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 Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Head and Neck Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Placebo
* Drug: Cisplatin
* Radiation: Accelerated Fractionation (AFX) Radiotherapy
* Radiation: Standard Fractionation (SFX) Radiotherapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Cisplatin + CRT<br>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<br>* Administered as an intravenous (IV) infusion every 3 weeks (Q3W)<br>* Other names: KEYTRUDA®;Drug: Cisplatin<br>* 100 mg/m^2 administered as an IV infusion Q3W<br>* Other names: Platinol®-AQ;Radiation: Accelerated Fractionation (AFX) Radiotherapy<br>* 70 Gray (Gy) given in 35 fractions over 6 weeks<br>Radiation: Standard Fractionation (SFX) Radiotherapy<br>* 70 Gy given in 35 fractions over 7 weeks<br>|
| Placebo Comparator: Placebo + Cisplatin + CRT<br>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<br>* Normal saline or dextrose solution administered as an IV infusion Q3W<br>Drug: Cisplatin<br>* 100 mg/m^2 administered as an IV infusion Q3W<br>* Other names: Platinol®-AQ;Radiation: Accelerated Fractionation (AFX) Radiotherapy<br>* 70 Gray (Gy) given in 35 fractions over 6 weeks<br>Radiation: Standard Fractionation (SFX) Radiotherapy<br>* 70 Gy given in 35 fractions over 7 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS is the time from date of randomization to the date of first record of any of the following events: death due to any cause; progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR) or biopsy as indicated for locoregional progression or recurrence or distant metastasis. As well as the first record of the following types of surgery: salvage surgery for persistent or residual disease at the primary tumor site requiring surgical removal when invasive cancer is present on final pathology; neck dissection or surgery (performed for clinical or radiological disease progression per RECIST 1.1) ≤ 20 weeks from end of CRT when invasive cancer is present; or neck dissection or surgery >20 weeks from end of CRT when invasive cancer is present. From product-limit (Kaplan-Meier) method for censored data. | Up to approximately 62 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is the time from randomization to death due to any cause, from product-limit (Kaplan-Meier) method for censored data. The hypothesis was that pembrolizumab in combination with CRT is superior to placebo in combination with CRT; but based on the protocol, because the statistical criterion for success in the primary EFS hypothesis was not met, the OS hypothesis was not tested | Up to approximately 62 months | 
| Number of Participants With Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. An AE is any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. | From time of first dose of study treatment until 90 days after last dose (up to approximately 19 months) | 
| Number of Participants Discontinuing Study Drug Due to an AE | An AE is any untoward medical occurrence in a participant administered study drug and which does not necessarily have to have a causal relationship with the study drug. An AE is any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy. | From time of first dose of study treatment until the end of treatment (up to approximately 16 months) | 
| Change From Baseline in Global Health Status/Quality of Life (GHS/QoL) | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) contains 30 items and measures five functional dimensions (physical, role, emotional, cognitive and social), three symptom items (fatigue, nausea/vomiting, and pain), six single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale. Using linear transformation, raw scores are standardized, so that scores range from 0 to 100, so that a higher score indicates a better overall GHS. A change from baseline of 10 points on the 100-point EORTC QLQ-C30 scale is considered as clinically relevant. Based on a constrained longitudinal data analysis (cLDA) model with the patient reported outcomes (PRO) scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of human papilloma virus (HPV) status and overall cancer stage. | Prior to the first dose of study treatment (Baseline) and up to Week 45 | 
| Change From Baseline in Swallowing, Speech, and Pain Symptoms | EORTC QLQ Head and Neck Questionnaire (H&N35) consists of 7 multi-item scales (pain in the mouth, problems with swallowing, senses, speech, social eating, social contact, and sexuality), Raw scores were standardized by linear transformation so that scores ranged from 0 to 100, with a higher score indicating more problems. Change from baseline in swallowing, speech, and pain symptoms was measured. A change from baseline of 10 points on the 100-point EORTC QLQ-H&N35 is considered as clinically relevant. Based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage. | Prior to the first dose of study treatment (Baseline) and up to Week 45 | 
| Change From Baseline in Physical Functioning | Participant responded to 5 questions from the EORTC QLQ-C30 about their physical functioning scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores were standardized, so that scores range from 0 to 100, where a higher score indicates a better quality of life. A change from baseline of 10 points on the 100-point scale is considered as clinically relevant. Based on a cLDA model with the PRO scores as the response variable with covariates for treatment, time, treatment by time interaction, and stratification factors of HPV status and overall cancer stage. | Prior to the first dose of study treatment (Baseline) and up to Week 45 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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