CD40 Agonist + PD-1 Inhibitor for Head and Neck Cancer

Overseen By Andrew Carter, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Immunosuppressants

Disqualifiers: Hepatitis B/C, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 5

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for a specific type of head and neck cancer not linked to HPV. Researchers are exploring the safety and immune effects of using a CD40 agonist (LVGN7409) and a PD-1 inhibitor (Nivolumab, also known as Opdivo) together before surgery. Participants include those with HPV-negative head and neck cancer who have surgery planned. This study is for individuals who have not previously received surgery or radiation for this type of cancer and are willing to follow the study procedures. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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 use immunosuppressive medications within 14 days before starting the study treatment, except for certain low-dose steroids and local steroid treatments.

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

Research shows that the PD-1 inhibitor LVGN3616 is usually well-tolerated. Studies with similar drugs have found that side effects are often manageable for patients with head and neck cancer, though some patients might experience immune-related side effects.

The safety of combining this drug with the CD40 agonist LVGN7409 remains under investigation. As a phase 1 trial, researchers primarily focus on assessing the safety and tolerability of this combination. Previous research on similar treatments suggests that most side effects are mild to moderate, though more serious reactions can occur.

Overall, early findings suggest the treatment could be manageable, but participants should be aware of potential side effects. Discussing any concerns with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a novel approach to tackling head and neck cancer. Unlike traditional treatments that often focus solely on inhibiting PD-1, LVGN3616 and LVGN7409 introduce a dual mechanism. LVGN3616 works as a PD-1 inhibitor, while LVGN7409 acts as a CD40 agonist, potentially enhancing the immune system's response against cancer cells. This combination could lead to a more robust and effective treatment by engaging the immune system in multiple ways. By targeting these distinct pathways, these treatments may offer new hope for patients with head and neck cancer.

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

Research has shown that nivolumab, a drug similar to LVGN3616, effectively treats head and neck cancer. It improves survival rates and causes fewer severe side effects compared to standard treatments. One study found that patients lived longer with nivolumab. In this trial, participants in Arm A will receive LVGN3616 alone.

Participants in Arm B will receive a combination of LVGN3616 and LVGN7409, a drug that helps activate the immune system. Early results suggest this combination could enhance the body's ability to fight cancer cells. This approach aims to strengthen the body's natural defenses to attack the tumor more effectively. While more research is needed, these treatments together show promise for treating HPV-negative head and neck cancer. ^{1 4 5 6 7}

Are You a Good Fit for This Trial?

Adults over 18 with HPV-negative squamous cell carcinoma in the head and neck area, who are not pregnant, can join this trial. They must weigh more than 30kg, have a life expectancy of at least 12 weeks, and agree to use effective contraception. Their cancer should be resectable (can be removed by surgery), they need to have a sample of their tumor available for study, and their major organs must function well.

Inclusion Criteria

My body weight is more than 30kg.

You are expected to live for at least 12 weeks.

You have signed a document that explains the study and have permission from a special group that makes sure the study is safe and fair.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Surgery Treatment

Participants receive a single administration of LVGN3616 or LVGN3616 and LVGN7409, followed by surgical resection

2 weeks

4 visits (in-person)

Post-Surgery Follow-up

Participants undergo guideline-based standard of care post-surgical adjuvant therapies and are monitored for safety and effectiveness

12 months

Quarterly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• LVGN3616
• LVGN7409

Trial Overview The trial is testing LVGN7409 (a CD40 agonist) combined with LVGN3616 (a PD-1 inhibitor) on patients before they undergo surgical removal of their cancer. It's an early-phase study looking at how safe these drugs are together and what effects they have on the immune system.

How Is the Trial Designed?

Group I: Arm A: PD1 Active Control 1 Intervention

Subjects in this arm will receive one dose of LVGN3616 (300mg).

Group II: Arm B: PD1 + CD40 Active Control 2 Interventions

Subjects in this arm will receive one dose of LVGN3616 (300mg) followed by one dose of CD40 LVGN7409 (1mg/kg).

LVGN3616 is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in United States as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in Japan as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

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 the phase II HAWK study involving 112 patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) who had high PD-L1 expression, durvalumab showed an objective response rate of 16.2%, with a notably higher rate of 29.4% in HPV-positive patients.

Durvalumab was found to have an acceptable safety profile, with 57.1% of patients experiencing treatment-related adverse events, but none were fatal, indicating it could be a viable treatment option for this difficult-to-treat patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy. Zandberg, DP., Algazi, AP., Jimeno, A., et al.[2020]

In a study of 34 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with PD-1 inhibitors, 29% experienced hyperprogression, where tumor growth accelerated during treatment.

Hyperprogression was significantly associated with regional recurrence, leading to shorter progression-free survival, but did not affect overall survival, highlighting the need for further research into the mechanisms behind this phenomenon.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Saâda-Bouzid, E., Defaucheux, C., Karabajakian, A., et al.[2022]

In a study of 185 patients with recurrent and/or metastatic head and neck squamous cell carcinoma, those who received nivolumab before taxane treatment showed a significantly higher objective response rate (39.4%) compared to those who did not receive nivolumab (26.3%).

The disease control rate was also better in the post-nivolumab group (69% vs. 50%), suggesting that taxane monotherapy may be an effective third-line treatment option after nivolumab, especially for patients who cannot benefit from first-line pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of previous nivolumab treatment on the response to taxanes in patients with recurrent/metastatic head and neck squamous cell carcinoma. Guiard, E., Clatot, F., Even, C., et al.[2021]

In a study of 22 patients with resectable locally advanced head and neck squamous cell carcinomas, the combination of pembrolizumab and chemotherapy resulted in a postoperative pathological complete response (pCR) rate of 36.4%, indicating significant efficacy as a neoadjuvant treatment.

The treatment did not adversely affect surgical safety, with a high rate of laryngeal function preservation at 90.9%, and no delays to surgery due to adverse drug reactions, although delayed wound healing was noted in 22.7% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of pembrolizumab with preoperative neoadjuvant chemotherapy in patients with resectable locally advanced head and neck squamous cell carcinomas. Wang, K., Gui, L., Lu, H., et al.[2023]

Pembrolizumab, a PD-1 inhibitor, has shown significant overall response rates and survival benefits in patients with recurrent or metastatic head and neck squamous cell carcinoma compared to chemotherapy alone, particularly in populations with high PD-L1 expression (CPS ≥ 20 and CPS ≥ 1).

The safety profile of pembrolizumab is comparable to other PD-1/PD-L1 inhibitors, with common side effects including diarrhea and hypothyroidism, but it has a favorable toxicity profile compared to the EXTREME chemotherapy regimen, highlighting the importance of PD-L1 scoring for patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of pembrolizumab for treating recurrent head and neck squamous cell carcinoma. Desilets, A., Soulières, D.[2022]

Nivolumab has been shown to significantly improve survival rates in patients with recurrent or metastatic platinum-resistant head and neck squamous cell carcinoma (HNSCC) compared to standard chemotherapy, highlighting its efficacy as an immunotherapy targeting the PD-1 receptor.

HNSCC tumors exhibit the highest levels of PD-L1 expression among various tumor types, with 6.2% showing genetic alterations in PD-L1, suggesting that these tumors may be particularly responsive to PD-1/PD-L1 targeted therapies and that further investigation into related co-targets is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The genetic landscape of programmed death ligand-1 (PD-L1) alterations in head and neck cancer. Heineman, TE., Widman, A., Kuan, EC., et al.[2021]

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]

Nivolumab, a programmed death-1 checkpoint inhibitor, can lead to rare immune-related adverse effects (irAEs) such as tracheobronchial chondritis, as demonstrated in a case study of a 72-year-old man with hypopharyngeal squamous cell carcinoma.

Despite the successful treatment of his cancer, the patient experienced significant respiratory symptoms due to tracheobronchial chondritis, which was effectively managed with steroid therapy, highlighting the need for awareness of this potential complication in patients receiving nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-related tracheobronchial chondritis: Extremely rare manifestation of an immune-related adverse effect. Kuba, K., Nakahira, M., Inoue, H., et al.[2021]

Citations

1. nature.com nature.com/articles/s41598-025-19197-y

Low-dose nivolumab plus induction chemotherapy for ... One-year progression-free survival and overall survival were 67% and 83%, respectively, with post-induction radical therapy (p < 0.001) and pCR/ ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7699139/

Real-World, Long-Term Outcomes of Nivolumab Therapy ... Nivolumab was approved for recurrent or metastatic head and neck cancer (R/M HNC) after platinum drug administration in Japan in March 2017. Further evidence of ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1602252

Nivolumab for Recurrent Squamous-Cell Carcinoma of the ... Nivolumab was associated with fewer toxic effects of grade 3 or 4 than standard therapy (13.1% vs. 35.1%) and with maintenance of quality of ...

4. opdivo.com opdivo.com/head-and-neck-cancer/clinical-trial-results

Clinical trial results for previously treated head and neck ... See how OPDIVO® (nivolumab) performed in clinical trials for certain adults with previously treated squamous cell head and neck cancer (SCCHN).

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8134300/

Effectiveness of nivolumab affected by prior cetuximab use ... The objective response rate was 23.1 vs 25.9% (p = 0.8455), median progression-free survival was 1.8 vs 3.0 months (p = 0.6650), and median overall survival was ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8003537/

Safety and Treatment Outcomes of Nivolumab for the ... Efficacy and safety of nivolumab in 100 patients with recurrent or metastatic head and neck cancer—A retrospective multicentre study. Acta ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33808781/

Safety and Treatment Outcomes of Nivolumab for the ... Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT. Keywords: head and neck ...