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Advanced Head and Neck Squamous Cell CarcinomaPhase 2NCT04454489

Quad Shot Radiotherapy in Combination With Immune Checkpoint Inhibition

A Phase 2 study testing Pembrolizumab (immunotherapy) and Quad-shot palliative radiotherapy in people with Advanced Head and Neck Squamous Cell Carcinoma and Recurrent Head and Neck Squamous Cell Carcinoma, run by Wake Forest University Health Sciences at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This is a single-arm, non-randomized pilot study to evaluate the efficacy and tolerability of combination quad-shot palliative radiotherapy with immunotherapy for advanced/recurrent/metastatic head and neck cancer. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pembrolizumab (immunotherapy) and Quad-shot palliative radiotherapy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
21 participants
Where
1 siteUnited States
Study dates
25 Feb 2021to 30 Apr 2025
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Advanced, recurrent or metastatic head and neck squamous cell carcinoma, as defined by clinical or pathological diagnosis of any of the following:
  • Locally advanced head and neck squamous cell carcinoma not suitable for curative local treatment.
  • Locally recurrent head and neck squamous cell carcinoma not suitable for curative local treatment within or outside a previously irradiated tissue.
  • Metastatic head and neck squamous cell carcinoma.
  • Target site in the head and neck region amenable to quad-shot palliative radiotherapy, for which palliative radiotherapy is recommended, as determined by the treating radiation oncologist.
  • Age 18 years or greater at time of registration.
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  • ECOG Performance Status of 0-2.
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign an IRB-approved informed consent document (either directly or via a legally authorized representative).
  • Willingness to provide blood and saliva samples for exploratory research purposes.
  • Organ and Marrow Function as defined below: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 9.0 g/dL, serum bilirubin ≤ 1.5 x ULN (institutional upper limit of normal), AST and ALT ≤ 2.5 x ULN (institutional upper limit of normal), serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:
  • MALES: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) (divided by) 72 x serum creatinine (mg/dL).
  • FEMALES: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 (divided by) 72 x serum creatinine (mg/dL)

Who cannot join

  • Radiation therapy to the planned quad-shot radiotherapy target region within 30 days of registration.
  • Prior radiotherapy to the head and neck that precludes safe delivery of study radiotherapy, as determined by the treating radiation oncologist.
  • Active medical conditions that are contraindications to study radiotherapy (i.e. scleroderma), as determined by the treating radiation oncologist.
  • Pregnant or lactating women are excluded from this study because radiotherapy is contraindicated in pregnancy and because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with immunotherapy.
  • Participation in another clinical study with an investigational product during the last 3 months.
  • Any previous treatment with a PD1 or PD-L1 inhibitor.
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  • Any anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within the last 30 days. Note: this excludes palliative radiotherapy to the non-target site.
  • Mean QT interval corrected for heart rate (QTc) ≥470 ms except for patients with pacemaker who have a paced ventricular rhythm.
  • Current or prior use of immunosuppressive medication within 30 days, with exceptions of intranasal and inhaled corticosteroids, a brief, non-sustained corticosteroids treatment for incidental problems such as allergies (at the discretion of the treating physician) or sustained systemic corticosteroids treatment at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid except for short course of prednisone that is prescribed for acute allergic situations or for prevention of an allergy to contrast substance utilized for imaging studies.
  • Any unresolved toxicity (>CTCAE grade > 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy).
  • Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1.
  • Active or prior documented autoimmune disease within the past 2 years, NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
  • Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
  • History of primary immunodeficiency.
  • History of allogeneic organ transplant.
  • History of hypersensitivity to any excipient in pembrolizumab.
  • History of pneumonitis or interstitial lung disease.
  • Subjects with uncontrolled seizures.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
  • Known history of active tuberculosis.
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving pembrolizumab.
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Wake Forest Baptist Comprehensive Cancer Center

    Winston-Salem, North Carolina, 27157

Other trials in United States

About this study

Official title: Quad-Shot Radiotherapy in Combination With Immune Checkpoint Inhibition for Advanced/Recurrent Head and Neck Cancer

This is a single-arm, non-randomized pilot study to evaluate the efficacy and tolerability of combination quad-shot palliative radiotherapy with immunotherapy for advanced/recurrent/metastatic head and neck cancer.

Read the detailed description

Primary Objective: Measure the overall response rate for immunotherapy given with quad-shot radiotherapy.

Secondary Objective(s)

  • Measure the response rate at the target lesion.
  • Measure the response rate at non-target sites in patients with non-target sites.
  • Evaluate the durability of response at the target lesion.
  • Evaluate progression-free survival.
  • Evaluate overall survival.
  • Assess the tolerability of the combination of quad-shot radiotherapy with immunotherapy in order to assess the feasibility of this treatment regimen.

Exploratory Objective: Evaluate the effect of quad- shot administration on increasing the immune activation by treatment with pembrolizumab and investigate possible mechanisms.

OUTLINE: Patients receive standard of care pembrolizumab intravenously (IV) over 30 minutes every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo quad-shot radiation therapy twice daily (BID) on 2 consecutive days between cycles 2-3 or 3-4, 6-7, and 11-12 of pembrolizumab treatment and in the last week of pembrolizumab treatment.

After completion of study treatment, patients are followed up at 1 and 2 months for adverse events monitoring. Patients will be followed until death for monitoring survival study endpoints. Frequency of visits will be established by the treating physician and will be done in person or over the phone.

Being tested
Pembrolizumab (immunotherapy), Quad-shot palliative radiotherapy
Medical subject headings
Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pembrolizumab (immunotherapy)Drug

    Pembrolizumab 200 mg will be given every 3 weeks to tumor progression or treatment tolerance.

  • Quad-shot palliative radiotherapyRadiation

    • Each cycle of quad-shot radiotherapy will be comprised of 14.8 Gy in 4 fractions (3.7 Gy per fraction) delivered twice daily (at least 6 hours apart) over two consecutive days.
    • All patients will receive 1 cycle of quad-shot radiotherapy between ICI cycles 2-3.
    • Subsequent cycles may occur between immunotherapy cycles 6-7 and 11-12, if more than 1 cycle can be safely delivered and the patient has experienced less than a partial response at protocol-specified tumor assessments (after C5 and C10). The eligibility for subsequent cycles will be at the discretion of the treating radiation oncologist.

    Therefore, the total prescription dose will be:

    • 14.8 Gy in 4 fractions for those that complete 1 cycle (all patients will receive 1 cycle)
    • 19.6 Gy in 8 fractions for those that complete 2 cycles
    • 44.4 Gy in 12 fractions for those that complete 3 cycles
Study groups in NCT04454489
Study groupRoleWhat they receive
Quad-shot palliative radiotherapy and ImmunotherapyExperimentalSystemic therapy (ICI) and radiotherapy will be administered according to the standard of care, according to the treating medical oncologist and radiation oncologist, respectively
Receives: Drug: Pembrolizumab (immunotherapy); Radiation: Quad-shot palliative radiotherapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Response -

    Overall response will be measured according to RECIST 1.1 criteria to determine the percentage of participants with either a partial or complete response and the corresponding 95% Clopper-Pearson exact confidence interval. The best overall response is the best response recorded from the start of the treatment across all time points.

    COMPLETE RESPONSE: Disappearance (or decrease to the point at which measurement is not possible) of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (the sum may not be "0" if there are target nodes)

    PARTIAL RESPONSE: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters

    Measured: Up to 2 years

Secondary outcomes (9)

  1. Response Rate in the Target Lesions

    Response rate will be measured as the following:

    Complete: Disappearance (or decrease to the point at which measurement is not possible) of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

    Partial: At least a 30% decrease in the sum of diameters of target lesions. Progressive Disease: Greater than 20% increase in the sum of the longest diameters (SLD) taking as reference the smallest SLD recorded since the treatment started (nadir) and minimum 5 mm increase over the nadir. When sum becomes very small, increases within measurement error (2-3 mm) can lead to 20% increase.

    Stable Disease: Greater than 20% increase in the sum of the longest diameters (SLD) taking as reference the smallest SLD recorded since the treatment started (nadir) and minimum 5 mm increase over the nadir. When sum becomes very small, increases within measurement error (2-3 mm) can lead to 20% increase.

    Measured: Up to 2 years

  2. Response Rate in the Non-Target Lesions

    Response rate will be measured using RECIST 1.1:

    Complete: Disappearance (or decrease to the point at which measurement is not possible) of all non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm short axis).

    Partial: Non-complete response/Non-progressive disease: Persistence of 1 or more non-target lesion(s).

    Progressive Disease: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

    Stable Disease: Greater than 20% increase in the sum of the longest diameters (SLD) taking as reference the smallest SLD recorded since the treatment started (nadir) and minimum 5 mm increase over the nadir. When sum becomes very small, increases within measurement error (2-3 mm) can lead to 20% increase.

    Measured: Up to 2 years

  3. Duration of Response at the Target Lesions - Mean Measurement

    For the duration of response, among participants investigators will estimate both the mean duration and the corresponding 95% confidence intervals for the mean and inter-quartile range for the median. The duration of response at the target lesion will be defined as the duration from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date of recurrent or progressive disease.

    Measured: Up to 2 years

  4. Duration of Response at the Target Lesions - Median Measurement

    The duration of response at the target lesion(s) will be defined as the duration from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date of recurrent or progressive disease. For the duration of response, among participants investigators will estimate the median duration and the corresponding 95% confidence intervals for the mean and inter-quartile range for the median.

    Target Lesions:

    COMPLETE RESPONSE: Disappearance (or decrease to the point at which measurement is not possible) of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm (the sum may not be "0" if there are target nodes)

    PARTIAL RESPONSE: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters

    Measured: Up to 2 years

  5. Progression-Free Survival

    For progression-free survival investigators will estimate Kaplan Meier survival curves and the median time to progression-free survival, as well as survival rates at 6 months and 1 year post treatment. Progression-Free Survival is defined as the duration of time from registration to the time of progression, death, or date of last contact; those lost to follow-up will be censored.

    Measured: Up to 2 years.

  6. Progression-Free Survival - Survival Rate Percentages

    For progression-free survival investigators will estimate Kaplan Meier survival curves and the median time to progression-free survival, as well as survival rates at 6 months and 1 year post treatment. Progression-Free Survival is defined as the duration of time from registration to the time of progression, death, or date of last contact; those lost to follow-up will be censored.

    Measured: Up to 2 years.

  7. Overall Survival - Months

    For time to event measure of overall survival investigators will estimate Kaplan Meier survival curves and the median time to overall survival, as well as survival rates at 6 months and 1 year post treatment. Overall Survival is defined as the duration of time from registration to date of death or date of last contact; those lost to follow-up will be censored.

    Measured: Up to 2 years

  8. Overall Survival - Survival Rate Percentages

    For time to event measure of overall survival investigators will estimate Kaplan Meier survival curves and the median time to overall survival, as well as survival rates at 6 months and 1 year post treatment. Overall Survival is defined as the duration of time from registration to date of death or date of last contact; those lost to follow-up will be censored.

    Measured: Up to 2 years

  9. Tolerability - Adverse Events Assessed Using PRO-CTCAE Version 5.0

    Tolerability of intervention will be assessed using Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Event (PRO CTCAE). Investigators will estimate the percentage of patients with different adverse events using a 95% Clopper Pearson exact confidence level. Listed adverse events were grade 3+ and deemed at least possibly related to therapy.

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jul 2020
  2. Study start25 Feb 2021
  3. Primary completion18 Feb 2025
  4. Study completion30 Apr 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
21 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04454489
Sponsor's protocol ID
IRB00066650
Other IDs
WFBCCC 60320, P30CA012197
Status last verified
Nov 2025
First submitted
23 Jun 2020
Last updated
19 Nov 2025
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Hughes RT, Smith S, Lycan TW Jr, Bunch PM, D'Agostino RB Jr, Frizzell BA, Kinney RD, Rashid S, Triozzi P, Zhang W, Furdui CM, Porosnicu M. Pembrolizumab Plus Quad-Shot Radiotherapy for Recurrent, Unresectable, or Metastatic Head and Neck Cancer: A Nonrandomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2026 Aug 1;152(8):768-775. doi: 10.1001/jamaoto.2026.1527.

    PubMed 42313403

  • Hughes RT, Gebeyehu RR, Kalada JM, Lycan TW, Frizzell BA, Kinney RD, D'Agostino RB, Bunch PM, Triozzi P, Zhang W, Furdui CM, Porosnicu M. Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer. Future Oncol. 2023 Jul;19(22):1523-1534. doi: 10.2217/fon-2022-1146. Epub 2023 May 18.

    PubMed 37199326

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab (immunotherapy) and Quad-shot palliative radiotherapy in people with Advanced Head and Neck Squamous Cell Carcinoma and Recurrent Head and Neck Squamous Cell Carcinoma, run by Wake Forest University Health Sciences at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Nov 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response - (time frame: Up to 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04454489, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2025.

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