Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC) MedDRA version: 20.0 Level: PT Classification code 10060121 Term: Squamous cell carcinoma of head and neck System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration uni
Sponsors
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Participants are eligible to be included in the study only if all of the following criteria apply: 1. Have histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma as assessed by the investigator based on baseline imaging and clinical assessment that is either: a. Stage III oropharyngeal p16 positive that is T4 (N0-N2), M0 OR b. Stage III or IVA oropharyngeal p16 negative OR c. Stage III or IVA larynx/hypopharynx/oral cavity (independent of p16). 2. Be eligible for primary surgery based on investigator decision and per local practice. 3. Male/female participants who are at least 18 years of age on the day of signing informed consent 4. A male participant must agree to use a contraception during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period. 5. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) OR b.) A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment. 6. The participant (or legally acceptable representative if applicable) provides written informed consent for the study. The participant may also provide consent for Future Biomedical Research. However the participant may participate in the main study without participating in Future Biomedical Research. 7. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator/radiology. 8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate). Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 9. Have results from (local) testing of HPV status for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using ‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and standard protocol. Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 70% or more of the tumor cells. If HPV status was previously tested using this method, no additional testing is required. 10. Have an ECOG performance status of 0 to 1 performed within 10 days of treatment initiation. 11. Have adequate organ function, as defined. Specimens must be collected within 10 days prior to the start of study treatment. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 300 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 300
Exclusion criteria
Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: 1. Has Stage T4B and/or N3 LA HNSCC and/or distant metastases. 2. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC. 3. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or within 24 hours prior to the start of RT ± cisplatin. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. 4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 5. Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to randomization/allocation. 6. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 7. 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 the first dose of study treatment. 8. 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 the first dose of study drug. 9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. 10. Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator and radiology review. 11. Has Grade =2 audiometric hearing loss. 12. Has Grade =2 neuropathy. 13. Has Grade 3-4 bleeding due to the underlying malignancy. 14. If participant has received major surgery, and the participant has not recovered adequately from the toxicity and/or complications from the intervention prior to randomization. 15. Has had previous allogeneic tissue/solid organ transplant. 16. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients, RT or cisplatin or their analogs. 17. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 18. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 19. Has an active infection requiring systemic therapy. 20. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority. 21. Has a known history of or is positive for Hepati
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To compare the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery between participants who receive neoadjuvant therapy with pembrolizumab and participants who do not. 2. To compare the event-free survival (EFS) as assessed by blinded independent central review (BICR) between participants who receive pembrolizumab neoadjuvant therapy and pembrolizumab with radiotherapy (RT) ± cisplatin as adjuvant therapy and participants who receive only RT ± cisplatin as adjuvant therapy.;Secondary Objective: 1. To compare overall survival (OS) between participants who receive pembrolizumab neoadjuvant therapy and pembrolizumab with RT ± cisplatin as adjuvant therapy and participants who receive only RT ± cisplatin as adjuvant therapy. 2. To evaluate the rate of pathological complete response (pCR) as assessed by the central pathologist at the time of definitive surgery. 3. To evaluate global health status/quality of life (QoL) scores using the European Organisation for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, and swallowing, speech and pain symptoms using the EORTC Head and Neck–Specific QoL questionnaire (EORTC QLQH&N35). 4. To determine the safety and tolerability of pembrolizumab as neoadjuvant therapy and in combination with RT ± cisplatin as adjuvant therapy.;Primary end point(s): 1. Major pathological response - defined as participant with =10% viable tumor in resected tumor tissue. 2. Event-free survival (EFS) - defined as the time from the date of randomization to the date of first record of any of the following events: radiographic disease progression per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by BICR, local or distant recurrence (for participants who are disease free after surgery); death due to any cause.;Timepoint(s) of evaluation of this end point: 27 months and 36 months | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall survival - defined as time from randomization to death due to any cause. 2. Pathological complete response - defined as participant having no viable tumor tissue within entirely submitted and evaluated gross lesions. 3. Change from baseline in the QoL and symptom scores from the global health status/QoL scales (items 29 and 30) of the EORTC QLQ-C30, and the swallowing multi-item scale (items 35-38), speech multi-item scale (items 46, 53-54), and pain multi-item scale (items 31-34) of the EORTC QLQ-H&N35. 4. Participant experiencing adverse events (AEs) 5. Participant discontinuing study drug due to AEs;Timepoint(s) of evaluation of this end point: 27, 36 and 48 months | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, France, Germany, Hungary, Ireland, Israel, Korea, Republic of, Poland, Portugal, Russian Federation, Spain, Taiwan, Ukraine, United Kingdom, United States
Outcome results
None listed