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)

• ClinicalTrials.gov Identifier: NCT03040999
• Recruitment Status: Active, not recruiting
• First Posted: February 2, 2017
• Last Update Posted: February 27, 2020
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Tracking Information

• First Submitted Date: February 1, 2017
• First Posted Date: February 2, 2017
• Last Update Posted Date: February 27, 2020
• Actual Study Start Date: April 5, 2017
• Estimated Primary Completion Date: April 16, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 15, 2019)

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.

• Original Primary Outcome Measures (submitted: February 1, 2017): EFS per RECIST Version 1.1 by BICR [ Time Frame: Up to 5 years ]

Current Secondary Outcome Measures (submitted: October 15, 2019)

• 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

Original Secondary Outcome Measures (submitted: February 1, 2017)

• Overall Survival (OS) [ Time Frame: Up to 5 years ]
• Number of Participants with 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 Discontinuing Study Treatment Due to AEs [ Time Frame: From time of first dose of study treatment until the end of treatment (up to 1 year) ]
• Change From Baseline in Global Health Status/Quality of Life (GHS/QoL) Using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) [ 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) [ Time Frame: Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (up to 5 years) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief 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)
• 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)
• 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Head and Neck Neoplasms

Intervention

• Biological: Pembrolizumab
  Administered as an intravenous (IV) infusion every 3 weeks (Q3W)
  Other Name: KEYTRUDA®
• 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

Study Arms

• 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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Cisplatin
  • Radiation: Accelerated Fractionation (AFX) Radiotherapy
  • Radiation: Standard Fractionation (SFX) Radiotherapy
• 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.
  Interventions:

  • Drug: Placebo
  • Drug: Cisplatin
  • Radiation: Accelerated Fractionation (AFX) Radiotherapy
  • Radiation: Standard Fractionation (SFX) Radiotherapy

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: February 1, 2017): 780
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 29, 2023
• Estimated Primary Completion Date: April 16, 2021 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Brazil, Canada, Colombia, Czechia, France, Germany, Israel, Italy, Japan, Korea, Republic of, Netherlands, New Zealand, Poland, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Argentina, Chile, Czech Republic, Hungary, Mexico, Puerto Rico, Ukraine

Administrative Information

• NCT Number: NCT03040999
• Other Study ID Numbers: 3475-412; 2016-003934-25 ( EudraCT Number ); MK-3475-412 ( Other Identifier: Merck ); 173640 ( Registry Identifier: JAPIC-CTI ); KEYNOTE-412 ( Other Identifier: Merck )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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

• Responsible Party: Merck Sharp & Dohme Corp.
• Study Sponsor: Merck Sharp & Dohme Corp.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

• PRS Account: Merck Sharp & Dohme Corp.
• Verification Date: February 2020