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Clinical Trials List

Protocol NumberMK3475-689
NCT Number(ClinicalTrials.gov Identfier)NCT03765918

2018-05-31 - 2027-12-31

Phase III

Recruiting4

ICD-10C76.0

Malignant neoplasm of head, face and neck

A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

  • Trial Applicant

    Merck Sharp & Dohme (I.A.) LLC

  • Sponsor

    Merck Sharp & Dohme Corp.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Chia-Jui Yen Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Audit

None

Principal Investigator YI-CHUN LIU Division of Radiation Therapy
Taichung Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 簡志彥 Division of Otolaryngology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator RUEY-LONG HONG Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Audit

None

Condition/Disease

Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

Objectives

Primary To compare the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery between participants who receive neoadjuvant therapy with pembrolizumab and participants who do not. Objective: To compare the event-free survival (EFS) as assessed by BICR between participants who receive pembrolizumab neoadjuvant therapy and pembrolizumab with radiotherapy (RT) ± cisplatin as adjuvant therapy and participants who receive only RT ± cisplatin as adjuvant therapy. Secondary  Objective: To compare OS between participants who receive pembrolizumab neoadjuvant therapy and pembrolizumab with RT ± cisplatin as adjuvant therapy and participants who receive only RT ± cisplatin as adjuvant therapy.  Objective: To evaluate the rate of pathological complete response (pCR) as assessed by the central pathologist at the time of definitive surgery.  Objective: To evaluate global health status/quality of life (QoL) scores using the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, and swallowing, speech and pain symptoms using the EORTC Head and Neck–Specific QoL questionnaire (EORTC QLQ-H&N35).  Objective: To determine the safety and tolerability of pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy.

Test Drug

Pembrolizumab (MK-3475)/KEYTRUDA

Active Ingredient

Pembrolizumab (Humanized anti-PD-1 mAb)

Dosage Form

Injection

Dosage

100 mg/ 4 mL/ Vial

Endpoints

Primary Outcome Measures :
Major Pathological Response (mPR) [ Time Frame: Up to 30 days post-sugery ]
The proportion of participants with a major pathological response (mPR) as assessed by the Central Pathologist at the time of definitive surgery. mPR is defined as ≤10% invasive squamous cell carcinoma within the resected primary tumor specimen and all the sampled regional lymph nodes.

Event-free Survival (EFS) [ Time Frame: Up to 5 years ]
EFS is the time from the date of randomization to the date of first record of any of the following events: disease progression; local or distant recurrence as assessed with imaging or biopsy as indicated; or death due to any cause.


Secondary Outcome Measures :
Overall Survival (OS) [ Time Frame: Up to 5 years ]
OS is the time from randomization to death due to any cause.

Pathological Complete Response (pCR) [ Time Frame: Up to 30 days post-sugery ]
Pathological complete response (pCR) is measured as the proportion of participants with a pathological complete response as assessed by the central pathologist at the time of definitive surgery. pCR is defined as having no residual invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes.

Change From Baseline in Global Health Status/Quality of Life Scale (GHS/QoL) [ Time Frame: Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years) ]
Change from baseline in the combined score of GHS/QoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 29 and 30

Change From Baseline in Global Health Status/Physical Functioning Scales [ Time Frame: Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years) ]
Change from baseline in the combined score of physical functioning scale using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 1 through 5

Change from Baseline in Swallowing, Speech, and Pain Symptoms [ Time Frame: Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years) ]
Change from baseline in the combined score of swallowing, speech, and pain symptoms using the European Organization for Research and Treatment of Cancer Head and Neck Questionnaire (EORTC QLQ-H&N35) items 31-38, 46, and 53-54

Percentage of Participants Experiencing An Adverse Event (AEs) [ Time Frame: From time of first dose of study treatment until the end of follow-up (up to 5 years) ]
Percentage of participants experiencing any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy

Percentage of Participants Discontinuing Study Drug Due to AEs [ Time Frame: From time of first dose of study treatment until the end of treatment (up to 12 months) ]
Percentage of participants discontinuing study drug due to an AE

Inclution Criteria

Inclusion Criteria
Participants are eligible to be included in the study only if all of the following
criteria apply:
1. Have histologically confirmed new diagnosis of resectable, non-metastatic,
squamous cell carcinoma as assessed by the investigator based on baseline
imaging and clinical assessment that is either:
a. Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0
OR
b. Stage III or IVA oropharyngeal p16 negative
OR
c. Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16).
Note: Participants with newly diagnosed HNSCC who underwent partial
surgical resection and have gross residual disease are eligible for the study
if additional surgery and adjuvant treatment is required.
Note: Participants with multiple primary HNSCC tumors are eligible for
the study if at least one of the tumors meets eligibility criteria based on
staging after consultation with and approval by the Sponsor.
2. Be eligible for primary surgery based on investigator decision and per local
practice.
3. Male/female participants who are at least 18 years of age on the day of
signing informed consent
4. A male participant must agree to use a contraception as detailed in Protocol
Appendix 5 of this protocol during the treatment period and for at least 180
days after the last dose of study treatment and refrain from donating sperm
during this period.
5. A female participant is eligible to participate if she is not pregnant (see
Protocol Appendix 5), not breastfeeding, and at least one of the following
conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in
Protocol Appendix 5
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Protocol
Appendix 5 during the treatment period and for at least 180 days after the
last dose of study treatment.
6. The participant (or legally acceptable representative if applicable) provides
written informed consent for the study. The participant may also provide
consent for Future Biomedical Research. However the participant may
participate in the main study without participating in Future Biomedical
Research.
7. Have evaluable tumor burden (measurable and/or non-measurable tumor
lesions) assessed by computed tomography (CT) scan or magnetic
resonance imaging (MRI), based on RECIST 1.1 as assessed by the local
site investigator/radiology.
8. Have provided archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated for PD-L1
biomarker analysis from a core or excisional biopsy (fine needle aspirate
[FNA] is not adequate). Formalin-fixed, paraffin embedded tissue blocks
are preferred to slides. Newly obtained biopsies are preferred to archived
tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are
cut (details pertaining to tumor tissue submission can be found in the
Vendor Manual).
Note: Central pathological review for PD-L1 will not be performed before
inclusion.
Note: Adequacy of archival tissue sample for PD-L1 analysis will not be
assessed prior to the initiation of study treatment.
9. Have results from (local) testing of HPV status for oropharyngeal cancer
defined as p16 IHC testing using CINtec® p16 Histology assay (Ventana
Medical Systems Inc., Tucson AZ) using ‘Benchmark Ultra’ autostainer
(Ventana, Tucson, AZ) and standard protocol. Positive p16 expression is
defined as strong and diffuse nuclear and cytoplasmic staining in 70% or
more of the tumor cells (please see Protocol Section 9.1.6 - Presurgery
Tumor Tissue Collection for details). If HPV status was previously tested
using this method, no additional testing is required.
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status
of 0 to 1 performed within 10 days of treatment initiation.
Note: investigators to confirm no deterioration prior to initiation of
treatment.
11. Have adequate organ function. Specimens must be collected within 10
days prior to the start of study treatment

Exclusion Criteria

Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Has Stage T4B and/or N3 LA HNSCC and/or distant metastases.
2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral
cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown
primary HNC.
3. A WOCBP who has a positive urine pregnancy test within 72 hours prior to
randomization or within 24 hours prior to the start of RT ± cisplatin (see
Protocol Appendix 5). If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required. In such cases, the
participant must be excluded from participation if the serum pregnancy
result is positive.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2
agent or with an agent directed to another co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior radiotherapy treatment or systemic anti-cancer therapy
including investigational agents for the HNC under study prior to
randomization/allocation.
6. Has received a live vaccine within 30 days prior to the first dose of study
drug. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow
fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal
influenza vaccines for injection are generally killed virus vaccines and are
allowed; however, intranasal influenza vaccines (eg, FluMist® ) are live
attenuated vaccines and are not allowed.
7. Is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4 weeks
prior to the first dose of study treatment.
Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after
the last dose of the previous investigational agent.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any
other form of immunosuppressive therapy within 7 days prior the first dose
of study drug.
9. Has a known additional malignancy that is progressing or has required
active treatment within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or carcinoma in situ (eg, in situ cervical cancer or
breast carcinoma) that have undergone potentially curative therapy are not
excluded.
10. Has radiographically detectable (even if asymptomatic and/or previously
treated) central nervous system metastases and/or carcinomatous meningitis
as assessed by local site investigator and radiology review.
11. Has Grade ≥2 audiometric hearing loss.
Note: Audiometric abnormalities without corresponding clinical symptoms
of Grade ≥2 hearing loss will not be grounds for exclusion.
12. Has Grade ≥2 neuropathy.
13. Has Grade 3-4 bleeding due to the underlying malignancy
14. If participant has received major surgery, and the participant has not
recovered adequately from the toxicity and/or complications from the
intervention prior to randomization.
15. Has had previous allogeneic tissue/solid organ transplant.
16. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its
excipients (refer to the Investigator’s Brochure for a list of excipients), RT
or cisplatin or their analogs.
17. Has an active autoimmune disease that has required systemic treatment in
past 2 years (ie, with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) is not considered a form of systemic treatment and is
allowed.
18. Has a history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
19. Has an active infection requiring systemic therapy.
20. Has a known history of human immunodeficiency virus (HIV) infection.
No HIV testing is required unless mandated by local health authority.
21. Has a known history of or is positive for Hepatitis B (defined as hepatitis B
surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as
Hepatitis C virus [HCV] RNA [qualitative] is detected).
Note: no testing for Hepatitis B and Hepatitis C is required unless
mandated by local health authority.
22. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in the
best interest of the participant to participate, in the opinion of the treating
investigator.
23. Has known psychiatric or substance abuse disorders that would interfere
with cooperating with the requirements of the study.
24. Is pregnant or breastfeeding or expecting to conceive or father children
within the projected duration of the study, starting with the screening visit
through 180 days after the last dose of study treatment.

The Estimated Number of Participants

  • Taiwan

    30 participants

  • Global

    714 participants

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