The purpose of this research study is to look at the effect of a treatment regimen called CACTUX on head and neck cancer. The CACTUX regimen is a combination of three drugs called cisplatin, nab-paclitaxel, and cetuximab (although carboplatin may be given in place of cisplatin if participants have previously had problems receiving cisplatin). The use of nab-paclitaxel in this combination is different from routine care, in which a drug called 5FU is often given instead, but the investigators group has conducted previous research where the investigators incorporated nab-paclitaxel into routine treatment with cisplatin, 5FU, and cetuximab. The investigators are looking at the incidence of side effects with the CACTUX regimen as well as response of the disease and health status.

Inclusion Criteria:

• Histologically or cytologically confirmed incurable HNSCC of the oral cavity, oropharynx, larynx, hypopharynx, and/or Level 1-3 neck node with non-skin SCC and unknown primary. "Incurable" is defined as metastatic disease or a local or regional recurrence in a previously irradiated site that is unresectable (or patient declines resection).

• 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 per RECIST 1.1.

• At least 18 years of age.

• ECOG performance status ≤ 1

• Adequate hematologic, renal, and hepatic function as defined below:

  • Leukocytes ≥ 3,000/mcL
  • Absolute neutrophil count ≥ 1,500/mcl
  • Platelets ≥ 100,000/mcl
  • Total bilirubin ≤ 1.5 mg/dL
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, alkaline phosphatase ≤ 2.5 x IULN, unless bone metastasis is present in the absence of liver metastasis
  • Creatinine at or below IULN (males 0.7-1.30 mg/dl; females 0.6-1.10 mg/dl) OR Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal

• At least 4 months since completion of curative therapy, if given previously.

• Availability of diagnostic tumor tissue specimens for correlative studies.

• 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.

• 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 systemic therapy for incurable disease.
• Grade 2 or higher peripheral neuropathy at screening.
• A history of other malignancy ≤ 2 years previous; 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, incidental finding of prostate cancer (TNM stage of T1a or T1b), or synchronous H&N primaries
• Currently receiving any other investigational agents.
• Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to cisplatin, nab-paclitaxel, or other agents used in the study. Previous grade 1 or 2 allergic reaction to cetuximab is permissible.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and/or breastfeeding. Patient must have a negative pregnancy test within 72 hours of start of study treatment.
• Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with the study drugs. 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.