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

NCT ID: NCT06912087

Last Updated: 2025-12-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-09-29
• Study Completion Date: 2027-06-05

Brief Summary

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).

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Zanzalintinib

Intervention Type: DRUG

Experimental receptor tyrosine kinases (RTKs)

Cetuximab

Intervention Type: DRUG

Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).

Pembrolizumab

Intervention Type: DRUG

FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1)

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.

Group Type: EXPERIMENTAL

Zanzalintinib

Intervention Type: DRUG

Experimental receptor tyrosine kinases (RTKs)

Cetuximab

Intervention Type: DRUG

Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).

Pembrolizumab

Intervention Type: DRUG

FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1)

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

Group Type: EXPERIMENTAL

Zanzalintinib

Intervention Type: DRUG

Experimental receptor tyrosine kinases (RTKs)

Cetuximab

Intervention Type: DRUG

Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).

Pembrolizumab

Intervention Type: DRUG

FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1)

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.

Group Type: EXPERIMENTAL

Zanzalintinib

Intervention Type: DRUG

Experimental receptor tyrosine kinases (RTKs)

Cetuximab

Intervention Type: DRUG

Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).

Pembrolizumab

Intervention Type: DRUG

FDA approved monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1)

Interventions

Zanzalintinib

Experimental receptor tyrosine kinases (RTKs)

Intervention Type: DRUG

Cetuximab

Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR).

Intervention Type: 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)

Intervention Type: DRUG

Other Intervention Names

XL 092; XL-092; XL092; Erbitux; Keytruda

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Exelixis

INDUSTRY

Sponsor Role: collaborator

University of Chicago

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ari Rosenberg, MD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago Medicine Comprehensive Cancer Center

Locations

University of Chicago Medicine Comprehensive Cancer Center

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Clinical Trials Intake

Role: CONTACT

cancerclinicaltrials@bsd.uchicago.edu

1-855-702-8222

Facility Contacts

Cancer Trial Intake

Role: primary

cancerclinicaltrials@bsd.uchicago.edu

1-855-702-8222

Other Identifiers

IRB24-1994

Identifier Type: -

Identifier Source: org_study_id