This Phase I clinical trial evaluates the safety, tolerability, and optimal dosing of Zanzalintinib in combination with Pembrolizumab and Cetuximab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC). The study aims to establish the maximally tolerated dose (MTD) and recommended Phase II dose (RP2D) while also exploring efficacy outcomes, including progression-free survival (PFS) and overall survival (OS).

This Phase I, single-site clinical trial investigates the combination therapy of Zanzalintinib, an oral tyrosine kinase inhibitor, with Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, and Cetuximab, an anti-EGFR monoclonal antibody, in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC). The primary objective is to determine the maximally tolerated dose (MTD) and the recommended Phase II dose (RP2D) of Zanzalintinib in combination with Pembrolizumab and Cetuximab.

Secondary objectives include evaluating safety, tolerability, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives will investigate the effects of the treatment on plasma circulating tumor DNA (ctDNA) levels, immune phenotype, genetic alterations, and histopathologic changes in tumor biopsies.

The trial uses a dose-escalation design, with a 42-day treatment cycle, to assess safety and dose-limiting toxicities. This combination targets the immune-suppressive tumor microenvironment, aiming to overcome resistance mechanisms and improve clinical outcomes for a population with limited therapeutic options.

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).

The document you provided does not include a specific IPD (Individual Patient Data) Sharing Plan or details regarding what patient data may be shared with other researchers. Typically, this information is outlined in separate documentation, such as consent forms or data sharing agreements, and would depend on institutional policies or specific regulatory requirements.

If you require more detailed information about the plan to share IPD for this study, I recommend contacting the Principal Investigator or the University of Chicago Medicine Comprehensive Cancer Center directly to inquire about their data sharing practices.