Immunotherapy + Radiation + Surgery for Head and Neck Cancer

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Ohio State University Comprehensive Cancer Center

Must not be taking: Immunosuppressants, Immune checkpoint blockers

Disqualifiers: HIV, Hepatitis B, C, Autoimmune, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 110

45 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to treat head and neck squamous cell cancer that persists or returns after previous treatments. Researchers examine how pembrolizumab (an immunotherapy that aids the immune system in fighting cancer) and radiation therapy perform when used before and during surgery. The study involves different groups, each receiving a combination of these treatments in various ways, to determine which is most effective and safe. Suitable participants have head and neck cancer that remains operable and have previously undergone treatments like surgery or chemotherapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this innovative approach.

Do I need to stop my current medications to join the trial?

The trial requires a 2-week washout period (time without taking certain medications) from prior therapy, so you may need to stop some medications before starting the trial. However, the protocol does not specify all medications that need to be stopped, so it's best to discuss your current medications with the trial team.

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

Research shows that pembrolizumab, a type of immunotherapy, is usually well-tolerated by patients. Studies have found that using pembrolizumab before surgery does not introduce new safety issues. It has been helpful in treating head and neck cancers, but like any medication, it may have side effects.

Intraoperative radiation therapy (IORT), used during surgery, has also proven to be safe. Research indicates it effectively controls tumors, with results similar to other types of radiation therapy.

External beam radiation therapy (EBRT) is another treatment option. It is known to improve outcomes for many cancer patients. Its safety is well-documented, and it can effectively manage cancer.

These treatments have been tested in various studies and have a good safety record, but risks can always exist. Considering joining a trial? Discussing it with a healthcare provider can offer more personalized information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for head and neck cancer because they combine immunotherapy with surgery and innovative radiation techniques. Pembrolizumab is an immunotherapy drug that helps the immune system recognize and attack cancer cells more effectively, offering a different mechanism compared to traditional chemotherapy and radiation. Additionally, the use of intraoperative radiation therapy (IORT) delivers a high dose of radiation directly to the tumor site during surgery, which may enhance effectiveness while minimizing damage to surrounding healthy tissue. Some arms of the study also explore the timing and dosage of external beam radiation therapy (EBRT), potentially providing more personalized and less toxic treatment options. This combination approach could lead to more effective treatments with fewer side effects, making it a promising area of research.

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

Research shows that pembrolizumab, a treatment in this trial, effectively treats recurring and spreading head and neck cancer. Studies have found that it can help patients live longer compared to other treatments. In this trial, some participants will receive pembrolizumab with intraoperative radiation therapy (IORT), which can accurately target difficult tumor areas and potentially help control the cancer. Other participants will receive external beam radiation therapy (EBRT) in addition to pembrolizumab and IORT. EBRT has improved outcomes for many patients by effectively controlling tumors. Together, these treatments offer a strong possibility of better results for people with head and neck cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Dukagjin M. Blakaj

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with certain types of head and neck cancers that are treatable by surgery but have persisted or returned after treatment. Participants must be in good health with proper organ function, not pregnant, and willing to use contraception. They should not have other recent cancers, HIV, hepatitis B or C, severe autoimmune diseases, untreated brain metastases, a history of severe immunotherapy side effects, or be on current immunosuppressive drugs.

Inclusion Criteria

Total Bilirubin =< 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (obtained within 14 days of randomization)

My kidney function, measured by creatinine levels or clearance, is within the required range.

I have had chemotherapy before.

Exclusion Criteria

Poorly controlled or serious medical or psychiatric illness likely to interfere with participation and/or compliance in this clinical trial

I haven't taken immunosuppressive drugs in the last 14 days.

I had a severe reaction to previous immunotherapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment

Patients receive pembrolizumab intravenously and undergo radiation therapy before surgery

4 weeks

1 visit (in-person) for pembrolizumab, 2 visits (in-person) for radiation

Surgery

Patients undergo salvage surgery

1 week

1 visit (in-person)

Post-surgery Treatment

Patients receive pembrolizumab every 3 weeks and undergo intraoperative radiation therapy

Up to 54 weeks

18 visits (in-person) for pembrolizumab, 1 visit (in-person) for IORT

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Follow-up visits at 90 and 180 days, then every 90 weeks for 24 months, and then every 6 months up to year 5

What Are the Treatments Tested in This Trial?

Interventions

• External Beam Radiation Therapy
• Intraoperative Radiation Therapy
• Pembrolizumab
• Salvage Surgery

Trial Overview

The study tests the effectiveness of pembrolizumab (an immune system-boosting drug) combined with radiation therapy before and during cancer surgery. The goal is to see if this combination helps reduce tumor size more effectively than previous treatments for persistent or recurrent head and neck squamous cell carcinoma.

How Is the Trial Designed?

Group I: Arm C (pembrolizumab, EBRT, salvage surgery, IORT) Experimental Treatment 5 Interventions

Patients receive pembrolizumab IV on day 1 of week 1, and undergo high dose EBRT for 2 fractions on 2 consecutive days during week 4. Patients also undergo salvage surgery during week 8. Beginning week 11, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 11. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

Group II: Arm B (pembrolizumab, EBRT, salvage surgery, IORT) Experimental Treatment 5 Interventions

Patients receive pembrolizumab IV on day 1 of week 1, and undergo low dose EBRT for 2 fractions on 2 consecutive days during week 4. Patients also undergo salvage surgery during week 8. Beginning week 11, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 11. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

Group III: Arm A (pembrolizumab, salvage surgery, IORT) Experimental Treatment 4 Interventions

Patients receive pembrolizumab IV on day 1 of week 1, and undergo salvage surgery during week 4. Beginning week 8, patients receive pembrolizumab IV every 3 weeks for up to 18 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo IORT for 1 fraction during week 9. Treatment with pembrolizumab may continue beyond initial progression per investigator-assessed clinical benefit and if the patient is tolerating pembrolizumab.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

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]

In a study with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., et al.[2023]

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

In a study of 167 patients with recurrent/metastatic squamous cell carcinoma of the head and neck treated with pembrolizumab, the median overall survival was 22.7 months and progression-free survival was 5.1 months for those receiving pembrolizumab alone, indicating significant efficacy.

The presence of immune-related adverse events (irAEs) was associated with better progression-free survival, suggesting that these side effects may serve as important prognostic factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study. Okada, T., Fushimi, C., Matsuki, T., et al.[2023]

The study investigates the combination of the immune checkpoint inhibitor pembrolizumab with a hypofractionated palliative radiotherapy regimen called quad-shot in 15 patients with advanced/recurrent head and neck squamous-cell carcinoma, aiming to enhance treatment efficacy and provide symptomatic relief.

Outcomes will assess disease response, survival, and treatment toxicity, while also exploring molecular biomarkers through multiomics analysis to understand the immune response to the combined treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer. Hughes, RT., Gebeyehu, RR., Kalada, JM., et al.[2023]

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

In a phase 1b trial involving 60 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, pembrolizumab was found to be well tolerated, with only 17% experiencing severe drug-related adverse events and no drug-related deaths.

The treatment showed clinically meaningful antitumor activity, with an overall response rate of 18%, and particularly higher in HPV-positive patients at 25%, indicating its potential as a viable therapy for advanced head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Seiwert, TY., Burtness, B., Mehra, R., et al.[2022]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

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]

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