Nab-Paclitaxel and Cisplatin or Nab-paclitaxel as Induction Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (HNSCC)

Inclusion Criteria: Arms 1 and 3 - AP

* Diagnosis of selected Stage III or IVa/b HNSCC. Arm 1: T2-T4 primary tumors. Arm 3: T2T1-T4 primary tumors. Although most of these patients will have regional nodal disease, patients with no nodal disease will also be eligible.
* Arm 1: Presence of disease at the oropharynx, hypopharynx, or larynx sub-sites.
* Arm 3: Presence of disease at the oropharynx sub-sites, which is HPV-related as verified by p16, a surrogate marker of HPV, or HPV ISH or PCR.
* Presence of 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.
* At least 18 years of age.
* Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 3 months after completing treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* Able to understand and willing to sign an IRB-approved written informed consent document.
* ECOG performance status ≤ 1.
* Adequate bone marrow and organ function as defined below:

  * ANC: ≥ 1500/mcL.
  * Platelets: \> 100,000/mcL.
  * Hemoglobin \> 9.0 g/dL
  * Total bilirubin ≤ 1.5 mg/dL
  * AST/ALT/alkaline phosphatase: ≤ 2.5 x ULN.
  * Serum creatinine: \< 1.5 mg/dL or calculated GFR ≥ 75 cc/min. CrCl by Cockcroft Gault will be used to estimate GFR.
  * Pulmonary: no requirement for supplemental oxygen and no evidence of moderate-severe chronic obstructive pulmonary disease (COPD) by pulmonary function tests (PFTs).

Inclusion Criteria: Arm 2 - A

* Diagnosis of selected Stage III or IVa/b HNSCC. T2-T4 primary tumors. (Patients with T1 tumors will be excluded). Although most of these patients will have regional nodal disease, patients with no nodal disease will also be eligible.
* Presence of disease at the oropharynx, hypopharynx, or larynx sub-sites.
* Presence of 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.
* At least 18 years of age.
* Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 3 months after completing treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
* Able to understand and willing to sign an IRB-approved written informed consent document.
* ECOG performance status \< 3.
* Adequate bone marrow and organ function as defined below:

  * ANC: ≥ 1500/mcL.
  * Platelets: ≥ 100,000/mcL.
  * Hemoglobin \> 9.0 g/dL
  * Total bilirubin ≤ 2.0 mg/dL
  * AST/ALT/alkaline phosphatase: ≤ 5x ULN.
  * Calculated GFR \>30 cc/min. CrCl by Cockcroft Gault will be used to estimate GFR.
  * Pulmonary: patients with a requirement for supplemental oxygen or evidence of moderate-severe COPD by PFTs are permitted to enroll.
* If a patient fully meets criteria for Arm 1, but has profound hearing loss and the physician feels that the patient should not receive Cisplatin, the patient will be eligible for Arm 2.
* If a patient fully meets criteria for Arm 1, but has a history of solid organ or bone marrow transplant, the patient will be eligible for Arm 2 (due to contraindications of Cisplatin with medications the patient is taking due to the transplant).

Exclusion Criteria (Arm 1 and Arm 2)

* Prior chemotherapy, prior EGFR targeted therapy, or prior radiation therapy for HNSCC.
* Disease at the nasopharyngeal, sinus, oral cavity, or other sub-site not specified as eligible.
* Diagnosis of unknown primary squamous cell carcinoma of the head and neck.
* History of prior invasive malignancy diagnosed within 3 years prior to study enrollment; exceptions are malignancies with a negligible risk of metastasis or death (e.g., expected 5-year OS \> 90%) that were treated with an expected curative outcome, such as squamous cell carcinoma of the skin, in-situ carcinoma of the cervix uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
* Receiving any other investigational agents.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the agents used in this study.
* Taking cimetidine or allopurinol. If currently taking either of these medications, patient must discontinue for one week before receiving treatment with nab-paclitaxel.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or serious psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant and/or breastfeeding. A negative serum or urine pregnancy test is required at screening for all female patients of childbearing potential.
* Known to be HIV-positive on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with the study agents. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
* Peripheral neuropathy \> grade 1.