Immunotherapy With MK-3475 in Surgically Resectable Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The goal of this trial is to test the ability of MK-3475 (pembrolizumab) to improve locoregional recurrence and distant metastatic rates in high-risk patients with locally advanced head and neck squamous cell carcinomas (HNSCCs) that are treated with current standard of care surgical approaches.

Official Title
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Immunotherapy With MK-3475 in Locoregionally Advanced, Surgically Resectable Head and Neck Squamous Cell Carcinoma

Conditions
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Cancer of Head and Neck, Head and Neck Cancer, Neoplasms, Head and Neck, Carcinoma, Squamous Cell of Head and Neck, Squamous Cell Carcinoma of the Head and Neck, Squamous Cell Carcinoma, Head and Neck

Intervention / Treatment
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* Biological: MK-3475 (neoadjuvant)
* Procedure: Surgery
* Radiation: Intensity modulated radiation therapy
* Radiation: Image-guided radiation therapy
* Drug: Cisplatin
* Biological: MK-3475 (adjuvant)
* Procedure: Peripheral blood


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed stage III or IV HNSCC oral cavity, hypopharynx, oropharynx, larynx (excluding p16 or HPV-positive oropharynx primaries and sinonasal primaries). Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam by RECIST 1.1. At least 18 years of age. ECOG performance status ≤ 1 Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 x IULN OR Direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver metastases) Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 30 mL/min/1.73 m2 for patients with creatinine levels > 1.5 x IULN INR ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants Sexually active women of childbearing potential and men must agree to use 2 methods of contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 120 days after last dose of MK-3475. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Prior treatment for head and neck cancer. Patients with HPV-positive or p16-positive oropharyngeal SCCA. Patients with sinonasal SCCAs Patients with metastatic SCCA neck disease with an unknown primary tumor site Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Received a live vaccine within 30 days prior to the first dose of MK-3475. 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 (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated viruses and are not allowed. A history of other malignancy ≤ 3 years previous with the exception of previous head and neck cancer treated only by surgery, basal cell or squamous cell carcinoma of the skin which were treated with local resection only, or carcinoma in situ of the cervix. Note: patients with synchronous head and neck cancer primaries are an exception to this criterion and may qualify for the study. 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 the first dose of MK-3475. Currently receiving any other investigational agents or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of MK-3475. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, immunosuppression, autoimmune conditions, underlying pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Pregnant and/or breastfeeding. Patient must have a negative serum or urine pregnancy test within 72 hours of study entry. Known history of active TB (bacillus tuberculosis). Known history of hepatitis B (defined as hepatitis B survace antigen [HBsAg] reactive) or known active hepatitis C (defined as HCV RNA [qualitative] is detected) infection. Note: know testing for hepatitis B and hepatitis C is required unless mandated by local health authority. Known history of HIV (HIV 1/2 antibodies).

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Neoadjuvant MK-3475 and Adjuvant MK-3475<br>MK-3475 will be given intravenously once approximately 2-3 weeks prior to standard of care surgery. Adjuvant therapy will be dictated by surgical pathology and occurs after standard of care surgery and will consist of: risk-based intensity modulated radiation therapy consisting of 60 Gy in 2 Gy once-daily fraction size (total of 30 fractions)once-daily fraction size (total of 30 fractions) optional image-guided radiation therapy risk-based cisplatin administered intravenously on Days 1, 22, and 43 of treatment course MK-3475 will be given intravenously once every 3 weeks for a maximum of 6 doses if participant is considered high-risk based surgical pathology from standard of care surgery. These doses of MK-3475 will be given after surgery and after all acute toxicities of post-operative standard of care chemotherapy and radiation have resolved to grade 1 or less. | Biological: MK-3475 (neoadjuvant)<br> <br> * Other names: Keytruda;Procedure: Surgery<br>* Standard of care<br>Radiation: Intensity modulated radiation therapy<br>* Recommended, standard of care<br>* Other names: IMRT;Radiation: Image-guided radiation therapy<br>* Recommended, standard of care<br>* Other names: IGRT;Drug: Cisplatin<br>* Standard of care<br>* Other names: DDP;Biological: MK-3475 (adjuvant)<br> <br> * Other names: Keytruda;Procedure: Peripheral blood<br>* -Baseline, time of surgery (between day 14-24 inclusive), 3 months post surgery, 6 months post surgery, 9 months post surgery, 12 months post surgery<br>|
| Experimental: Cohort 2: Neoadjuvant MK-3475<br>-MK-3475 will be given once intravenously and then given again 21 days after dose 1 (14-24 days before standard of care surgery) | Biological: MK-3475 (neoadjuvant)<br> <br> * Other names: Keytruda;Procedure: Surgery<br>* Standard of care<br>Radiation: Intensity modulated radiation therapy<br>* Recommended, standard of care<br>* Other names: IMRT;Radiation: Image-guided radiation therapy<br>* Recommended, standard of care<br>* Other names: IGRT;Drug: Cisplatin<br>* Standard of care<br>* Other names: DDP;Procedure: Peripheral blood<br>* -Baseline, time of surgery (between day 14-24 inclusive), 3 months post surgery, 6 months post surgery, 9 months post surgery, 12 months post surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Recurrence Rates in Cohorts 1 and 2 | -The percentage of participants who developed local-regional recurrence within one year of surgery | Within 1 year of surgery (surgery occurred within 13-22 days after neoadjuvant MK-3475 dose) | 
| Distant Failure Rate in Cohorts 1 and 2 | -The percentage of participants who developed distant failure within one year of surgery. Distant disease is cancer that is found in another part of the body that is far away from where the original (primary) tumor first formed. | Within 1 year of surgery (surgery occurred within 13-22 days after neoadjuvant MK-3475 dose) | 
| Rate of Major Pathologic Treatment Effect in Cohort 1 | Major pathologic treatment effect=pathologic tumor response (pTR). pTR was defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor): pTR-0 (>10%), pTR-1 (10-49%), and pTR-2 (≥50%). | At the time of surgery (surgery occurred within 13-22 days after neoadjuvant MK-3475 dose) | 
| Rate of Major Pathologic Treatment Effect in Cohort 2 | Major pathologic treatment effect=pathologic tumor response (pTR). pTR was defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor): pTR-0 (>10%), pTR-1 (10-49%), and pTR-2 (≥50%). | At the time of surgery (surgery occurred within 13-22 days after last neoadjuvant MK-3475 dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Cohort 1 and 2 Who Experienced Reportable Adverse Events | Reportable adverse events will be tracked for 30 days following the last day of study treatment. For the purposes of this protocol, reportable adverse events are events thought to be possibly, probably, or definitely related to MK-3475. Events thought to be probably or definitely related to surgery, adjuvant chemotherapy, or radiotherapy need not be recorded. | Through 30 days after last dose of MK-3475 | 
| Number of Surgical Complications and/or Delays in Cohorts 1 and 2 |  | At the time of surgery (approximately 2-3 weeks after registration) | 
| Locoregional Recurrence Rates in Cohorts 1 and 2 |  | Through completion of follow-up (estimated to be 5 years after treatment) | 
| Rate of Distant Metastases (DM) in Cohorts 1 and 2 |  | Through completion of follow-up (estimated to be 5 years after treatment) |