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)
![]() |
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 evaluated by the U.S. Federal Government. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT03040999 |
Recruitment Status :
Active, not recruiting
First Posted : February 2, 2017
Last Update Posted : December 9, 2022
|
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Head and Neck Neoplasms | Biological: Pembrolizumab Drug: Placebo Drug: Cisplatin Radiation: Accelerated Fractionation (AFX) Radiotherapy Radiation: Standard Fractionation (SFX) Radiotherapy | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 804 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Treatment |
Official 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) |
Actual Study Start Date : | April 5, 2017 |
Actual Primary Completion Date : | May 31, 2022 |
Estimated Study Completion Date : | June 29, 2024 |

Arm | Intervention/treatment |
---|---|
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.
|
Biological: Pembrolizumab
Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
Other Name: KEYTRUDA® Drug: Cisplatin 100 mg/m^2 administered as an IV infusion Q3W
Other Names:
Radiation: Accelerated Fractionation (AFX) Radiotherapy 70 Gray (Gy) given in 35 fractions over 6 weeks Radiation: Standard Fractionation (SFX) Radiotherapy 70 Gy given in 35 fractions over 7 weeks |
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.
|
Drug: Placebo
Normal saline or dextrose solution administered as an IV infusion Q3W Drug: Cisplatin 100 mg/m^2 administered as an IV infusion Q3W
Other Names:
Radiation: Accelerated Fractionation (AFX) Radiotherapy 70 Gray (Gy) given in 35 fractions over 6 weeks Radiation: Standard Fractionation (SFX) Radiotherapy 70 Gy given in 35 fractions over 7 weeks |
- 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 disease progression or death.
- Overall Survival (OS) [ Time Frame: Up to 5 years ]OS is the time from randomization to death due to any cause.
- Adverse Events (AEs) [ Time Frame: From time of first dose of study treatment until the end of follow-up (up to 5 years) ]Number of participants experiencing any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy
- Treatment Discontinuations Due to AEs [ Time Frame: From time of first dose of study treatment until the end of treatment (up to 1 year) ]Number of participants discontinuing study drug due to an AE
- Change From Baseline in Global Health Status/Quality of Life (GHS/QoL) [ Time Frame: Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (up to 5 years) ]Change from baseline in GHS/QoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30)
- Change From Baseline in Swallowing, Speech, and Pain Symptoms [ Time Frame: Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (up to 5 years) ]Change from baseline in swallowing, speech, and pain symptoms using the EORTC Head and Neck Questionnaire (EORTC QLQ-H&N35)
- Change From Baseline in Physical Functioning [ Time Frame: Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (up to 5 years) ]Change From Baseline in Physical Functioning Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1- 5 Score

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03040999

Study Director: | Medical Director | Merck Sharp & Dohme LLC |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | Merck Sharp & Dohme LLC |
ClinicalTrials.gov Identifier: | NCT03040999 |
Other Study ID Numbers: |
3475-412 MK-3475-412 ( Other Identifier: Merck ) 173640 ( Registry Identifier: JAPIC-CTI ) KEYNOTE-412 ( Other Identifier: Merck ) 2016-003934-25 ( EudraCT Number ) |
First Posted: | February 2, 2017 Key Record Dates |
Last Update Posted: | December 9, 2022 |
Last Verified: | December 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf |
URL: | http://engagezone.msd.com/ds_documentation.php |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Head and Neck Squamous Cell Carcinoma Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1) Programmed Cell Death Receptor Ligand 2 (PD-L2) PD1 |
PD-1 PDL1 PD-L1 PDL2 |
Carcinoma Carcinoma, Squamous Cell Squamous Cell Carcinoma of Head and Neck Head and Neck Neoplasms Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms |
Neoplasms, Squamous Cell Neoplasms by Site Cisplatin Pembrolizumab Antineoplastic Agents Antineoplastic Agents, Immunological |