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)

Study Description

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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) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review (BICR).

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	780 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
Estimated Primary Completion Date :	April 16, 2021
Estimated Study Completion Date :	June 29, 2023

Arms and Interventions

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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.	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: Platinol®; Platinol®-AQ 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.	Drug: Placebo; Normal saline solution administered as an IV infusion Q3W Drug: Cisplatin; 100 mg/m^2 administered as an IV infusion Q3W; Other Names: Platinol®; Platinol®-AQ 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

Outcome Measures

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Primary Outcome Measures :

1. 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 per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) or death.

Secondary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: Up to 5 years ]
   OS is the time from randomization to death due to any cause.
2. 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
3. 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
4. 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)
5. 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)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.
• Has provided tissue for Programmed Cell Death Receptor Ligand 1 (PD-L1) biomarker analysis from a core or excisional biopsy
• 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

Contacts and Locations

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Contacts

Contact: Toll Free Number	1-888-577-8839	Trialsites@merck.com

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Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

Study Director:	Medical Director	Merck Sharp & Dohme Corp.

More Information

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Additional Information:

Merck Oncology Clinical Trial Information 

Responsible Party:	Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:	NCT03040999 History of Changes
Other Study ID Numbers:	3475-412; 2016-003934-25 ( EudraCT Number ); MK-3475-412 ( Other Identifier: Merck Registration Number ); 173640 ( Registry Identifier: JAPIC-CTI )
First Posted:	February 2, 2017
Last Update Posted:	April 20, 2018
Last Verified:	April 2018

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Merck Sharp & Dohme Corp.:

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

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms	Neoplasms, Squamous Cell; Neoplasms by Site; Pembrolizumab; Cisplatin; Antineoplastic Agents