Inclusion Criteria:

          -  Histologically or cytologically confirmed incurable HNSCC of the oral cavity,
             oropharynx, larynx, hypopharynx, and/or Level 1-3 neck node with non-cutaneous 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).

          -  Progression following platin and immunotherapy given for incurable disease.

          -  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.

          -  Tissue available (either initial diagnostic or recurrent tissue specimen) for p16
             testing.

          -  At least 18 years of age.

          -  ECOG performance status ≤ 3

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

               -  Absolute neutrophil count ≥ 1,000/mcl

               -  Platelets ≥ 75,000/mcl

               -  Total bilirubin ≤ 1.5 mg/dL

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN, unless bone
                  metastasis is present in the absence of liver metastasis

               -  Creatinine below ULN (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

          -  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 1 month 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:

          -  Other active malignancy with the exception of basal cell or squamous cell carcinoma of
             the skin which were treated with local resection only, carcinoma in situ of the
             cervix, or synchronous H&N primaries.

          -  Currently receiving any other investigational agents.

          -  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 7
             days of start of study treatment.

          -  Known active central nervous system (CNS) metastases. Subjects with previously treated
             brain metastases may participate provided they are stable (without evidence of
             progression by imaging for at least four weeks prior to the first dose of trial
             treatment and any neurologic symptoms have returned to baseline), have no evidence of
             new or enlarging brain metastases, and are not using steroids for at least 28 days
             prior to treatment.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to mitomycin C or other agents used in the study.

          -  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.