A Vaccine (ISA101b) and Pembrolizumab with Cisplatin and IMRT for the Treatment of Intermediate Risk HPV-16 Associated Head and Neck Squamous Cell Carcinoma

Inclusion Criteria

• Patients must have histologically-confirmed head and neck squamous cell carcinoma with no evidence of distant metastasis. The primary site will be the oropharynx. Patients with squamous cell carcinoma of unknown primary, metastatic to cervical lymph nodes, are permitted to enroll provided all other eligibility criteria are met
• Patients must have intermediate risk disease, defined below. Staging evaluation should be determined by imaging studies and complete head and neck exam in accordance with the American Joint committee on Cancer Staging Manual, 7th edition * Patients must meet one of the following criteria: ** Oropharynx: p16(+) PLUS HPV in situ hybridization (ISH) (+) AND one of the following ** T3 OR >= N2a AND >= 10 pack-years tobacco exposure ** T4 or N2c/N3 disease irrespective of tobacco exposure ** Unknown primary: p16(+) PLUS HPV ISH(+) AND one of the following ** >= N2a AND >= 10 pack-years tobacco exposure ** N2c/N3 disease irrespective of tobacco exposure * Note: for patients with oropharyngeal or unknown primary tumors, p16 status must be known, and HPV-16 ISH should also be performed. p16-positive disease is defined as >= 70% of tumor cells demonstrating diffuse nuclear and cytoplasmic staining by p16 immunohistochemistry (IHC)
• Patients should be considered not a candidate for curative-intent surgery with diagnosis of American Joint Committee on Cancer (AJCC) 7th edition stage III, IVa, or IVb disease. Diagnostic excisional biopsy of primary tumor and/or nodal sites is permitted * Diagnostic simple palatine or lingual tonsillectomy is permitted, provided patient has Response Evaluation Criteria in Solid Tumors (RECIST)-measurable nodal disease * Patients with a second HNSCC primary tumor are eligible for this study, provided more than 2 years have elapsed since the first diagnosis of HNSCC, the original tumor was managed with surgery only (no adjuvant chemotherapy or radiotherapy), and has not recurred
• Patients with simultaneous primaries are excluded, with the exception of patients with bilateral tonsil/base of tongue HPV+ cancers or patients with T1-2, N0, M0 differentiated thyroid carcinoma (resected or management deferred), who are eligible
• No prior systemic (chemotherapy or biologic/molecular targeted therapy) or radiation treatment for head and neck cancer * Patients may have received chemotherapy or radiation for a previous, curatively treated non-HNSCC malignancy, provided at least 2 years have elapsed * Patients must be untreated with radiation above the clavicles
• Patients with a history of curatively-treated non-HNSCC malignancy must be disease-free for at least 2 years except for excised and cured: carcinoma-in-situ of breast or cervix; non-melanoma skin cancer; T1-2, N0, M0 resected differentiated thyroid carcinoma; superficial bladder cancer; T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection
• The patient must consent to a research biopsy at baseline, and during week 2 of pembrolizumab/ISA101b vaccination, prior to start of cisplatin-IMRT, as well as another optional biopsy in week 2 after the start of IMRT. All patients will be evaluated for the feasibility of research biopsy at the time of enrollment, as a condition of eligibility. The performing physician must agree that a cup forceps biopsy or an 18 to 14 gauge core needle biopsy can be safely performed. Every effort will be made to couple the baseline research biopsy to a standard of care diagnostic or staging procedure. NOTE: Patients who have had research tissue procured under an omnibus tissue consent, who are determined to have sufficient tissue for analysis of immune-inflammatory biomarkers per the study principal investigator (PI), may substitute the archived tissue and do not need to undergo baseline research biopsy. Such tissue must have been obtained within the prior 24 weeks and no interval anti-cancer therapy administered
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must have clinical evidence of disease
• Absolute neutrophil count (ANC) >= 1,500 /mm^3 (performed within 10 weeks of treatment initiation)
• Platelets >= 100,000 / mm^3 (performed within 10 weeks of treatment initiation)
• Hemoglobin ≥ 9.0 g/dL (performed within 10 weeks of treatment initiation)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min (for subject with creatinine levels > 1.5 X institutional ULN) determined by 24-hour collection or estimated by Cockcroft-Gault formula (performed within 10 weeks of treatment initiation)
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 10 weeks of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN (performed within 4 weeks of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 10 weeks of treatment initiation)
• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 10 weeks of treatment initiation)
• Written informed consent must be obtained from all patients prior to study registration. Patients should have the ability to understand and the willingness to sign a written informed consent document
• If a woman of childbearing potential, documentation of negative pregnancy within 4 weeks prior to first dose. Sexually active patients must agree to use adequate contraceptive measures, while on study and for 120 days after the last dose of study drug. All fertile female subjects (and their partners) must agree to use a highly effective method of contraception. Should a woman become pregnant or suspect she is pregnant while in this study, she should inform her treating physician immediately. A negative pregnancy test should be documented during screening and then within 72 hours of first dose
• Male participants: A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period

Exclusion Criteria

• Oral cavity, larynx, hypopharynx or nasopharyngeal primary site
• Current participation in or previous participation in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment
• Prior treatment with anti-HPV agents except prevention HPV vaccines
• History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agents (pembrolizumab and ISA101b [e.g. montanide and components of reconstitution solution for ISA101b])
• Distant metastatic disease including central nervous system (CNS) or leptomeningeal metastases is not allowed
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the cisplatin and IMRT involved in this protocol may be significantly immunosuppressive. Patients with known HIV, CD4 counts >= 250/uL, and undetectable viral loads who are stable on an antiretroviral regimen may be included
• Received prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e. =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study
• Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Received prior therapy 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)
• Significant pulmonary disease, including pulmonary hypertension, history of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis
• History or current evidence of any other medical or psychiatric condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Peripheral neuropathy >= grade 2
• Significant cardiovascular disease, including: * Cardiac failure New York Heart Association (NYHA) class III or IV * Myocardial infarction, severe or unstable angina within 6 months prior to study day 1 * History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation) * Ventricular cardiac arrhythmias requiring anti-arrhythmic medications * Known left ventricular ejection fraction (LVEF) =< 50%
• Significant thrombotic or embolic events within 3 months prior to study day 1. Significant thrombotic or embolic events include but are not limited to stroke or transient ischemic attack (TIA). Catheter-related thrombosis is not a cause for exclusion. Diagnosis of deep vein thrombosis or pulmonary embolism is allowed if the patient is clinically stable and has completed or is on stable anti-coagulation therapy
• Major surgery within 6 weeks prior to study day 1 (subjects must have completely recovered from any previous surgery prior to study day 1). Biopsy, diagnostic tonsillectomy, airway tumor debulking or excisional lymph node biopsy do not constitute major surgery
• Active infection requiring antibiotics or antifungals within 7 days prior to first dose of study drug
• Significant electrolyte imbalance prior to enrollment (note that patients may be supplemented to achieve acceptable electrolyte values): * Hypomagnesemia < 1.2 mg/dL or 0.5 mmol/L * Hypokalemia < 3.0 mmol/L
• Women must not be pregnant or breastfeeding because chemotherapy and/or pembrolizumab may be harmful to the fetus or the nursing infant. Pregnant women are excluded from this study because chemotherapy and/or pembrolizumab have the potential for teratogenic or abortifacient effects
• Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and are not allowed
• Has had an allogenic tissue/solid organ transplant