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

20 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination of CD40 Agonist and PD-1 Inhibitor for head and neck cancer?

Nivolumab, a PD-1 inhibitor, has shown better survival rates than standard chemotherapy for certain head and neck cancers, according to the CheckMate-141 trial. ^{1 2 3 4 5}

What is known about the safety of PD-1 inhibitors like Nivolumab for head and neck cancer?

PD-1 inhibitors, such as Nivolumab, are generally safe but can cause side effects like diarrhea, skin rash, and thyroid issues. Rarely, they may lead to serious lung inflammation or other immune-related problems. ^{3 4 6 7 8}

What makes the CD40 Agonist + PD-1 Inhibitor drug unique for head and neck cancer?

This drug combines a CD40 agonist, which helps activate the immune system, with a PD-1 inhibitor like nivolumab, which prevents cancer cells from hiding from the immune system, offering a novel approach by potentially enhancing the immune response against head and neck cancer. ^{1 3 4 5 9}

What is the purpose of this trial?

Prospective, open-label, phase 1 study of CD40 agonist (LVGN7409) and PD-1 inhibition (LVGN3616) in patients with resectable Human Papillomavirus (HPV)-negative mucosal head/neck squamous cell carcinoma (HNSCC). This protocol proposes to study the safety and immunological effects of LVGN7409, a CD40 agonistic antibody, when administered in combination with PD-1 inhibition prior to surgical resection.

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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 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 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 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]

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]

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]

References

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

The genetic landscape of programmed death ligand-1 (PD-L1) alterations in head and neck cancer. [2021]

2. England 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. [2021]

3. England 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial. [2022]

5. England 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. [2021]

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

Nivolumab-related tracheobronchial chondritis: Extremely rare manifestation of an immune-related adverse effect. [2021]

7. Switzerland 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. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of pembrolizumab for treating recurrent head and neck squamous cell carcinoma. [2022]

9. England 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. [2020]