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NCT04454489

Quad Shot Radiotherapy in Combination With Immune Checkpoint Inhibition

Completed Phase 2 Results posted Last updated 19 November 2025
What this trial tests

Phase 2 trial testing Pembrolizumab (immunotherapy) in Advanced Head and Neck Squamous Cell Carcinoma in 21 participants. Completed in 30 April 2025.

Timeline
25 February 2021
Primary endpoint
18 February 2025
30 April 2025

Quick facts

Lead sponsorWake Forest University Health Sciences
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment21
Start date25 February 2021
Primary completion18 February 2025
Estimated completion30 April 2025
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

Wake Forest University Health Sciences

Who can join

18 and older, any sex, with Advanced Head and Neck Squamous Cell Carcinoma or Recurrent Head and Neck Squamous Cell Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Response - Primary · Up to 2 years

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 ta

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy40.016.3 – 67.7
Response Rate in the Target Lesions Secondary · Up to 2 years

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 with

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy40.016.3 – 67.7
Response Rate in the Non-Target Lesions Secondary · Up to 2 years

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

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy100.3 – 44.5
Duration of Response at the Target Lesions - Mean Measurement Secondary · Up to 2 years

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.

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy11.63.89 – 19.31
Duration of Response at the Target Lesions - Median Measurement Secondary · Up to 2 years

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 pathol

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy9.444.37 – 22.98
Progression-Free Survival Secondary · Up to 2 years.

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.

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy9.23.4 – 17.2
Progression-Free Survival - Survival Rate Percentages Secondary · Up to 2 years.

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.

6 months survival
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy12
12 months survival
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy7
Overall Survival - Months Secondary · Up to 2 years

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.

GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy14.94.9 – 25.8
Overall Survival - Survival Rate Percentages Secondary · Up to 2 years

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.

6 months
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy14
12 months
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy10
Tolerability - Adverse Events Assessed Using PRO-CTCAE Version 5.0 Secondary · Up to 2 years

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.

Leukocytosis
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32
Dysphagia
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy278 – 55
Abdominal Pain
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32
Dry Mouth
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32
Nausea
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32
Fatigue
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32
Infection
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32
Weight Loss
GroupValue95% CI
Quad-shot Palliative Radiotherapy and Immunotherapy70 – 32

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were recorded with each treatment cycle, up to 2 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Quad-shot Palliative Radiotherapy and Immunotherapy
Serious: 15/20 (75%)
Deaths: 13/20

Serious adverse events (24 terms)

ReactionSystemQuad-shot Palliative Radio…
DeathGeneral disorders
Disease progressionGeneral disorders
DysphagiaGastrointestinal disorders
Infections and InfestationsInfections and infestations
Weight LossInvestigations
ParesthesiaNervous system disorders
FloatersEye disorders
Abdominal PainGastrointestinal disorders
Colonic perforationGastrointestinal disorders
Oral hemorrhageGastrointestinal disorders
Injury, poisoning and procedural complicationsInjury, poisoning and procedural complications
Tracheostomy site bleedingInjury, poisoning and procedural complications
HypercalcemiaMetabolism and nutrition disorders
Generalized muscle weaknessMusculoskeletal and connective tissue disorders
Tumor HemorrhageNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Facial muscle weaknessNervous system disorders
HeadacheNervous system disorders
StrokeNervous system disorders
Vasovagal ReactionNervous system disorders
HemorrhageRespiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Respiratory AspirationRespiratory, thoracic and mediastinal disorders
Bullous (Dermatitis) PemphigoidSkin and subcutaneous tissue disorders
Thromboembolic EventVascular disorders
Other adverse events (71 terms — click to expand)

ReactionSystemQuad-shot Palliative Radio…
FatigueGeneral disorders
Lymphocyte count decreaseInvestigations
Dry mouthGastrointestinal disorders
HyperglycemiaMetabolism and nutrition disorders
AnemiaBlood and lymphatic system disorders
HypertensionVascular disorders
HyponatremiaMetabolism and nutrition disorders
DysphagiaGastrointestinal disorders
PruritusSkin and subcutaneous tissue disorders
Weight lossInvestigations
Tumor painNeoplasms benign, malignant and unspecified (incl cysts and polyps)
TSH increaseInvestigations
HypoalbuminemiaMetabolism and nutrition disorders
HoarsenessRespiratory, thoracic and mediastinal disorders
Edema of limbsGeneral disorders
DysgeusiaNervous system disorders
EosinophiliaBlood and lymphatic system disorders
TachycardiaCardiac disorders
HypothyroidismEndocrine disorders
DiarrheaGastrointestinal disorders
NauseaGastrointestinal disorders
HypoglycemiaMetabolism and nutrition disorders
Sore throatRespiratory, thoracic and mediastinal disorders
Abdominal painGastrointestinal disorders
GERDGastrointestinal disorders
Oral painGastrointestinal disorders
Alkaline Phosphatase increaseInvestigations
Lipase increaseInvestigations
Serum amylase increasedInvestigations
AnorexiaMetabolism and nutrition disorders
HyperkalemiaMetabolism and nutrition disorders
CoughRespiratory, thoracic and mediastinal disorders
Productive CoughRespiratory, thoracic and mediastinal disorders
Low HemoglobinBlood and lymphatic system disorders
Ear painEar and labyrinth disorders
VomitingGastrointestinal disorders
ThrushInfections and infestations
AST increaseInvestigations
HypomagnesemiaMetabolism and nutrition disorders
ArthritisMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Death, Disease progression, Dysphagia, Infections and Infestations, Weight Loss, Paresthesia, Floaters, Abdominal Pain.

Data from ClinicalTrials.gov NCT04454489 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons.
    Naimi A, Mohammed RN, Raji A, Chupradit S, et al · · 2022 · cited 350× · PMID 35392976 · DOI 10.1186/s12964-022-00854-y
  2. Radiotherapy and Immunotherapy for Head and Neck Cancer: Current Evidence and Challenges.
    Qian JM, Schoenfeld JD. · · 2020 · cited 47× · PMID 33614492 · DOI 10.3389/fonc.2020.608772
  3. Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma.
    Veigas F, Mahmoud YD, Merlo J, Rinflerch A, et al · · 2021 · cited 30× · PMID 33804419 · DOI 10.3390/cancers13051018
  4. Combining Radiotherapy and Immunotherapy in Head and Neck Cancer.
    Runnels J, Bloom JR, Hsieh K, Dickstein DR, et al · · 2023 · cited 23× · PMID 37626594 · DOI 10.3390/biomedicines11082097
  5. Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer.
    Plavc G, Jesenko T, Oražem M, Strojan P. · · 2020 · cited 19× · PMID 33143094 · DOI 10.3390/cancers12113197
  6. Overcoming Resistance to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma.
    García-Sancha N, Corchado-Cobos R, Bellido-Hernández L, Román-Curto C, et al · · 2021 · cited 14× · PMID 34680282 · DOI 10.3390/cancers13205134
  7. Combinatorial Hypofractionated Radiotherapy and Pembrolizumab in Anaplastic Thyroid Cancer.
    Tan JSH, Tay TKY, Ong EHW, Fehlings M, et al · · 2024 · cited 12× · PMID 38181007 · DOI 10.1530/etj-23-0144
  8. Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer.
    Hughes RT, Gebeyehu RR, Kalada JM, Lycan TW, et al · · 2023 · cited 6× · PMID 37199326 · DOI 10.2217/fon-2022-1146

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Other recruiting trials for Advanced Head and Neck Squamous Cell Carcinoma

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