Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03040999




Registration number
NCT03040999
Ethics application status
Date submitted
1/02/2017
Date registered
2/02/2017
Date last updated
19/09/2024

Titles & IDs
Public title
Study of Pembrolizumab (MK-3475) or Placebo With Chemoradiation in Participants With Locally Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-412/KEYNOTE-412)
Scientific title
A Randomized Phase III Study of Pembrolizumab Given Concomitantly With Chemoradiation and as Maintenance Therapy Versus Chemoradiation Alone in Subjects With Locally Advanced Head and Neck Squamous Cell Carcinoma (KEYNOTE-412)
Secondary ID [1] 0 0
MK-3475-412
Secondary ID [2] 0 0
3475-412
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
Kidney
Cancer 0 0 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Other - Pembrolizumab
Treatment: Drugs - Placebo
Treatment: Drugs - Cisplatin
Treatment: Other - Accelerated Fractionation (AFX) Radiotherapy
Treatment: Other - Standard Fractionation (SFX) Radiotherapy

Experimental: Pembrolizumab + Cisplatin + CRT - Participants receive a priming dose of pembrolizumab before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of pembrolizumab and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of pembrolizumab alone as maintenance therapy for a total of 17 cycles of pembrolizumab. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with pembrolizumab.

Placebo comparator: Placebo + Cisplatin + CRT - Participants receive placebo before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of placebo and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of placebo alone for a total of 17 cycles of placebo. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with placebo.


Treatment: Other: Pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)

Treatment: Drugs: Placebo
Normal saline or dextrose solution administered as an IV infusion Q3W

Treatment: Drugs: Cisplatin
100 mg/m\^2 administered as an IV infusion Q3W

Treatment: Other: Accelerated Fractionation (AFX) Radiotherapy
70 Gray (Gy) given in 35 fractions over 6 weeks

Treatment: Other: Standard Fractionation (SFX) Radiotherapy
70 Gy given in 35 fractions over 7 weeks
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free Survival (EFS)
Timepoint [1] 0 0
Up to approximately 62 months
Secondary outcome [1] 0 0
Overall Survival (OS)
Timepoint [1] 0 0
Up to approximately 62 months
Secondary outcome [2] 0 0
Number of Participants With Adverse Events (AEs)
Timepoint [2] 0 0
From time of first dose of study treatment until 90 days after last dose (up to approximately 19 months)
Secondary outcome [3] 0 0
Number of Participants Discontinuing Study Drug Due to an AE
Timepoint [3] 0 0
From time of first dose of study treatment until the end of treatment (up to approximately 16 months)
Secondary outcome [4] 0 0
Change From Baseline in Global Health Status/Quality of Life (GHS/QoL)
Timepoint [4] 0 0
Prior to the first dose of study treatment (Baseline) and up to Week 45
Secondary outcome [5] 0 0
Change From Baseline in Swallowing, Speech, and Pain Symptoms
Timepoint [5] 0 0
Prior to the first dose of study treatment (Baseline) and up to Week 45
Secondary outcome [6] 0 0
Change From Baseline in Physical Functioning
Timepoint [6] 0 0
Prior to the first dose of study treatment (Baseline) and up to Week 45

Eligibility
Key inclusion criteria
* Has a pathologically proven new diagnosis of oropharyngeal p16 positive, oropharyngeal p16 negative, or larynx/hypopharynx/oral cavity (independent of p16) squamous cell carcinoma. Participants with oral cavity tumors need to have unresectable disease. Participants with multiple synchronous tumors are not eligible for the study.
* Has provided tissue for Programmed Cell Death Receptor Ligand 1 (PD-L1) biomarker analysis from a core or excisional biopsy. If an excisional or incisional biopsy has been performed, participants remain eligible for the study provided the residual disease meets the staging criteria required for the trial (e.g., excisional biopsy of a lymph node with residual T4 primary). Prior surgical debulking, including tonsillectomy, for the head and neck cancer under study is not allowed.
* Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan or magnetic resonance imaging, based on RECIST version 1.1
* Is eligible for definitive CRT and not considered for primary surgery based on investigator decision
* Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to receiving the first dose of study therapy
* Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study therapy
* 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Is currently participating or has participated in a study with an investigational agent or using an investigational device within 4 weeks of the first dose of study therapy
* Has received prior therapy with an anti-Programmed Cell Death Receptor 1 (PD-1), anti-PD-L1, anti-Programmed Cell Death Receptor Ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in clinical studies with pembrolizumab
* Has received a live vaccine within 30 days prior to the first dose of study therapy
* 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
* Has had prior systemic therapy, targeted therapy, radiotherapy treatment or radical surgery for head and neck cancer under study
* Has not recovered from major surgery prior to starting study therapy
* Has known active Hepatitis B or C
* Has known history of Human Immunodeficiency Virus (HIV)
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study therapy
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
* Has history of a diagnosed and/or treated hematologic or primary solid tumor malignancy, unless in remission for at least 5 years prior to randomization
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has had previous allogeneic tissue/solid organ transplant
* Has active infection requiring systemic therapy
* Has a history of severe hypersensitivity reaction to pembrolizumab, Cisplatin or radiotherapy or their analogs
* Is pregnant or breast feeding or expecting to conceive or father children throughout the study period and for up to 180 days after the last dose of study therapy

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
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/04/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/08/2024
Sample size
Target
Accrual to date
Final
804
Recruitment in Australia
Recruitment state(s)
NSW, (Australia)NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
Liverpool Hospital ( Site 0301) - Liverpool
Recruitment hospital [2] 0 0
Blacktown Hospital Western Sydney Local Health District ( Site 0304) - Blacktown
Recruitment hospital [3] 0 0
Princess Alexandra Hospital ( Site 0305) - Brisbane
Recruitment hospital [4] 0 0
Royal Brisbane and Women s Hospital ( Site 0302) - Herston
Recruitment hospital [5] 0 0
Royal Adelaide Hospital ( Site 0303) - Adelaide
Recruitment hospital [6] 0 0
Peter MacCallum Cancer Centre ( Site 0300) - Melbourne
Recruitment postcode(s) [1] 0 0
2170 - Liverpool
Recruitment postcode(s) [2] 0 0
2148 - Blacktown
Recruitment postcode(s) [3] 0 0
4102 - Brisbane
Recruitment postcode(s) [4] 0 0
4029 - Herston
Recruitment postcode(s) [5] 0 0
5000 - Adelaide
Recruitment postcode(s) [6] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Connecticut
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Indiana
Country [5] 0 0
United States of America
State/province [5] 0 0
Louisiana
Country [6] 0 0
United States of America
State/province [6] 0 0
Massachusetts
Country [7] 0 0
United States of America
State/province [7] 0 0
Michigan
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
Montana
Country [10] 0 0
United States of America
State/province [10] 0 0
Nevada
Country [11] 0 0
United States of America
State/province [11] 0 0
New York
Country [12] 0 0
United States of America
State/province [12] 0 0
Ohio
Country [13] 0 0
United States of America
State/province [13] 0 0
Oregon
Country [14] 0 0
United States of America
State/province [14] 0 0
Pennsylvania
Country [15] 0 0
United States of America
State/province [15] 0 0
South Carolina
Country [16] 0 0
United States of America
State/province [16] 0 0
Texas
Country [17] 0 0
United States of America
State/province [17] 0 0
Virginia
Country [18] 0 0
United States of America
State/province [18] 0 0
Washington
Country [19] 0 0
Austria
State/province [19] 0 0
Graz
Country [20] 0 0
Austria
State/province [20] 0 0
Linz
Country [21] 0 0
Austria
State/province [21] 0 0
Salzburg
Country [22] 0 0
Austria
State/province [22] 0 0
Vienna/Wien
Country [23] 0 0
Belgium
State/province [23] 0 0
Brussels
Country [24] 0 0
Belgium
State/province [24] 0 0
Gent
Country [25] 0 0
Belgium
State/province [25] 0 0
Leuven
Country [26] 0 0
Belgium
State/province [26] 0 0
Liege
Country [27] 0 0
Belgium
State/province [27] 0 0
Namur
Country [28] 0 0
Brazil
State/province [28] 0 0
Bahia
Country [29] 0 0
Brazil
State/province [29] 0 0
Ceara
Country [30] 0 0
Brazil
State/province [30] 0 0
Rio Grande Do Norte
Country [31] 0 0
Brazil
State/province [31] 0 0
Rio Grande Do Sul
Country [32] 0 0
Brazil
State/province [32] 0 0
RS
Country [33] 0 0
Brazil
State/province [33] 0 0
Sao Paulo
Country [34] 0 0
Brazil
State/province [34] 0 0
SP
Country [35] 0 0
Brazil
State/province [35] 0 0
Ribeirao Preto
Country [36] 0 0
Brazil
State/province [36] 0 0
Rio de Janeiro
Country [37] 0 0
Canada
State/province [37] 0 0
Alberta
Country [38] 0 0
Canada
State/province [38] 0 0
Ontario
Country [39] 0 0
Canada
State/province [39] 0 0
Quebec
Country [40] 0 0
Colombia
State/province [40] 0 0
Antioquia
Country [41] 0 0
Colombia
State/province [41] 0 0
Valle Del Cauca
Country [42] 0 0
Colombia
State/province [42] 0 0
Bogota
Country [43] 0 0
Czechia
State/province [43] 0 0
Brno
Country [44] 0 0
Czechia
State/province [44] 0 0
Hradec Kralove
Country [45] 0 0
Czechia
State/province [45] 0 0
Olomouc
Country [46] 0 0
Czechia
State/province [46] 0 0
Ostrava
Country [47] 0 0
Czechia
State/province [47] 0 0
Praha 8
Country [48] 0 0
Czechia
State/province [48] 0 0
Praha
Country [49] 0 0
France
State/province [49] 0 0
Le Mans
Country [50] 0 0
France
State/province [50] 0 0
Limoges
Country [51] 0 0
France
State/province [51] 0 0
Toulouse Cedex 09
Country [52] 0 0
France
State/province [52] 0 0
Vandoeuvre les Nancy
Country [53] 0 0
France
State/province [53] 0 0
Villejuif
Country [54] 0 0
Germany
State/province [54] 0 0
Erlangen
Country [55] 0 0
Germany
State/province [55] 0 0
Gera
Country [56] 0 0
Germany
State/province [56] 0 0
Hamburg
Country [57] 0 0
Germany
State/province [57] 0 0
Hannover
Country [58] 0 0
Germany
State/province [58] 0 0
Luebeck
Country [59] 0 0
Germany
State/province [59] 0 0
Munchen
Country [60] 0 0
Germany
State/province [60] 0 0
Ulm
Country [61] 0 0
Israel
State/province [61] 0 0
Haifa
Country [62] 0 0
Israel
State/province [62] 0 0
Jerusalem
Country [63] 0 0
Israel
State/province [63] 0 0
Petah Tikva
Country [64] 0 0
Israel
State/province [64] 0 0
Ramat Gan
Country [65] 0 0
Israel
State/province [65] 0 0
Tel Aviv
Country [66] 0 0
Italy
State/province [66] 0 0
MO
Country [67] 0 0
Italy
State/province [67] 0 0
Firenze
Country [68] 0 0
Italy
State/province [68] 0 0
Milano
Country [69] 0 0
Italy
State/province [69] 0 0
Napoli
Country [70] 0 0
Italy
State/province [70] 0 0
Padova
Country [71] 0 0
Italy
State/province [71] 0 0
Pavia
Country [72] 0 0
Japan
State/province [72] 0 0
Chiba
Country [73] 0 0
Japan
State/province [73] 0 0
Hokkaido
Country [74] 0 0
Japan
State/province [74] 0 0
Hyogo
Country [75] 0 0
Japan
State/province [75] 0 0
Kagawa
Country [76] 0 0
Japan
State/province [76] 0 0
Miyagi
Country [77] 0 0
Japan
State/province [77] 0 0
Hiroshima
Country [78] 0 0
Japan
State/province [78] 0 0
Osaka
Country [79] 0 0
Japan
State/province [79] 0 0
Tokyo
Country [80] 0 0
Korea, Republic of
State/province [80] 0 0
Chungcheongbuk Do
Country [81] 0 0
Korea, Republic of
State/province [81] 0 0
Gyeonggi-do
Country [82] 0 0
Korea, Republic of
State/province [82] 0 0
Daejeon
Country [83] 0 0
Korea, Republic of
State/province [83] 0 0
Seoul
Country [84] 0 0
Netherlands
State/province [84] 0 0
Alkmaar
Country [85] 0 0
Netherlands
State/province [85] 0 0
Amsterdam
Country [86] 0 0
Netherlands
State/province [86] 0 0
Groningen
Country [87] 0 0
Netherlands
State/province [87] 0 0
Nijmegen
Country [88] 0 0
Netherlands
State/province [88] 0 0
Rotterdam
Country [89] 0 0
New Zealand
State/province [89] 0 0
Newtown
Country [90] 0 0
Poland
State/province [90] 0 0
Dolnoslaskie
Country [91] 0 0
Poland
State/province [91] 0 0
Mazowieckie
Country [92] 0 0
Poland
State/province [92] 0 0
Bielsko-Biala
Country [93] 0 0
Poland
State/province [93] 0 0
Gdynia
Country [94] 0 0
Poland
State/province [94] 0 0
Gliwice
Country [95] 0 0
Poland
State/province [95] 0 0
Krakow
Country [96] 0 0
Poland
State/province [96] 0 0
Szczecin
Country [97] 0 0
Poland
State/province [97] 0 0
Warszawa
Country [98] 0 0
Spain
State/province [98] 0 0
Barcelona
Country [99] 0 0
Spain
State/province [99] 0 0
Hospitalet de Llobregat
Country [100] 0 0
Spain
State/province [100] 0 0
Madrid
Country [101] 0 0
Spain
State/province [101] 0 0
Malaga
Country [102] 0 0
Spain
State/province [102] 0 0
Valencia
Country [103] 0 0
Taiwan
State/province [103] 0 0
Kaohsiung
Country [104] 0 0
Taiwan
State/province [104] 0 0
Taichung
Country [105] 0 0
Taiwan
State/province [105] 0 0
Tainan
Country [106] 0 0
Taiwan
State/province [106] 0 0
Taipei
Country [107] 0 0
Taiwan
State/province [107] 0 0
Taoyuan
Country [108] 0 0
Turkey
State/province [108] 0 0
Adana
Country [109] 0 0
Turkey
State/province [109] 0 0
Ankara
Country [110] 0 0
Turkey
State/province [110] 0 0
Istanbul
Country [111] 0 0
Turkey
State/province [111] 0 0
Izmir
Country [112] 0 0
Turkey
State/province [112] 0 0
Kocaeli
Country [113] 0 0
Turkey
State/province [113] 0 0
Malatya
Country [114] 0 0
United Kingdom
State/province [114] 0 0
Norfolk
Country [115] 0 0
United Kingdom
State/province [115] 0 0
Staffordshire
Country [116] 0 0
United Kingdom
State/province [116] 0 0
Suffolk
Country [117] 0 0
United Kingdom
State/province [117] 0 0
London
Country [118] 0 0
United Kingdom
State/province [118] 0 0
Preston
Country [119] 0 0
United Kingdom
State/province [119] 0 0
Southampton
Country [120] 0 0
United Kingdom
State/province [120] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to determine the efficacy and safety of pembrolizumab given concomitantly with chemoradiation (CRT) and as maintenance therapy versus placebo plus CRT in participants with locally advanced head and neck squamous cell carcinoma (LA HNSCC). The primary hypothesis is that pembrolizumab in combination with CRT is superior to placebo in combination with CRT with respect to event-free survival (EFS).
Trial website
https://clinicaltrials.gov/study/NCT03040999
Trial related presentations / publications
Machiels JP, Tao Y, Burtness B, Tahara M, Licitra L, Rischin D, Waldron J, Simon C, Gregoire V, Harrington K, Alves GV, Figueiredo Lima IP, Pointreau Y, M Hughes BG, Aksoy S, Hetnal M, Ge JY, Brown H, Cheng J, Bidadi B, Siu LL. Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Future Oncol. 2020 Jun;16(18):1235-1243. doi: 10.2217/fon-2020-0184. Epub 2020 Jun 3.
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03040999