Recruiting
Phase 1

Zanzalintinib, Pembrolizumab, Cetuximab

Sponsor:

University of Chicago

Code:

NCT06912087

Conditions

Head and Neck Neoplasms

Carcinoma, Squamous Cell

Neoplasm Recurrence, Local

Neoplasm Metastasis

Recurrent Squamous Cell Carcinoma

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Zanzalintinib

Cetuximab

Pembrolizumab

Study Details

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

Study ID

NCT06912087

Start date

Sep 29, 2025

Status verified date

Nov, 2025

Completion date

Jun 5, 2027

Anticipated

Primary completion date

Jun 5, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

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 Design

Enrollment

36 participants

Anticipated

Allocation

Non randomized

Intervention Model

Sequential

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

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

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.

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

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.

Interventions

Zanzalintinib

Experimental receptor tyrosine kinases (RTKs)

Cetuximab

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

Pembrolizumab

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

Primary outcome measure

  • Maximally Tolerated Dose (MTD) of Zanzalintinib in Combination with Pembrolizumab and Cetuximab [ Time Frame: end of DLT evaluation period (first 28 days of treatment) ]
  • Recommended Phase II Dose (RP2D) of Zanzalintinib in Combination with Pembrolizumab and Cetuximab [ Time Frame: End of enrollment ]

Central Contacts and Locations

Central contacts

Clinical Trials Intake

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

Locations

University of Chicago Medicine Comprehensive Cancer Center

Recruiting

Chicago, Illinois, United States, 60637

Contacts

Cancer Trial Intake

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

Principal Investigator:

Ari Rosenberg, MD

More Information

Sponsor

University of Chicago

Last update posted

Dec 2, 2025

Last verified

Nov, 2025

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-08. This information was provided to ClinicalTrials.gov by University of Chicago on 2025-12-02.