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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03765918




Registration number
NCT03765918
Ethics application status
Date submitted
6/11/2018
Date registered
5/12/2018
Date last updated
9/08/2019

Titles & IDs
Public title
Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689)
Scientific title
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)
Secondary ID [1] 0 0
2017-001139-38
Secondary ID [2] 0 0
3475-689
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Head and Neck Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Pembrolizumab 200 mg
Treatment: Other - Radiotherapy 60 Gray/day
Treatment: Other - Radiotherapy 66 Gray/day
Treatment: Other - Radiotherapy 70 Gray/day
Treatment: Drugs - Cisplatin 100 mg/m^2

Experimental: Pembro Neoadjuvant+Pembro SOC Adjuvant - Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of a 21-day cycle for 2 cycles as a neoadjuvant prior to surgery. Following surgical resection, high risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 every 3 weeks (Q3W) for fifteen 21-day cycles plus standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 Q3W for fifteen 21-day cycles plus standard of care radiotherapy as adjuvant therapy.

Active Comparator: No Neoadjuvant+SOC Adjuvant - Participants receive no neoadjuvant prior to surgery. Following surgical resection, high risk participants receive standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive standard of care radiotherapy as adjuvant therapy.


Other interventions: Pembrolizumab 200 mg
200 mg administered by intravenous (IV) infusion on Day 1 of each 21-day cycle

Treatment: Other: Radiotherapy 60 Gray/day
Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy.

Treatment: Other: Radiotherapy 66 Gray/day
High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy.

Treatment: Other: Radiotherapy 70 Gray/day
Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy.

Treatment: Drugs: Cisplatin 100 mg/m^2
100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Other
Intervention code [3] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Major Pathological Response (mPR) - 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.
Timepoint [1] 0 0
Up to 30 days post-sugery
Primary outcome [2] 0 0
Event-free Survival (EFS) - 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.
Timepoint [2] 0 0
Up to 5 years
Secondary outcome [1] 0 0
Overall Survival (OS) - OS is the time from randomization to death due to any cause.
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [2] 0 0
Pathological Complete Response (pCR) - 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.
Timepoint [2] 0 0
Up to 30 days post-sugery
Secondary outcome [3] 0 0
Change From Baseline in Global Health Status/Quality of Life Scale (GHS/QoL) - 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
Timepoint [3] 0 0
Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)
Secondary outcome [4] 0 0
Change From Baseline in Global Health Status/Physical Functioning Scales - 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
Timepoint [4] 0 0
Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)
Secondary outcome [5] 0 0
Change from Baseline in Swallowing, Speech, and Pain Symptoms - 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
Timepoint [5] 0 0
Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)
Secondary outcome [6] 0 0
Percentage of Participants Experiencing An Adverse Event (AEs) - 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
Timepoint [6] 0 0
From time of first dose of study treatment until the end of follow-up (up to 5 years)
Secondary outcome [7] 0 0
Percentage of Participants Discontinuing Study Drug Due to AEs - Percentage of participants discontinuing study drug due to an AE
Timepoint [7] 0 0
From time of first dose of study treatment until the end of treatment (up to 12 months)

Eligibility
Key inclusion criteria
- Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous
cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive
oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no
distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or
IVA larynx/hypopharynx/oral cavity primaries

- Is eligible for primary surgery based on investigator decision and per local practice

- Female and male participants of reproductive potential must agree to use adequate
contraception throughout the study period and for up to 180 days after the last dose
of study therapy

- Male participants must refrain from donating sperm throughout the study period and for
up to 180 days after the last dose of study therapy

- Female participant that is not pregnant or breastfeeding

- Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed
by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST
version 1.1

- Has provided newly obtained core or excisional biopsy of a tumor lesion not previously
irradiated

- Has results from testing of HPV status for oropharyngeal cancer defined as p16

- Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed
within 10 days of randomization
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Has Stage T4B and/or N3 LA HNSCC and/or distant metastases

- Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as
nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer
(HNC)

- Female participant who has a positive urine pregnancy test within 72 hours prior to
study start or within 24 hours prior to the start of radiotherapy with or without
cisplatin

- Has received prior therapy with an anti-programmed cell death receptor 1(PD-1),
anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death
receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory
T-cell receptor

- Has received prior radiotherapy treatment or systemic anti-cancer therapy including
investigational agents for the HNC under study prior to study start

- Has received a live vaccine within 30 days prior to randomization

- 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 randomization

- 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 to randomization

- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years with the exception of basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical
cancer or breast carcinoma) that have undergone potentially curative therapy

- Has radiographically detectable (even if asymptomatic and/or previously treated)
central nervous system metastases and/or carcinomatous meningitis

- Has Grade =2 audiometric hearing loss

- Has Grade =2 neuropathy

- Has Grade 3-4 bleeding due to the underlying malignancy

- Has received major surgery or has not recovered adequately from the toxicity and/or
complications from the intervention prior to study start

- Has had previous allogeneic tissue/solid organ transplant

- Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients,
radiotherapy, cisplatin or their analogs

- Has an active autoimmune disease that has required systemic treatment in past 2 years

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis

- Has an active infection requiring systemic therapy

- Has a known history of human immunodeficiency virus (HIV) infection

- 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] ribonucleic acid is detected).

- 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 investigator

- Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Royal Brisbane and Women s Hospital ( Site 0050) - Herston
Recruitment postcode(s) [1] 0 0
4029 - Herston
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
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United States of America
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Colorado
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Florida
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United States of America
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Idaho
Country [5] 0 0
United States of America
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Illinois
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United States of America
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Kansas
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United States of America
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Massachusetts
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United States of America
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Michigan
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Minnesota
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Missouri
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Montana
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New Mexico
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New York
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North Carolina
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Oregon
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Pennsylvania
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South Dakota
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Tennessee
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Utah
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Virginia
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Washington
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Argentina
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Buenos Aires
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Argentina
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Rosario
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Argentina
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San Juan
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Austria
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Graz
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Austria
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Linz
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Austria
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Salzburg
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Austria
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Vienna
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Belgium
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Gent
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Belgium
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Haine Saint Paul
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Bahia
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Rio Grande Do Norte
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RS
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Chile
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Colombia
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Bogota
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Gera
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Luebeck
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Sevilla
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Switzerland
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Bellinzona
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Zuerich
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Taipei
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Ukraine
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Ukraine
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Dnipropetrovsk
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Ukraine
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Dnipro
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Ukraine
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Kropyvnytskyi
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Ukraine
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Kyiv
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United Kingdom
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Cottingham-Hull
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United Kingdom
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London
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United Kingdom
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Sheffield

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme Corp.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is a randomized, active-controlled, open-label study of pembrolizumab (Pembro) given
prior to surgery and pembrolizumab in combination with standard of care radiotherapy (with or
without cisplatin), as post-surgical therapy in treatment naïve participants with newly
diagnosed Stage III/IVA, resectable, locoregionally advanced, head and neck squamous cell
carcinoma (LA-HNSCC). Efficacy outcomes will be stratified by programmed cell death ligand 1
(PD-L1) combined positive score (CPS) status. The primary hypothesis is that pembrolizumab
given before surgery and after surgery in combination with radiotherapy (with or without
cisplatin) improves major pathological response and event-free survival compared to
radiotherapy (with or without cisplatin) given after surgery alone.
Trial website
https://clinicaltrials.gov/show/NCT03765918
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme Corp.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Toll Free Number
Address 0 0
Country 0 0
Phone 0 0
1-888-577-8839
Fax 0 0
Email 0 0
Trialsites@merck.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03765918