Entolimod in Treating Patients With Stage III-IV Squamous Cell Head and Neck Cancer Receiving Cisplatin and Radiation Therapy

Inclusion Criteria: * Histologically proven diagnosis of squamous cell carcinoma (stage III - IV) of the nasopharynx, oropharynx, oral cavity, paranasal sinuses, larynx, hypopharynx; the tumor must be human papillomavirus (HPV) negative or the patient should have a greater than 10 packs year smoking history; OR need for post-operative concurrent chemoradiotherapy (extracapsular extension, positive surgical margin, more than 1 lymph node positive, stage III - IV disease, perineural invasion, vascular tumor embolus) for histologically proven squamous cell carcinoma of the paranasal sinuses, nasopharynx, larynx, hypopharynx, with extension to structures of the oropharynx * Have an Eastern Cooperative Oncology Group (ECOG) performance status of =\< 2 * Induction chemotherapy (up to 3 cycles of cetuximab/taxanes/platinum based regimens) is allowed * Patients or their legal representatives must be able to comprehend and provide written informed consent * Absolute neutrophil count =\> 1,500/uL * Platelets \>= 100,000/uL * Total bilirubin within normal institutional limits * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit normal (ULN) * Calculated creatinine clearance \>= 60 mL/min (Cockcroft-Gault equation) * 12-Lead Electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention * Bazett's corrected QT (QTcB) interval \< 470 msec at any timepoint prior to receiving the first dose of study drug (mean of replicate values, correction per institutional standard) and no history of Torsades des Pointes or other symptomatic QTcB abnormality * Absence of orthostatic hypotension * Patients must be sufficiently recovered from induction chemotherapy to allow initiation therapy Exclusion Criteria: * Women of childbearing potential who do not have a negative serum pregnancy test performed within 7 days prior to the start of study drug * Male and female patients of child-bearing potential who do not agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received * Contraindication to full course chemoradiotherapy with cisplatin * Previous treatment with a toll-like receptor 5 (TLR5) agonist * Presence of neutralizing antibodies to CBLB502 * Patients with an active infection or with a fever \>= 38.5ºC within 3 days of the first scheduled day of dosing; patients who are registered but develop a fever of \>= 38.5ºC may remain in the study if the fever abates prior to the expiration of the screening procedures; if the screening procedures have expired, the patient may be re-screened once afebrile * Patients with a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory or inflammatory illness that could preclude their participation in the study, pose an undue medical hazard or interfere with the interpretation of the study results, including, but not limited to, patients with congestive heart failure (New York Heart Association \[NYHA\] class 3 or class 4); unstable angina; cardiac arrhythmia; recent (within the preceding 6 months) myocardial infarction or stroke; hypertension requiring \> 2 medications for adequate control; diabetes mellitus with \> 2 episodes of ketoacidosis in the preceding 12 months; chronic obstructive pulmonary disease (COPD) requiring \> 2 hospitalizations in the preceding 12 months * Patients with a history of, or known autoimmune disease, but not limited to systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, ankylosing spondylitis, sarcoidosis, vasculitis, Wegener's granulomatosis, Hashimoto's thyroiditis, ulcerative colitis, Crohn's disease, Goodpasture's disease, multiple sclerosis, etc. * Patients with any other medical, psychiatric or social condition that would preclude their participation in the study, pose an undue medical hazard, interfere with the conduct of the study or interfere with interpretation of the study results * Patients taking sucralfate, palifermin or amifostine * Patients receiving hematopoietic growth factors * Patients currently taking, or who have taken within 30 days of the initiation of protocol therapy, any immunomodulatory therapy, including pharmacologic doses of glucocorticoids (topical and inhalation glucocorticoids are permitted), azathioprine, methotrexate, interferon-alpha, interferon-beta, interluekin-2, etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, etc * Patients with a history of hypersensitivity reactions to any of the components of CBLB502 or cisplatin * Women who are pregnant or lactating or who are planning on becoming pregnant during the study or for 90 days after completion of the study * Patients who have received an investigational therapy within 4 weeks of signing the informed consent for the current study * Patients with a history of, patients who were treated for, or patients who are suspected of having, hepatitis B, and hepatitis C or human immunodeficiency virus (HIV); patients suspected of having any of these conditions should undergo appropriate evaluations prior to being enrolled in the study * Surgery with significant defect or flap in the oral cavity * Poor dentition or ill-fitting dental appliances (can be enrolled if this can be corrected by a dentist prior to start of radiation therapy) * Presence of other medical conditions causing mucositis (e.g., rheumatologic, gastroesophageal reflux, etc.)