• Overall response rate (ORR) - (complete response + partial response) [ Time Frame: Through completion of treatment (estimated to be 12 weeks) ]
  • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
• Duration of response (DoR) [ Time Frame: Through completion of treatment (estimated to be 12 weeks) ]
  -The duration of response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
• Progression-free survival (PFS) [ Time Frame: Through completion of follow-up (estimated to be 15 months) ]
  • Defined as the days from the date of treatment start to progression or death. The alive patients without progression are censored at the last follow-up.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. ): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
• Frequency of adverse events [ Time Frame: From start of treatment through 30 days after completion of treatment (estimated to be 16 weeks) ]
  -Will be measured by CTCAE v. 5.0
• Dose delivery as measured by percent of full doses given over time [ Time Frame: Through completion of treatment (estimated to be 12 weeks) ]

• Overall response rate (ORR) - (complete response + partial response) [ Time Frame: Through completion of treatment (estimated to be 12 weeks) ]
  • Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
  • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
• Duration of response (DoR) [ Time Frame: Through completion of treatment (estimated to be 12 weeks) ]
  -The duration of response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
• Progression-free survival (PFS) [ Time Frame: Through completion of follow-up (estimated to be 15 months) ]
  • Defined as the days from the date of treatment start to progression or death. The alive patients without progression are censored at the last follow-up.
  • Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. ): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
• Frequency of adverse events [ Time Frame: From start of treatment through 28 days after completion of treatment (estimated to be 16 weeks) ]
  -Will be measured by CTCAE v. 5.0
• Dose delivery as measured by percent of full doses given over time [ Time Frame: Through completion of treatment (estimated to be 12 weeks) ]

• Drug: Palbociclib
  Administered on an outpatient basis
  Other Name: Ibrance
• Drug: Cetuximab
  Given intravenously over approximately 60 minutes
  Other Name: Erbitux

• Experimental: Arm 1: Palbociclib + Cetuximab
  • Palbociclib by mouth 125 mg/daily on Days 1-21 of each 28 day cycle
  • Cetuximab: Initial dose 400mg/m^2 intravenous (IV); Subsequent doses 250 mg/m^2 IV, weekly
  Interventions:

  • Drug: Palbociclib
  • Drug: Cetuximab
• Active Comparator: Arm 2: Cetuximab
  -Cetuximab: Initial dose 400mg/m^2 intravenous (IV); Subsequent doses 250 mg/m^2 IV, weekly
  Intervention: Drug: Cetuximab

Inclusion Criteria:

• Histologically or cytologically confirmed RM-HNSCC that is HPV-unrelated disease; defined as SCC of the oral cavity, larynx, or hypopharynx and p16 negative SCC of the oropharynx or p16 negative non-cutaneous SCC unknown primary of the neck.
• CDKN2A loss-of-function (LOF) alteration: mutation or homozygous deletion described on genomic sequencing report.
• 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.
• Disease progression on a PD-1/L1 inhibitor-containing regimen (given as monotherapy or in combination with other therapy).
• Received no more than three lines of prior therapy for RM-HNSCC.
• At least 18 years of age.
• ECOG performance status ≤ 1.

• Normal bone marrow and organ function as defined below:

  • Hemoglobin ≥ 8 g/L
  • Absolute neutrophil count ≥ 1,000/mcl
  • Platelets ≥ 100,000/mcl
  • Total bilirubin ≤ 3 x institutional upper limit of normal (IULN)
  • AST(SGOT)/ALT(SGPT) ≤ 5 x IULN (for cases involving liver metastases, AST/ALT ≤ 10 x IULN)
  • Serum creatinine < 3 x IULN or creatinine clearance > 30 mL/min by Cockcroft-Gault
• The effects of palbociclib and cetuximab on the developing human fetus are unknown. For this reason and because CDK 4/6 inhibitors are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 30 days after completion of the study
• 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 treatment with cetuximab for recurrent or metastatic disease (however, prior cetuximab given as a component of multimodality therapy for newly diagnosed, locally advanced, non-metastatic HNSCC is allowable).
• Prior treatment with a CDK4/6 inhibitor for RM-HNSCC.
• Currently receiving any other investigational agents.
• A history of other malignancy with the exception of malignancies for which all treatment was completed at least 1 year before registration and the patient has no evidence of recurrent/persistent disease.
• Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib or other agents used in the study (excluding cetuximab).
• Prior grade 3 or 4 (per CTCAE 5.0) hypersensitivity reaction to cetuximab.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• QTc >500 msec (using Bazette formula).
• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended. Recommend exclusion of specific ART agents based on predicted drug-drug interactions (i.e. for sensitive CYP3A4 substrates, concurrent strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers (efavirenz) should be contraindicated).