Clinical Trials /

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)

NCT03765918

Description:

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 major pathological response and event-free survival compared to radiotherapy (with or without cisplatin) given after surgery alone.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 3475-689
  • SECONDARY ID: 2017-001139-38
  • SECONDARY ID: MK-3475-689
  • NCT ID: NCT03765918

Conditions

  • Head and Neck Neoplasms

Interventions

DrugSynonymsArms
Pembrolizumab 200 mgKEYTRUDA®, MK-3475Pembro Neoadjuvant+Pembro SOC Adjuvant
Cisplatin 100 mg/m^2Platinol®, Platinol-AQ®Pembro Neoadjuvant+Pembro SOC Adjuvant

Purpose

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 major pathological response and event-free survival compared to radiotherapy (with or without cisplatin) given after surgery alone.

Trial Arms

NameTypeDescriptionInterventions
Pembro Neoadjuvant+Pembro SOC AdjuvantExperimentalParticipants 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.
  • Pembrolizumab 200 mg
  • Cisplatin 100 mg/m^2
No Neoadjuvant+SOC AdjuvantActive ComparatorParticipants 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.
  • Cisplatin 100 mg/m^2

Eligibility 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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Major Pathological Response (mPR)
Time Frame:Up to 30 days post-sugery
Safety Issue:
Description:The proportion 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.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description:OS is the time from randomization to death due to any cause.
Measure:Pathological Complete Response (pCR)
Time Frame:Up to 30 days post-sugery
Safety Issue:
Description:Pathological complete response (pCR) is measured as the proportion 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.
Measure:Change From Baseline in Global Health Status/Quality of Life Scale (GHS/QoL)
Time Frame:Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)
Safety Issue:
Description:Change from baseline in the combined score of GHS/QoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 29 and 30
Measure:Change From Baseline in Global Health Status/Physical Functioning Scales
Time Frame:Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)
Safety Issue:
Description: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
Measure:Change from Baseline in Swallowing, Speech, and Pain Symptoms
Time Frame:Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)
Safety Issue:
Description: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
Measure:Percentage of Participants Experiencing An Adverse Event (AEs)
Time Frame:From time of first dose of study treatment until the end of follow-up (up to 5 years)
Safety Issue:
Description: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
Measure:Percentage of Participants Discontinuing Study Drug Due to AEs
Time Frame:From time of first dose of study treatment until the end of treatment (up to 12 months)
Safety Issue:
Description:Percentage of participants discontinuing study drug due to an AE

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • PD-1
  • PD1
  • Programmed Cell Death-1
  • Programmed Cell Death 1
  • Programmed Cell Death-Ligand 1 (PD-L1)
  • Programmed Cell Death-Ligand 2 (PD-L2)
  • PDL1
  • PDL2

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