The 5-Fluorouracil Response and Optimization STudy (The FROST Trial): A Randomized Phase II Trial of Two Dosage Regimens (2D-Q2W vs 4D-Q3W) of 5-Fluorouracil (5-FU) in Patients With Platinum and PD-1 Inhibitor Pre-treated Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Inclusion Criteria: * Histologically or cytologically confirmed: * RM-HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx, OR * p16+ (HPV-related) level 2-3 neck node and unknown primary site, OR * Second primary HNSCC in a previously radiated field not amenable to curative-intent surgery and/or re-radiation. * Measurable disease per RECIST 1.1. * Previously treated with platinum-based chemotherapy, RM disease within 6 months of definitive cisplatin + radiation therapy (DCisRT) or post-operative adjuvant cisplatin + radiation therapy (POACisRT) OR progressive disease on or after or intolerance to platinum agent given for RM disease. * Previously treated with PD-1 inhibitor, RM disease within 6 months of PD-1 inhibitor given as part of curative-intent therapy OR progressive disease on or after PD-1 inhibitor given for RM disease OR intolerance to prior PD-1 inhibitor in the curative or metastatic setting. * At least 18 years of age * ECOG performance status ≤ 2 * Adequate bone marrow and organ function as defined below: * Absolute neutrophil count ≥ 1.0 K/cumm * Platelets ≥ 100 K/cumm * Hemoglobin ≥ 8.0 g/dL * Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3 x IULN) * AST(SGOT)/ALT(SGPT)/Alkaline Phosphatase (ALP) ≤ 3.0 x IULN. For subjects with documented bone metastasis, ALP ≤ 5.0 x IULN. * Serum creatinine \<3 mg/dL or creatinine clearance \> 30 mL/min by Cockcroft- Gault. * The effects of 5-FU on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 30 days after last dose of 5-FU * Recovery to baseline or ≤ grade 1 from AEs due to prior therapy, unless AEs are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, or ≤ grade 2 neuropathy are permitted. * Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants. Exclusion Criteria: * Prior 5-FU given to treat RM-HNSCC. * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial. * Currently receiving any other investigational agents. * RM or incurable second primary SCC of cutaneous, nasopharynx, paranasal/nasal/sinus origin. * DPYD deficiency (poor or intermediate metabolizer) as determined by next generation sequencing through blood or saliva (results of historical testing are accepted). * Severe hepatic impairment (Child-Pugh C) or history of hepatitis B or C. * Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression. * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-FU or other agents used in the study. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative urine pregnancy test within 14 days of study registration. * HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.