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)

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ClinicalTrials.gov Identifier: NCT03040999

Recruitment Status : Recruiting

First Posted : February 2, 2017

Last Update Posted : August 17, 2018

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Sponsor:

Information provided by (Responsible Party):

Merck Sharp & Dohme Corp.

Study Description

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


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

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Head and neck squamous cell carcinoma

Drug Information available for: Cisplatin Pembrolizumab

U.S. FDA Resources

Arms and Interventions

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: 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. 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: 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

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:

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. 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:

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

Primary Outcome Measures :

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 :

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
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)
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

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
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. 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

Contacts and Locations

Information from the National Library of Medicine

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

Contacts


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

Show 145 Study Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators


Study Director:	Medical Director	Merck Sharp & Dohme Corp.

More Information

Additional Information:

Merck Oncology Clinical Trial Information This link exits the ClinicalTrials.gov site


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 Key Record Dates
Last Update Posted:	August 17, 2018
Last Verified:	August 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

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