Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689)

Study Overview
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Brief Summary
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This is a randomized, active-controlled, open-label study of pembrolizumab (Pembro) given prior to surgery and pembrolizumab in combination with standard of care radiotherapy (with or without cisplatin), as post-surgical therapy in treatment naïve participants with newly diagnosed Stage III/IVA, resectable, locoregionally advanced, head and neck squamous cell carcinoma (LA-HNSCC). Efficacy outcomes will be stratified by programmed cell death ligand 1 (PD-L1) combined positive score (CPS) status. The primary hypothesis is that pembrolizumab given before surgery and after surgery in combination with radiotherapy (with or without cisplatin) improves event-free survival compared to radiotherapy (with or without cisplatin) given after surgery alone.

Official Title
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A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

Conditions
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Head and Neck Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab 200 mg
* Radiation: Radiotherapy 60 Gray/day
* Radiation: Radiotherapy 66 Gray/day
* Radiation: Radiotherapy 70 Gray/day
* Drug: Cisplatin 100 mg/m^2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries. Is eligible for primary surgery based on investigator decision and per local practice 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. Male participants must refrain from donating sperm throughout the study period and for up to 180 days after the last dose of study therapy Female participant that is not pregnant or breastfeeding Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST version 1.1 Has provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated Has results from testing of HPV status for oropharyngeal cancer defined as p16 Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of randomization Exclusion Criteria: Has Stage T4B and/or N3 LA HNSCC and/or distant metastases 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 (HNC) Female participant who has a positive urine pregnancy test within 72 hours prior to study start or within 24 hours prior to the start of radiotherapy with or without cisplatin. Has received prior therapy with an anti-programmed cell death receptor 1(PD-1), anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to study start Has received a live vaccine within 30 days prior to randomization Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis Has Grade ≥2 audiometric hearing loss Has Grade ≥2 neuropathy Has Grade 3-4 bleeding due to the underlying malignancy Has received major surgery or has not recovered adequately from the toxicity and/or complications from the intervention prior to study start Has had previous allogeneic tissue/solid organ transplant Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, radiotherapy, cisplatin or their analogs Has an active autoimmune disease that has required systemic treatment in past 2 years Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] ribonucleic acid is detected). Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembro Neoadjuvant+Pembro SOC Adjuvant<br>Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of a 21-day cycle for 2 cycles as a neoadjuvant prior to surgery. Following surgical resection, high risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 every 3 weeks (Q3W) for fifteen 21-day cycles plus standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 Q3W for fifteen 21-day cycles plus standard of care radiotherapy as adjuvant therapy. | Biological: Pembrolizumab 200 mg<br>* 200 mg administered by intravenous (IV) infusion on Day 1 of each 21-day cycle<br>* Other names: MK-3475;Radiation: Radiotherapy 60 Gray/day<br>* Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy.<br>Radiation: Radiotherapy 66 Gray/day<br>* High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy.<br>Radiation: Radiotherapy 70 Gray/day<br>* Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy.<br>Drug: Cisplatin 100 mg/m^2<br>* 100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle<br>* Other names: Platinol-AQ®;|
| Active Comparator: No Neoadjuvant+SOC Adjuvant<br>Participants receive no neoadjuvant prior to surgery. Following surgical resection, high risk participants receive standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive standard of care radiotherapy as adjuvant therapy. | Radiation: Radiotherapy 60 Gray/day<br>* Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy.<br>Radiation: Radiotherapy 66 Gray/day<br>* High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy.<br>Radiation: Radiotherapy 70 Gray/day<br>* Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy.<br>Drug: Cisplatin 100 mg/m^2<br>* 100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle<br>* Other names: Platinol-AQ®;|

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 the date of randomization to the date of first record of any of the following events: radiographic disease progression; local or distant progression or recurrence as assessed with imaging or biopsy as indicated; or death due to any cause. Radiographic disease progression during neoadjuvant phase that precludes surgery will be considered an event; a secondary malignancy will not be considered an event. | Up to  80 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response (mPR) | The percentage of participants with a major pathological response (mPR) as assessed by the Central Pathologist at the time of definitive surgery. mPR is defined as ≤10% invasive squamous cell carcinoma within the resected primary tumor specimen and all the sampled regional lymph nodes. | Up to  64 months | 
| Overall Survival (OS) | OS is the time from randomization to death due to any cause. | Up to  92 months | 
| Pathological Complete Response (pCR) | Pathological complete response (pCR) is measured as the percentage of participants with a pathological complete response as assessed by the central pathologist at the time of definitive surgery. pCR is defined as having no residual invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes. | Up to  64 months | 
| Change From Baseline in Global Health Status/Quality of Life Scale (GHS/QoL) | Change from baseline in the combined score of global health status (GHS)/quality of life (QoL) using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 29 and 30. Participant responses to questions regarding overall health/QoL will be scored on a 7-point scale (1=Very poor to 7=Excellent) with a higher score indicating better overall health status. | Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to  92 months) | 
| Change From Baseline in Global Health Status/Physical Functioning Scales | Change from baseline in the combined score of physical functioning scale using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 1 through 5. Participant responses to questions regarding their physical functioning will be scored on a 4-point scale (1=Not at All to 4=Very Much) with a higher score indicating worse physical functioning. | Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to  92 months) | 
| Change from Baseline in Swallowing, Speech, and Pain Symptoms | Change from baseline in the combined score of swallowing, speech, and pain symptoms using the European Organization for Research and Treatment of Cancer Head and Neck Questionnaire (EORTC QLQ-H&N35) items 31-38, 46, and 53-54. Participant responses to questions regarding problems with swallowing, speech and pain in the mouth will be scored on a 4-point scale (1=Not at all to 4=Very much) with a higher score indicating more problems. | Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to  92 months) | 
| Percentage of Participants Experiencing An Adverse Event (AEs) | Percentage of participants experiencing 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 follow-up (up to  92 months) | 
| Percentage of Participants Discontinuing Study Drug Due to AEs | Percentage of participants discontinuing study drug due to an AE | From time of first dose of study treatment until the end of treatment (up to 12 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)