Dose Finding Study of Zanzalintinib With Pembrolizumab and Cetuximab in Head and Neck SCC

Inclusion Criteria:

* Histologically or cytologically confirmed recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), which is considered incurable by local therapies.
* Primary tumor locations: oropharynx, oral cavity, hypopharynx, larynx, nasopharynx, and sinonasal. Unknown primary is also eligible.
* Age: Participants must be at least 18 years old.
* ECOG Performance Status: Must be 0-1.
* Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
* For oropharyngeal cancer: HPV (p16) testing is required. p16 Immunohistochemistry (IHC) is sufficient for Human Papillomavirus (HPV) testing.
* Programmed cell death ligand 1 (PD-L1) combined positive score (CPS) : For patients with previously untreated R/M disease, a combined positive score (CPS) of 1 or greater is required. There is no PD-L1 restriction for patients who have previously received anti-PD(L)1 therapy.
* Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from any adverse events (AEs), including immune-related AEs from prior treatments.
* Adequate organ and marrow function, including:
* Absolute neutrophil count (ANC) ≥ 1500/mm3.
* Platelets ≥ 100,000/mm3.
* Hemoglobin ≥ 9 g/dL.
* Normal liver and kidney function.
* Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
* Contraception: Sexually active fertile subjects must agree to use a highly effective method of contraception during the study and for 2 months after the last dose of cetuximab and 4 months after the last dose of pembrolizumab.

Exclusion Criteria:

* Prior treatment with Zanzalintinib or other vascular endothelial growth factor receptor (VEGFR)-targeted therapies, -Cetuximab, or other epidermal growth factor receptor (EGFR) inhibitors.
* More than two prior lines of systemic therapy in the recurrent/metastatic setting.
* Relapsed disease within 3 months of definitive therapy.
* Prior treatment with small molecule kinase inhibitors, chemotherapy, biologic, or other anticancer therapies within certain time frames (2-4 weeks before the first dose of study treatment).
* Brain metastases or cranial epidural disease unless stable after treatment for at least 4 weeks.
* Concomitant anticoagulation with oral anticoagulants or platelet inhibitors, unless on stable doses of acceptable anticoagulants.
* Active infection requiring systemic treatment or significant cardiovascular, gastrointestinal, or other serious health issues that may affect study participation.
* Known or suspected autoimmune disease, except for specific conditions like type I diabetes or controlled skin disorders.
* Pregnancy or breastfeeding: Women must not be pregnant or breastfeeding at screening.
* Other malignancies within the past 2 years (except for certain low-grade cancers like localized skin cancers).