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)
- Trial ID
- 2022-500254-41-00
- Protocol
- MK-3475-689
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **pembrolizumab** as neoadjuvant therapy and in combination with radiotherapy (RT) ± cisplatin as adjuvant therapy to only RT ± cisplatin as adjuvant therapy with respect to event-free survival (EFS), as assessed by blinded independent central review (BICR), in participants with Stage III-IVA resectable locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC) whose tumors express PD-L1 CPS≥10, CPS≥1, and in all participants, regardless of CPS status. This objective is clinically relevant as it aims to determine the efficacy of pembrolizumab in improving EFS, which is a critical endpoint in cancer treatment, potentially leading to better long-term outcomes for patients.
Secondary objectives include:
- Comparing pembrolizumab neoadjuvant therapy to no neoadjuvant therapy regarding the rate of major pathological response (mPR) at the time of definitive surgery.
- Comparing pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy to only RT ± cisplatin as adjuvant therapy with respect to overall survival (OS).
- Evaluating the rate of pathological complete response (pCR) at the time of definitive surgery.
- Assessing global health status/quality of life (QoL) and physical functioning scores using the EORTC QoL questionnaire (QLQ)-C30, and swallowing, speech, and pain symptoms using the EORTC Head and Neck–Specific QoL questionnaire (EORTC QLQ-H&N35).
- Determining the safety and tolerability of pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy.
Participants
The clinical trial involves a total of **472 participants** diagnosed with **Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having a histologically confirmed new diagnosis of resectable, non-metastatic squamous cell carcinoma, and being eligible for primary surgery. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, ensuring that participants are in relatively good health. Both genders are required to adhere to contraception guidelines, and male participants must refrain from donating sperm during and after the study period. The trial population is diverse, including vulnerable populations, and considers lifestyle factors such as reproductive health and tumor burden assessment through imaging techniques. The selection process ensures that participants have provided newly obtained biopsy samples and have undergone local testing for HPV status in cases of oropharyngeal cancer.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy of **pembrolizumab** as a neoadjuvant therapy and in combination with standard care as adjuvant therapy for patients with Stage III-IVA resectable locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC). The trial aims to compare the event-free survival (EFS) of participants receiving pembrolizumab in combination with radiotherapy (RT) ± **cisplatin** against those receiving only RT ± cisplatin. The study is expected to run from December 17, 2018, to July 30, 2026, with the primary endpoint being EFS, assessed by blinded independent central review (BICR) per RECIST 1.1 criteria.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis, tumor burden assessment, and HPV status. Following randomization, participants will receive treatment according to their assigned group. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, with assessments to evaluate the primary and secondary endpoints, including major pathological response (mPR), overall survival (OS), and quality of life changes.
The expected duration of participant involvement is up to 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must adhere to study protocols, including the use of adequate contraception and refraining from sperm donation, to remain eligible throughout the study. The trial's methodology ensures rigorous assessment of pembrolizumab's efficacy and safety in the specified patient population, contributing valuable data to the field of oncology.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, as an experimental medication. KEYTRUDA is provided as a 25 mg/mL **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via **intravenous infusion**. The maximum daily dose of pembrolizumab is 200 mg, with a total maximum dose of 3400 mg over a treatment period of up to 12 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified as a monoclonal antibody, and is utilized in this study as a neoadjuvant therapy and in combination with standard-of-care therapies for the treatment of locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC).
In addition to pembrolizumab, the study includes the administration of **cisplatin** as a non-experimental treatment. Cisplatin is provided in the form of a **solution for injection/infusion** and is also administered via intravenous infusion. The dosing regimen for cisplatin is based on body surface area, with a maximum daily dose of 100 mg/m² and a total maximum dose of 300 mg/m² over a treatment period of up to 7 days. Cisplatin is a chemical-based therapeutic agent and is used in combination with radiotherapy as part of the standard-of-care adjuvant therapy in this clinical trial.
Participant compliance with the dosing schedules for both pembrolizumab and cisplatin will be monitored throughout the study. The trial aims to evaluate the efficacy of pembrolizumab as a neoadjuvant therapy and in combination with standard-of-care therapies, compared to standard-of-care therapies alone, in terms of event-free survival in participants with LA HNSCC.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-free Survival (EFS)**, which will be evaluated according to RECIST 1.1 criteria and assessed by a blinded independent central review (BICR). This assessment will focus on participants with tumors expressing PD-L1 CPS≥10, CPS≥1, and all participants regardless of CPS status. Secondary endpoints include Major Pathological Response (mPR), Overall Survival (OS), Pathological Complete Response (pCR), and changes from baseline in Global Health Status/Quality of Life Scale (GHS/QoL), as well as changes in physical functioning scales and symptoms such as swallowing, speech, and pain. Additionally, the percentage of participants experiencing adverse events (AEs) and those discontinuing the study drug due to AEs will be monitored.
Inclusion and Exclusion Criteria
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 (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay.
- 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 locoregionally advanced head and neck squamous cell carcinoma (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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 17 Dec 2018 | 31 |
 Belgium | Not Recruiting | 17 Dec 2018 | 8 |
 France | Not Recruiting | 17 Dec 2018 | 15 |
 Germany | Not Recruiting | 17 Dec 2018 | 73 |
 Hungary | Not Recruiting | 17 Dec 2018 | 12 |
 Ireland | Not Recruiting | 17 Dec 2018 | 5 |
 Poland | Not Recruiting | 17 Dec 2018 | 29 |
 Portugal | Not Recruiting | 17 Dec 2018 | 20 |
 Spain | Not Recruiting | 17 Dec 2018 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 12 | PRD4323105 |
CISPLATIN | Test | — | INTRAVENOUS INFUSION | 100 | 7 | SUB07483MIG |