Pembrolizumab + Radiotherapy for Recurrent Head and Neck Cancer

(QUADSHOT Trial)

Overseen By SCC IIT Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Oklahoma

Must not be taking: Immunosuppressants, PD-1 inhibitors

Disqualifiers: Other cancers, Autoimmune disease, others

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

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

Compensation: Varies

Number of Visits: 3

30 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. However, you cannot use immunosuppressive medications within 28 days before starting the trial, except for certain low-dose corticosteroids.

What data supports the effectiveness of the treatment Pembrolizumab + Radiotherapy for Recurrent Head and Neck Cancer?

Research shows that pembrolizumab, an immune system-boosting drug, has shown antitumor activity in head and neck cancer, and when combined with a special type of radiotherapy called 'quad-shot', it may help control the disease and relieve symptoms. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and Radiotherapy safe for treating head and neck cancer?

Pembrolizumab, used alone or with radiotherapy, has been studied for head and neck cancer and other conditions. Common side effects include fatigue, cough, nausea, and rash, while serious side effects can include lung inflammation, liver inflammation, and thyroid issues. The safety profile is considered acceptable for patients with advanced cancer, but close monitoring is necessary. ^{1 2 5 6 7}

How is the treatment of Pembrolizumab + QUADSHOT Radiotherapy unique for recurrent head and neck cancer?

This treatment combines pembrolizumab, an immune therapy that helps the body's immune system attack cancer cells, with QUADSHOT radiotherapy, a special type of radiation given in short, intense bursts to relieve symptoms and enhance the immune response. This combination is unique because it aims to improve the effectiveness of immune therapy in cases where traditional treatments are not effective. ^{1 2 3 8 9}

What is the purpose of this trial?

The purpose of this study is to test the safety of palliative "QUAD SHOT" radiotherapy combined with pembrolizumab and evaluate the effects of the combination treatment patients with recurrent cancer of head and neck.

Research Team

Christina Henson, MD

Principal Investigator

University of Oklahoma

Eligibility Criteria

Adults with recurrent head and neck squamous cell carcinoma, who have evaluable lesions and whose cancer is not suitable for curative treatment. Participants must be at least six months past any prior radiation therapy, have adequate organ function, agree to use contraception if of reproductive potential, and not have used immunosuppressive medication recently.

Inclusion Criteria

Must have evaluable lesion per RECIST v1.1

Written informed consent and any locally-required authorization obtained from the patients prior to performing any protocol-related procedures, including screening evaluations

I have been diagnosed with squamous cell carcinoma in my head or neck.

Exclusion Criteria

I have had an autoimmune disease in the last 2 years.

I cannot have radiotherapy due to a genetic condition.

My cancer is a non-squamous cell type of salivary gland cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Combination Treatment

Participants receive pembrolizumab and QUAD SHOT radiotherapy. Pembrolizumab is administered once every 3 weeks, and QUAD SHOT radiotherapy is administered twice a day for two days every 4 weeks. This cycle is repeated 3 times.

12 weeks

3 cycles of treatment

Maintenance Treatment

Participants receive pembrolizumab alone once every 3 weeks until unacceptable toxicity or tumor progression.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pembrolizumab
• QUADSHOT Radiotherapy

Trial Overview 'QUAD SHOT' radiotherapy combined with pembrolizumab is being tested for safety and effectiveness in treating patients with recurrent head and neck cancer. The study aims to see how well these treatments work together.

Participant Groups

Group I: Pembrolizumab + QUADSHOT Radiotherapy Experimental Treatment 1 Intervention

Combination Treatment * Pembrolizumab by IV once on day 1 of 21 day cycle, begin 7 days before the first round of QUAD SHOT radiotherapy. * QUAD SHOT radiotherapy twice a day for two days, begin 7 days after the first dose of pembrolizumab; repeat every 28 days for up to 3 rounds. Maintenance Treatment * Pembrolizumab by IV once on day 1 of 21 day cycle * On day 21, if the medical oncologist feels that the patient may safely continue treatment, patient will receive a new 21 days cycle of treatment with pebrolizumab.

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?

University of Oklahoma

Lead Sponsor

Trials

484

Recruited

95,900+

Findings from Research

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]

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 of 21 patients with advanced head and neck cancer, the QUAD-Shot hypofractionated radiotherapy regimen combined with chemotherapy resulted in an 85.7% objective response rate, with 23.8% achieving complete response and 61.9% showing partial response.

All patients who completed the treatment experienced symptom relief, and the median overall survival was 7 months, indicating that this treatment is both effective and well-tolerated for patients not eligible for curative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypofractionated Palliative Radiotherapy with Concurrent Radiosensitizing Chemotherapy for Advanced Head and Neck Cancer Using the "QUAD-SHOT Regimen". Gamez, ME., Agarwal, M., Hu, KS., et al.[2019]

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]

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]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer. [2023]

2. England 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. [2023]

3. England 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. [2021]

4. Greece pubmed.ncbi.nlm.nih.gov

Hypofractionated Palliative Radiotherapy with Concurrent Radiosensitizing Chemotherapy for Advanced Head and Neck Cancer Using the "QUAD-SHOT Regimen". [2019]

5. England 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. [2019]

6. England 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. [2019]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. [2023]

9. United States 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. [2022]