Immunoradiotherapy for Head and Neck Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Providence Health & Services

Must not be taking: Oral steroids

Disqualifiers: Active infection, Autoimmune diseases, others

Stay on Your Current Meds You can continue your current medications while participating

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treat head and neck squamous cell carcinoma (HNSCC) by combining immunotherapy and radiation before surgery. The goal is to determine if this method can safely reduce tumor size, enhancing surgical effectiveness. Participants may receive different combinations of the drug nivolumab (Opdivo) and radiation therapy. This trial suits individuals with squamous cell carcinoma in the head or neck area who are preparing for surgery and can safely undergo these treatments. Participants are particularly needed if their cancer is associated with HPV, a virus linked to some types of cancer. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on chronic oral steroids at a dose of 20mg or more of prednisone daily, you may not be eligible to participate.

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

Research shows that nivolumab, a medicine used in these trials, has been tested in other studies with people who have head and neck cancer. The CheckMate-141 study indicated that nivolumab is generally safe, and most patients can handle the side effects.

For the radiation part of the treatment, shorter schedules, like the three-day and five-day plans in these trials, have been studied before. Research suggests they are safe for some patients with advanced head and neck cancer and are often well-tolerated, especially by older adults.

In summary, both nivolumab and the radiation therapies being tested have demonstrated safety in earlier studies, with side effects that can usually be managed. This suggests a promising safety profile for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine nivolumab, an immune checkpoint inhibitor, with radiation therapy in new ways to potentially enhance cancer treatment. Unlike traditional treatments that often rely solely on surgery, chemotherapy, or radiation, this approach uses nivolumab to stimulate the immune system to recognize and attack cancer cells more effectively. The combination of nivolumab with radiation before and after surgery might improve outcomes by reducing tumor size and preventing recurrence, offering a promising new strategy for tackling 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 type of immunotherapy, may effectively treat head and neck cancer. One study found that patients lived longer with nivolumab compared to standard treatments and experienced fewer severe side effects. Another study found that combining nivolumab with chemotherapy increased the chances of being cancer-free after treatment. In this trial, participants in different treatment cohorts will receive varying combinations of nivolumab and radiation therapy. Radiation therapy, used alongside nivolumab, improves outcomes and reduces symptoms in about 75% of head and neck cancer patients. Shorter radiation schedules, like the 3-day or 5-day plans in this trial, have effectively managed the disease and are generally easy for patients to handle. These findings suggest that using nivolumab with radiation might help shrink tumors before surgery. ^{3 6 7 8 9}

Who Is on the Research Team?

Rom Leidner, MD

Principal Investigator

Providence Health and Services

Are You a Good Fit for This Trial?

Adults with head and neck squamous cell carcinoma scheduled for surgery can join. They must have certain blood counts, be HPV status known, able to consent, and have an acceptable performance status. Pregnant women or those not using contraception are excluded, as well as individuals on high-dose steroids or with active autoimmune diseases.

Inclusion Criteria

Patients with history of psychiatric illness judged by the investigator as able to understand the investigational nature and risks associated with the therapy

Laboratory values within specified ranges

My cancer's HPV status has been checked.

Exclusion Criteria

History of or current active autoimmune disease posing an active and significant morbidity risk

I take 20mg or more of prednisone or its equivalent daily.

Clinical factors such as bleeding, active infection, or psychiatric factors that would preclude safe participation and compliance with study procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Immunoradiotherapy

Participants receive nivolumab and radiation therapy prior to surgical resection to assess safety and feasibility

6 weeks

Multiple visits for treatment administration

Surgical Resection

Participants undergo surgical resection of tumors following neoadjuvant therapy

1 week

1 visit (in-person)

Adjuvant Therapy

Participants receive additional nivolumab doses and risk-adapted adjuvant therapy as per standard of care

12 weeks

6 visits (in-person, every 4 weeks)

Follow-up

Participants are monitored for disease-free and overall survival

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab
• Radiation (3 days)
• Radiation (5 days)
• Surgical Resection

Trial Overview The trial is testing if giving Nivolumab (an immunotherapy drug) combined with a short course of radiation before surgery can safely shrink tumors in patients with head and neck cancer. The study will separate participants into groups based on their HPV status.

How Is the Trial Designed?

Group I: Treatment Cohort 4 Experimental Treatment 3 Interventions

Nivolumab administration (3 doses) and radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).

Group II: Treatment Cohort 3 Experimental Treatment 3 Interventions

Radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).

Group III: Treatment Cohort 2 Experimental Treatment 3 Interventions

Nivolumab administration (3 doses) and radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).

Group IV: Treatment Cohort 1 Experimental Treatment 3 Interventions

Nivolumab administration (3 doses) and radiation (5 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).

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

Approved in United States as Keytruda for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Endometrial carcinoma
• Esophageal carcinoma
• Gastric cancer

Approved in European Union as Keytruda for:

• Melanoma
• Non-small cell lung cancer
• Urothelial carcinoma
• Head and neck squamous cell carcinoma
• Renal cell carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Endometrial carcinoma
• Esophageal carcinoma
• Gastric cancer

Who Is Running the Clinical Trial?

Providence Health & Services

Lead Sponsor

Trials

131

Recruited

827,000+

Providence Cancer Center, Earle A. Chiles Research Institute

Collaborator

Trials

21

Recruited

500+

Published Research Related to This Trial

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]

The combination of stereotactic body radiation therapy (SBRT) with the anti-PD-1 drug nivolumab was found to be safe and did not delay surgery in 21 patients with advanced head and neck cancer, meeting the primary safety endpoint of the study.

This treatment approach resulted in a high major pathological response (mPR) rate of 86% and a pathological complete response (pCR) rate of 67%, indicating that adding SBRT may enhance the effectiveness of immunotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. Leidner, R., Crittenden, M., Young, K., et al.[2022]

Immunotherapy, specifically pembrolizumab and nivolumab, has been FDA approved since 2016 for treating recurrent/metastatic head and neck squamous cell carcinoma, showing significant effectiveness in patients who have not responded to platinum-based treatments.

Advanced practice providers play a crucial role in managing immune-related adverse events (irAEs) associated with these immunotherapies, and the Care Step Pathways (CSPs) developed for this purpose help in diagnosing and managing conditions like thyroiditis and skin toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibitor Immunotherapy for Head and Neck Cancer: Incorporating Care Step Pathways for Effective Side-Effect Management. Fazer, C.[2020]

In a study of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with nivolumab, the median overall survival was 9.6 months, with a two-year survival rate of 25%, indicating long-term efficacy in a real-world setting.

The study found that better overall response rates (18% overall response, 48% disease control) and the occurrence of immune-related adverse events (irAEs) were associated with improved survival outcomes, suggesting these factors could serve as important markers for patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World, Long-Term Outcomes of Nivolumab Therapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck and Impact of the Magnitude of Best Overall Response: A Retrospective Multicenter Study of 88 Patients. Matsuki, T., Okamoto, I., Fushimi, C., et al.[2020]

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]

Neoadjuvant immunotherapy targeting the PD-1/PD-L1 axis in head and neck cancer has shown a favorable overall objective response rate of 45.9% across eight clinical trials involving 260 patients.

Importantly, there were no deaths reported due to immune-related toxicities, indicating that this treatment approach is not only effective but also safe in the neoadjuvant setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant immunotherapy prior to surgery for mucosal head and neck squamous cell carcinoma: Systematic review. Amin, N., Maroun, CA., El Asmar, M., et al.[2022]

In a study of platinum-sensitive recurrent or metastatic head and neck squamous cell carcinomas involving 36 patients, both nivolumab and pembrolizumab showed effectiveness, with median overall survival of 16.9 months for nivolumab and 19.2 months for pembrolizumab, indicating similar efficacy between the two treatments.

The median progression-free survival was 4.8 months for nivolumab and 9.3 months for pembrolizumab, with objective response rates of 38% and 47%, respectively, suggesting that both drugs are viable options for treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Nivolumab and Pembrolizumab in Platinum-sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Yamashita, G., Okamoto, I., Ito, T., et al.[2023]

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]

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]

Citations

1. 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 ...

2. 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).

3. asco.org asco.org/about-asco/press-center/news-releases/adding-nivolumab-chemoradiotherapy-after-surgery-can-decrease-chance-recurrence

Adding Nivolumab to Chemoradiotherapy After Surgery ... “The outcome for patients with locoregionally advanced head and neck cancers remains generally poor, with only 50% to 55% of patients free ...

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

Real-World, Long-Term Outcomes of Nivolumab Therapy ... No real-world, long-term outcomes of immunotherapy with nivolumab for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have ...

5. 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/ ...

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

Safety and Treatment Outcomes of Nivolumab for the ... This study demonstrates similar progression free survival and overall survival as that seen in the CHECKMATE-141 study.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA2

NIVOPOSTOP (GORTEC 2018-01): A phase III randomized ... Safety analysis up to 9 months after CRT was based on patients who received at least one administration of treatment. Patients experiencing ...

8. news.bms.com news.bms.com/news/details/2016/First-Presentation-of-Overall-Survival-Data-for-Opdivo-nivolumab-Shows-Significant-Survival-Benefit-at-One-Year-Versus-Investigators-Choice-in-Recurrent-or-Metastatic-Squamous-Cell-Carcinoma-of-the-Head-and-Neck/default.aspx

First Presentation of Overall Survival Data for Opdivo® ... The one-year survival rate for Opdivo was 36% compared to 16.6% for investigator's choice. The safety profile of Opdivo in CheckMate -141 was ...

9. firstwordpharma.com firstwordpharma.com/story/5967773

ASCO25: Opdivo cuts cancer return risk by 24% in HNSCC ... Among patients who received the Opdivo combination, 63.1% had no signs of cancer recurrence three years post-treatment, compared with 52.5% for ...