Neoadjuvant Immunoradiotherapy for Head and Neck Cancer

Not currently recruiting at 2 trial locations

Overseen By George Morris, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Providence Health & Services

Must not be taking: Anti-PD-1, Anti-PD-L1

Disqualifiers: Pregnancy, Immunodeficiency, Active infection, 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)

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

Compensation: Varies

Number of Visits: 18

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments to determine if they are more effective than surgery alone for certain types of head and neck cancer. The focus is on using immunotherapy and radiation before surgery to treat stage III and IVA HPV-negative head and neck squamous cell carcinoma (HNSCC). Participants will receive pembrolizumab (an immunotherapy) alongside targeted radiation therapy, known as Stereotactic Body Radiation Therapy (SBRT), before undergoing surgery. This trial may suit those diagnosed with this specific type of head and neck cancer who plan to have surgery. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on chronic systemic steroid therapy exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study drug. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or any form of immunosuppressive therapy, you may need to stop these at least 7 days before starting the study treatment.

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

Research has shown that combining pembrolizumab, a type of immunotherapy, with stereotactic body radiation therapy (SBRT) is generally well-tolerated. Studies have found that these treatments together can shrink tumors and increase survival rates. Importantly, they tend to cause fewer side effects than traditional chemotherapy.

Other studies indicate that pembrolizumab and SBRT can be administered safely, with a focus on protecting healthy tissues. While powerful, these treatments are carefully managed to avoid harming healthy parts of the body. Overall, evidence supports that these treatments are safe for most people, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it combines pembrolizumab, an immunotherapy drug, with stereotactic body radiation therapy (SBRT) and surgery to tackle head and neck cancer more aggressively. Pembrolizumab works by boosting the body's immune system to recognize and attack cancer cells, which is different from traditional chemotherapy that directly kills cancer cells but can also harm healthy ones. The precise targeting of SBRT allows for higher doses of radiation to be delivered to the tumor with minimal damage to surrounding tissues. This combination aims to enhance the effectiveness of treatment, potentially leading to better outcomes and fewer side effects than standard treatments alone.

What evidence suggests that neoadjuvant immunoradiotherapy might be an effective treatment for head and neck cancer?

This trial will evaluate the combination of pembrolizumab, stereotactic body radiation therapy (SBRT), and surgery for treating head and neck cancer. Research has shown that using pembrolizumab with SBRT and surgery might enhance treatment effectiveness. One study found that this combination can activate the body's immune system to fight tumors, even in cancers typically resistant to immune system treatment alone. Another study found that adding pembrolizumab to radiation therapy and surgery helped patients live longer without disease recurrence. Although no evidence proves this combination works better throughout the body than pembrolizumab alone, it appears to control cancer effectively in the treated area. Overall, research suggests this method could be a promising way to treat head and neck cancer. ^{1 3 6 7 8}

Who Is on the Research Team?

R. Bryan Bell, MD, DDS, FACS

Principal Investigator

Providence Health & Services

Are You a Good Fit for This Trial?

Adults with stage III-IVA HPV-negative head and neck squamous cell carcinoma (HNSCC) who are candidates for surgery. They must have proper organ function, not be pregnant or breastfeeding, agree to use contraception, and have an ECOG performance status of 0 to 1. Excluded are those with prior head & neck radiotherapy, recent live vaccines, active autoimmune diseases requiring treatment in the past 2 years, active infections needing systemic therapy, certain psychiatric/substance abuse disorders.

Inclusion Criteria

My cancer is stage III-IVA, HPV-negative, and I'm set for surgery with pre-surgery anti-PD-1 and radiation.

I am fully active or can carry out light work.

I agree to use birth control during and for 75 days after my treatment.

Exclusion Criteria

I have active brain metastases or carcinomatous meningitis.

Patients with prior history of solid organ and/or allo-transplantation

I have an immune system disorder or I'm on long-term steroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Immunoradiotherapy

Participants receive pembrolizumab and stereotactic body radiation therapy (SBRT) prior to surgical resection

7 weeks

3 visits (in-person) for pembrolizumab administration

Surgery

Definitive surgical resection of tumors

1 week

1 visit (in-person) for surgery

Adjuvant Therapy

Risk-adapted adjuvant therapy including pembrolizumab every 3 weeks for 14 additional doses

42 weeks

14 visits (in-person) for pembrolizumab administration

Follow-up

Participants are monitored for disease-free and overall survival

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Stereotactic Body Radiation Therapy
• Surgical Resection

Trial Overview The trial is testing neoadjuvant immunoradiotherapy (NIRT) using Pembrolizumab combined with Stereotactic Body Radiation Therapy over five days before surgical resection in patients with HNSCC. The goal is to assess how effective this pre-surgery treatment is at treating cancer.

How Is the Trial Designed?

Group I: Pembrolizumab + SBRT + Surgery Experimental Treatment 3 Interventions

Pembrolizumab administration (3 dose) every 3 weeks and 1 dose before radiation (5 days) therapy followed by an additional administration of Pembrolizumab (2 doses) prior to restaging and surgical resection followed by risk-adapted adjuvant therapy, per standard of care. Patient will then be treated with adjuvant pembrolizumab every 3 weeks for 14 additional doses (17 doses total)

Stereotactic Body Radiation Therapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Stereotactic Body Radiation Therapy for:

• Non-small cell lung cancer (NSCLC)
• Melanoma
• Renal cell carcinoma (RCC)
• Prostate cancer
• Oligoprogressive cancers

Approved in European Union as Stereotactic Body Radiation Therapy for:

• Non-small cell lung cancer (NSCLC)
• Melanoma
• Renal cell carcinoma (RCC)
• Prostate cancer
• Oligoprogressive cancers

Approved in Canada as Stereotactic Body Radiation Therapy for:

• Non-small cell lung cancer (NSCLC)
• Melanoma
• Renal cell carcinoma (RCC)
• Prostate cancer
• Oligoprogressive cancers

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

CyberKnife stereotactic ablative radiotherapy (SABR) for treating intermediate- to very-high-risk prostate cancer showed a high 3-year biochemical relapse-free survival rate of 90.2%, indicating its efficacy in managing this condition.

The treatment was well-tolerated, with no patients experiencing severe toxicity (≥ grade 3), and only mild genitourinary and gastrointestinal side effects were reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy with CyberKnife in the treatment of locally advanced prostate cancer: preliminary results. Fan, CY., Chao, HL., Huang, WY., et al.[2017]

Stereotactic ablative brachytherapy (SABT) demonstrated good local control rates for unresectable or inoperable head and neck cancers, with local control rates of 89.2% at 6 months and 69.4% at 24 months, based on a study of 37 patients over a median follow-up of 34 months.

The treatment was found to be safe, with only mild adverse reactions reported in 29.7% of patients, and no severe complications (grade 3 or higher), indicating that SABT is a minimally invasive option with fewer side effects compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study on unresectable or inoperable head and neck cancers treated with stereotactic ablative brachytherapy. Zhao, G., Wang, Z., Li, C., et al.[2023]

In a study involving 50 patients with unresectable locally recurrent squamous cell carcinoma of the head and neck, the combination of stereotactic body radiation therapy (SBRT) and cetuximab resulted in a 1-year locoregional progression-free survival rate of 60%, indicating promising efficacy for this treatment approach.

The treatment was found to be relatively safe, with only 6% of patients experiencing acute or late grade 3 toxicities, suggesting that SBRT combined with cetuximab could be a viable option for patients who have limited salvage treatments available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. Vargo, JA., Ferris, RL., Ohr, J., et al.[2022]

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]

Stereotactic ablative radiotherapy (SABR) for recurrent head and neck cancer in previously irradiated areas showed a 1-year local control rate of 64.2% and an overall survival rate of 67.5% over a median follow-up of 12 months, indicating its efficacy in this challenging patient population.

SABR was well tolerated, with only 31.3% of patients experiencing acute Grade 2 skin toxicity and 28% experiencing Grade 3 mucosal toxicity, which is significantly lower than the 50-70% toxicity rates associated with other salvage treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy (SABR) for recurrent and previously irradiated head and neck cancers. Anand, AK., Dua, B., Bansal, AK., et al.[2022]

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]

The JAVELIN Head and Neck 100 study is a Phase III clinical trial investigating the effectiveness of avelumab, a PD-L1 inhibitor, combined with standard chemoradiotherapy (CRT) for high-risk, locoregionally advanced squamous cell carcinomas of the head and neck.

This study addresses a critical gap in research, as there are currently no prospective studies evaluating immune checkpoint inhibitors in the definitive treatment of nonmetastatic HNSCC, which is important for improving outcomes in patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. Yu, Y., Lee, NY.[2020]

Stereotactic ablative radiotherapy (SABR) for primary renal cell carcinoma (RCC) demonstrated a high local control rate of 97.2% across 26 studies involving 372 patients, indicating its effectiveness even in larger, inoperable tumors.

The treatment was associated with low toxicity, with only 1.5% of patients experiencing grade 3-4 adverse effects, and a minimal change in renal function, suggesting that SABR is a safe option for managing primary RCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Emerging Role of Stereotactic Ablative Radiotherapy for Primary Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. Correa, RJM., Louie, AV., Zaorsky, NG., et al.[2022]

Stereotactic ablative body radiotherapy (SABR) has shown a local control rate of over 90% in treating primary renal cell carcinoma (RCC) across 589 cases, with low rates of severe toxicity (grade 3-4) ranging from 0-9%.

In patients with oligometastatic RCC, SABR can delay the need for systemic therapy for at least one year in 70-90% of cases, indicating its effectiveness as a treatment option and its compatibility with systemic therapies like targeted therapy or immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell Carcinoma. Ali, M., Mooi, J., Lawrentschuk, N., et al.[2022]

Stereotactic ablative radiotherapy (SABR) using Cyberknife demonstrated high effectiveness in treating stage I non-small-cell lung cancer, with 2-year local control, progression-free, and overall survival rates of 91.9%, 61.7%, and 84.8%, respectively, based on a study of 153 patients.

The treatment was generally safe, with only 8.1% of patients experiencing severe toxicities, including one case of grade 5 radiation pneumonitis, indicating that while SABR is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Ablative Radiotherapy Using CyberKnife for Stage I Non-small-cell Lung Cancer: A Retrospective Analysis. Hayashi, K., Suzuki, O., Shiomi, H., et al.[2022]

In a study of 100 patients with early-stage non-small cell lung cancer (NSCLC) treated with stereotactic ablative body radiotherapy (SABR), the 1-, 2-, and 3-year local control rates were 100%, 93.55%, and 84.33%, respectively, indicating high efficacy in tumor control.

The treatment was associated with low toxicity, with only 2% of patients experiencing Grade-3 side effects, suggesting that SABR is a safe option for patients who are inoperable or refuse surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definitive Treatment of Early-Stage Non-Small Cell Lung Cancer with Stereotactic Ablative Body Radiotherapy in a Community Cancer Center Setting. Heal, C., Ding, W., Lamond, J., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10919132/

A Pilot Study of Pembrolizumab Combined With Stereotactic ... In the SARC028 study of pembrolizumab, there was an 18% response rate and median PFS of 18 weeks for the 40 patients with soft tissue sarcoma.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03546582

NCT03546582 | SBRT +/- Pembrolizumab in Patients With ... This phase II trial with a safety run-in component will evaluate whether the addition of pembrolizumab to Stereotactic Body Radiation Therapy (SBRT) ...

3. nature.com nature.com/articles/s43018-025-01018-w

Combination of pembrolizumab and radiotherapy induces ... Combination of pembrolizumab and radiotherapy induces systemic antitumor immune responses in immunologically cold non-small cell lung cancer.

4. sciencedirect.com sciencedirect.com/science/article/pii/S294981982400030X

Feasibility of stereotactic radiotherapy with pembrolizumab ... Our findings convey no signal of enhanced systemic efficacy compared with historical data on pembrolizumab alone even if the local control rate is high.

5. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(24)01812-9/abstract

Safety and efficacy of pembrolizumab, radiation therapy ... Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10452591/

Combining Radiotherapy and Immunotherapy in Head ... Combining RT and immunotherapy has been shown to improve tumor response rates, increase survival, and reduce toxicity compared to traditional chemotherapy and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06211335

Study Details | NCT06211335 | Losartan, Pembrolizumab ... This phase Ib trial tests the safety, side effects and how well losartan, pembrolizumab and stereotactic body radiation therapy (SBRT) for the treatment of ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0959804924009201

Safety of combined ablative radiotherapy and immune ... We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.