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

NCT06912087 | Recruiting Phase 1 FDA Drug

• 1 other identifier: IRB24-1994
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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).

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Progression-Free Survival (PFS)

  2 years from the date of the final subject accrual on study

• Overall Survival (OS)

  2 years from the date of the final subject accrual on study

• Safety of zanzalintinib in combination with pembrolizumab and cetuximab

  End of treatment (about 24 months on average)

Study Arms (4)

Dose Escalation (Dose Level -1)

EXPERIMENTAL

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; Drug: Cetuximab; Drug: Pembrolizumab

Dose Escalation (Dose Level 0)

EXPERIMENTAL

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; Drug: Cetuximab; Drug: Pembrolizumab

Dose Escalation (Dose Level 1)

EXPERIMENTAL

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; Drug: Cetuximab; Drug: Pembrolizumab

Dose Expansion

EXPERIMENTAL

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; Drug: Cetuximab; Drug: Pembrolizumab

Interventions

Zanzalintinib DRUG

Experimental receptor tyrosine kinases (RTKs)

Also known as: XL 092, XL-092, XL092

Dose Escalation (Dose Level -1); Dose Escalation (Dose Level 0); Dose Escalation (Dose Level 1); Dose Expansion

Cetuximab DRUG

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

Also known as: Erbitux

Dose Escalation (Dose Level -1); Dose Escalation (Dose Level 0); Dose Escalation (Dose Level 1); Dose Expansion

Pembrolizumab DRUG

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

Also known as: Keytruda

Dose Escalation (Dose Level -1); Dose Escalation (Dose Level 0); Dose Escalation (Dose Level 1); Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• University of Chicago: lead
• Exelixis: collaborator

Study Sites (1)

University of Chicago Medicine Comprehensive Cancer Center

Chicago, Illinois, 60637, United States

RECRUITING

MeSH Terms

Conditions

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

Interventions

Cetuximab; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Squamous Cell; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ari Rosenberg, MD

  University of Chicago Medicine Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Clinical Trials Intake

CONTACT

1-855-702-8222; cancerclinicaltrials@bsd.uchicago.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2025
• First Posted: April 4, 2025
• Study Start: September 29, 2025
• Primary Completion (Estimated): June 5, 2027
• Study Completion (Estimated): June 5, 2027
• Last Updated: December 2, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

US (1)