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

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 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).

Study Overview

• Status: Recruiting
• Conditions: Head and Neck Neoplasms; Carcinoma, Squamous Cell; Neoplasm Metastasis; Neoplasm Recurrence, Local; Metastatic Squamous Cell Carcinoma; Recurrent Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Zanzalintinib; Drug: Cetuximab; Drug: Pembrolizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials Intake; Phone Number: 1-855-702-8222; Email: cancerclinicaltrials@bsd.uchicago.edu

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago Medicine Comprehensive Cancer Center
      • Principal Investigator: Ari Rosenberg, MD
      • Contact: Cancer Trial Intake; Phone Number: 1-855-702-8222; Email: cancerclinicaltrials@bsd.uchicago.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation (Dose Level -1); Participants receive the combination of the following drugs in 42-day cycles: Zanzalintinib at a dose of 20 mg daily on days 1-42 of each cycle; Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle; Pembrolizumab 400 mg on day 1 of each cycle	Drug: Zanzalintinib; Experimental receptor tyrosine kinases (RTKs); Other Names: XL092; XL 092; XL-092; Drug: Cetuximab; Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).; Other Names: Erbitux; Drug: Pembrolizumab; FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1); Other Names: Keytruda
Experimental: Dose Escalation (Dose Level 0); Participants receive the combination of the following drugs in 42-day cycles: Zanzalintinib at a dose of 40 mg daily on days 1-42 of each cycle; Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle; Pembrolizumab 400 mg on day 1 of each cycle This will be the first dose escalation enrolled. Dose Levels 1 and/or -1 will be enrolled depending on side effects seen in participants enrolled to this cohort.	Drug: Zanzalintinib; Experimental receptor tyrosine kinases (RTKs); Other Names: XL092; XL 092; XL-092; Drug: Cetuximab; Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).; Other Names: Erbitux; Drug: Pembrolizumab; FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1); Other Names: Keytruda
Experimental: Dose Escalation (Dose Level 1); Participants receive the combination of the following drugs in 42-day cycles: Zanzalintinib at a dose of 60 mg daily on days 1-42 of each cycle; Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle; Pembrolizumab 400 mg on day 1 of each cycle	Drug: Zanzalintinib; Experimental receptor tyrosine kinases (RTKs); Other Names: XL092; XL 092; XL-092; Drug: Cetuximab; Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).; Other Names: Erbitux; Drug: Pembrolizumab; FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1); Other Names: Keytruda
Experimental: Dose Expansion; Participants receive the combination of the following drugs in 42-day cycles: Zanzalintinib will be dosed daily (days 1-42) at the dose identified as recommended phase 2 dose during dose escalation.; Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle; Pembrolizumab 400 mg on day 1 of each cycle The expansion cohort will begin enrollment after the dose escalation cohorts have completed enrollment.	Drug: Zanzalintinib; Experimental receptor tyrosine kinases (RTKs); Other Names: XL092; XL 092; XL-092; Drug: Cetuximab; Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).; Other Names: Erbitux; Drug: Pembrolizumab; FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1); Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximally Tolerated Dose (MTD) of Zanzalintinib in Combination with Pembrolizumab and Cetuximab	The MTD will be defined as the dose combination with a dose-limiting toxicities (DLT) rate closest to the target DLT rate of 25%.	end of DLT evaluation period (first 28 days of treatment)
Recommended Phase II Dose (RP2D) of Zanzalintinib in Combination with Pembrolizumab and Cetuximab	The RP2D will be defined as the MTD identified after enrollment to all cohorts.	End of enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	The secondary outcome measure of Progression-Free Survival (PFS) will assess the time from the first dose of the study drug (Zanzalintinib, Pembrolizumab, and Cetuximab) to the date of documented disease progression (PD) based on RECIST v1.1 or death, whichever occurs first. This measure will help evaluate the efficacy of the combination therapy in delaying disease progression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.	2 years from the date of the final subject accrual on study
Overall Survival (OS)	The secondary outcome measure of Overall Survival (OS) will evaluate the time from the first dose of the study drug (Zanzalintinib, Pembrolizumab, and Cetuximab) to the date of death from any cause. This outcome will help assess the overall impact of the combination therapy on patient survival in recurrent and/or metastatic squamous cell carcinoma of the head and neck.	2 years from the date of the final subject accrual on study
Safety of zanzalintinib in combination with pembrolizumab and cetuximab	Adverse events (AEs) leading to discontinuation or death, and severity of AEs will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.	End of treatment (about 24 months on average)

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: Exelixis
• Investigators: Principal Investigator: Ari Rosenberg, MD, University of Chicago Medicine Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2025
• Primary Completion (Estimated): June 5, 2027
• Study Completion (Estimated): June 5, 2027

Study Registration Dates

• First Submitted: January 31, 2025
• First Submitted That Met QC Criteria: March 28, 2025
• First Posted (Actual): April 4, 2025

Study Record Updates

• Last Update Posted (Actual): December 2, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Carcinoma; Neoplasms, Squamous Cell; Pathological Conditions, Signs and Symptoms; Carcinoma, Squamous Cell; Neoplasm Metastasis; Head and Neck Neoplasms; Neoplasm Recurrence, Local; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; pembrolizumab
• Other Study ID Numbers: IRB24-1994

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No