Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC) MedDRA version: 21.0 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. This decision must be validated by members of a multidisciplinary team, including the surgical oncologist, medical oncologist and radiation oncologist 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 newly obtained core or excisional biopsy of a tumor lesion not previously irradiated for central PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate [FNA] is not adequate) for stratification prior to randomization. Repeat samples may be required if adequate tissue is not provided. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. 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 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 randomization. 11. Have adequate organ function. Specimens must be collected within 10 days prior to randomization. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 352 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 352
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 3 days 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 randomization. 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® [Influenza Vaccine Live, AstraZeneca]) 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 randomization. 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 to randomization. 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 Hepatitis B (defined as hepatitis B su
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1: To compare pembrolizumab neoadjuvant therapy to no neoadjuvant therapy with respect to the rate of major pathological response (mPR) as assessed by the central pathologist at the time of definitive surgery in participants whose tumors express PD-L1 CPS=1 and in all participants regardless of CPS status. 2: 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 EFS per RECIST 1.1 as assessed by BICR in participants whose tumors express PD-L1 CPS=1 and in all participants regardless of CPS status.;Timepoint(s) of evaluation of this end point: 44 months and 60 months;Secondary Objective: 1: 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 OS in participants whose tumors express PD-L1 CPS=1 and in all participants regardless of CPS status. 2: To evaluate the rate of pCR as assessed by the central pathologist at the time of definitive surgery in participants whose tumors express PDL1 CPS=1 and in all participants regardless of CPS status. 3: To evaluate 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 QLQH& N35) in participants whose tumors express PD-L1 CPS=1 and in all participants regardless of CPS status. 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 having less than or equal to 10% invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes 2. Event-free survival (EFS) - time from the date of randomizatio | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall survival - defined as time from the date of randomization to the date of death due to any cause. 2. Pathological complete response - defined as having no residual invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes 3.EORTC QLQ C30- global health status/QoL scales and physical functioning scales; EORTC QLQ-H&N35 swallowing multi-item scale, speech multi-item scale, and pain multi-item scale 4. Adverse events (AEs) 5. Study drug discontinuations due to AEs;Timepoint(s) of evaluation of this end point: 44, 60 and 76 months | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Colombia, France, Germany, Hungary, Israel, Korea, Republic of, Poland, Portugal, Russian Federation, Spain, Taiwan, Ukraine, United Kingdom, United States
Contacts
Public ContactGlobal Clinical Trial Operations
Merck Sharp & Dohme (UK) Ltd.
Outcome results
None listed