• Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma of the head and neck arising from the sinuses, nasal cavity, oral cavity, oropharynx, hypopharynx, and larynx. Other sites not listed will be subject to PI discretion.

‣ Advanced disease (Stage IV or M1 disease) not amenable to curative local therapy with surgery and/or radiation based approaches

⁃ Progression on first line anti-PD(L)1 therapy with or without chemotherapy or as part of a combination in a clinical trial

⁃ HPV status for oropharynx primary must be previously confirmed or can be performed on available archival or fresh biopsy via p16 immunohistochemistry or HPV specific testing via PCR or RNA ISH. Patients are able to enroll and initiate treatment so long as this is in progress. Exceptions may be made after discussion and review with P.I.

⁃ Have measurable disease per RECIST v1.1 criteria. Tumor lesions situated in previously radiated area may be utilized if they are measurable and progression has been demonstrated in these lesions.

• Male or female patients 18 years of age or older on the day of consent.

• ECOG Performance Status of 0 to 1.

• Adequate hematologic function within 30 days prior to registration, defined as follows:

‣ Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

⁃ Platelets ≥ 100,000 cells/mm3

⁃ Hemoglobin ≥ 9.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable

• Adequate renal function within 30 days prior to registration, defined as follows:

• o Serum creatinine \< 2.0 x upper limit of normal (ULN) or creatinine clearance (CCr)

• ≥ 30 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = \[(140 - age) x (wt in kg)\] \[(Serum Cr mg/dl) x (72)\] CCr female = 0.85 x (CrCl male)

• Adequate hepatic function within 30 days prior to registration, defined as follows:

‣ Total bilirubin ≤ 1.5 × ULN (except for unconjugated hyperbilirubinemia or Gilbert's syndrome). Direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 × ULN.

⁃ AST and ALT \< 2.5 x the upper limit of normal

⁃ Albumin ≥ 3 g/dL

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.

• Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

• Female patients are eligible to participate if they are not pregnant, not breastfeeding and at least one of the following conditions applies:

‣ Not a woman of childbearing potential

⁃ A woman of childbearing potential who agrees to use highly effective contraception from signing of the ICF through six months after the last study treatment administration.

∙ Notes:

∙ i. Female of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>1 year. ii. Highly effective contraception methods include:

• Total abstinence

• Male or female sterilization

• Combination of any 2 of the following categories (Categories 1+2, 1+3, or 2+3):

‣ Category 1: Use of oral, injected, or implanted hormonal methods of contraception.

⁃ Category 2: Placement of an intrauterine device or intrauterine system.

⁃ Category 3: Category 3: Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

⁃ A female participant who is of childbearing potential must have a negative serum β-human chorionic gonadotrophin (β-hCG) pregnancy test within 72 hours prior to the first administration of study treatment or be surgically/biologically sterile (hysterectomy or bilateral oophorectomy) or postmenopausal. Note: Postmenopausal females are defined as those who are:

• Age \> 50 years with amenorrhea for ≥ 12 months.

• Age ≤ 50 years with six months of spontaneous amenorrhea and follicle stimulating hormone level within postmenopausal range (\> 40 mIU/mL).

‣ Male patients must agree to use contraception and refrain from sperm and egg donation from the time period between signing of the ICF and through five months after the last dose of study drug

⁃ The subject must provide voluntary study-specific informed consent prior to study entry.