R) Five-Year Data Show Significant ... These five-year data demonstrate that the addition of ERBITUX to radiation therapy resulted in a significant increase in median overall survival for patients ...

9. ascopubs.org ascopubs.org/doi/10.1200/GO.24.00059

Efficacy and Safety of Biosimilar Cetuximab Versus ... This trial compared the efficacy and safety of biosimilar cetuximab versus innovator cetuximab (IC) in combination with platinum-based chemotherapy in patients ...

10. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-022-10440-7

Treatment outcomes of cetuximab-containing regimen in ... Recurrent/ metastatic squamous cell carcinoma of head and neck (R/M SCCNH) is still a difficult-to-treat disease with poor clinical outcomes ...