Zanzalintinib with pembrolizumab and cetuximab for recurrent or metastatic head and neck squamous cell cancer

A Phase I Study of Zanzalintinib With Pembrolizumab and Cetuximab in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

This trial tests whether adding the oral drug zanzalintinib to pembrolizumab and cetuximab is safe and finds the best dose for adults with recurrent or metastatic head and neck squamous cell cancer.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 36 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Chicago (Academic / other)
• Drugs / interventions: cetuximab, pembrolizumab, Zanzalintinib, chemotherapy
• Locations: 1 site (Chicago, Illinois)
• Trial ID: NCT06912087 on ClinicalTrials.gov

What this trial studies

This Phase I, single-site dose-escalation trial gives oral zanzalintinib together with pembrolizumab and cetuximab in 42-day treatment cycles to determine the maximally tolerated dose (MTD) and recommended Phase II dose (RP2D). The primary focus is safety and dose-limiting toxicities, with cohorts expanded as dose levels are explored. Secondary outcomes include response rates, progression-free survival, and overall survival, while exploratory analyses will track plasma ctDNA, immune phenotypes, tumor genetics, and biopsy changes. The trial is conducted at the University of Chicago and enrolls patients with recurrent and/or metastatic HNSCC who meet eligibility criteria.

Who should consider this trial

Good fit: Adults (≥18) with histologically confirmed recurrent or metastatic squamous cell carcinoma of the head and neck that is incurable by local therapy, measurable disease by RECIST 1.1, ECOG 0–1, and meeting PD-L1 criteria for untreated patients (CPS ≥1) are ideal candidates.

Not a fit: Patients with poor performance status (ECOG >1), uncontrolled serious comorbidities, inability to tolerate combination therapy, or contraindications to immunotherapy or EGFR-targeted treatment are unlikely to benefit.

Why it matters

Potential benefit: If successful, the combination could improve response and overcome resistance to prior therapies, offering a new option for patients with limited choices.

How similar studies have performed: Combining EGFR antibodies and PD-1 inhibitors has shown some activity in head and neck cancer but results have been mixed, and adding a novel oral TKI like zanzalintinib is largely experimental and unproven.

Eligibility criteria

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).

Where this trial is running

Chicago, Illinois

• University of Chicago Medicine Comprehensive Cancer Center — Chicago, Illinois, United States (Recruiting)

Study contacts

• Principal investigator: Ari Rosenberg, MD — University of Chicago Medicine Comprehensive Cancer Center
• Study coordinator: Clinical Trials Intake

Conditions Head and Neck Neoplasms; Carcinoma, Squamous Cell; Neoplasm Recurrence, Local; Neoplasm Metastasis; Recurrent Squamous Cell Carcinoma; Metastatic Squamous Cell Carcinoma