Zanzalintinib + Pembrolizumab + Cetuximab for Head and Neck Cancer

Overseen By Clinical Trials Intake

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Chicago

Must not be taking: Anticoagulants, Platelet inhibitors

Disqualifiers: Brain metastases, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines a new treatment combination for head and neck cancer that has recurred or spread and cannot be cured with local treatments. The goal is to determine the optimal dose of Zanzalintinib (a new potential drug) when used with Pembrolizumab and Cetuximab, and to evaluate how effectively this combination stops cancer growth and improves survival. Participants should have a confirmed diagnosis of this cancer type in areas such as the throat or mouth, with symptoms affecting daily life, like difficulty swallowing or breathing. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new drug.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on certain treatments like small molecule kinase inhibitors, chemotherapy, or biologic therapies, you may need to stop them 2-4 weeks before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of Zanzalintinib, Pembrolizumab, and Cetuximab might be safe and manageable for people with head and neck cancer. In earlier studies, this treatment was generally well-tolerated, and many patients experienced good disease control, meaning their cancer did not worsen.

Since this study is in the early stages, it primarily aims to determine the right dose and understand any side effects. Being in this phase means that safety information is still being collected. Pembrolizumab and Cetuximab are already used in other treatments and are generally considered safe. The safety of Zanzalintinib is still under investigation, but early results are promising. Prospective participants will receive a thorough explanation of all potential risks and benefits to help make an informed choice. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for head and neck cancer because it combines Zanzalintinib, a novel drug, with the established therapies Pembrolizumab and Cetuximab. Unlike traditional treatments that focus solely on one pathway, Zanzalintinib targets multiple pathways, potentially enhancing the immune system's ability to fight cancer more effectively. This combination could offer a more comprehensive approach, potentially improving outcomes for patients who have limited options with current therapies. By integrating these drugs, the treatment aims to leverage the strengths of each, potentially leading to better control of the disease.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

Research has shown that combining Zanzalintinib with immune checkpoint inhibitors, such as Pembrolizumab, leads to promising results. Earlier studies demonstrated that tumors shrink in 63% of cases and either shrink or stabilize in 90% of cases with this combination. In this trial, participants will receive a combination of Zanzalintinib, Pembrolizumab, and Cetuximab. Pembrolizumab effectively treats various cancers, including head and neck cancer. Cetuximab targets specific proteins on cancer cells to slow their growth. While researchers continue to study Zanzalintinib on its own, using these treatments together aims to enhance their overall effectiveness against cancer. This combination holds potential for better outcomes in head and neck cancer cases. ^{1 6 7 8 9}

Who Is on the Research Team?

Ari Rosenberg, MD

Principal Investigator

University of Chicago Medicine Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with recurrent or metastatic squamous cell carcinoma of the head and neck. Participants must have measurable disease, be able to provide tissue samples, and have adequate organ function. Specific eligibility criteria are not provided but typically exclude those with certain health conditions or treatments that could interfere with the study.

Inclusion Criteria

Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

I agree to use effective birth control during and after the study.

My cancer in the head or neck area has returned or spread and cannot be cured with surgery or radiation.

Exclusion Criteria

Prior treatment within specified time frames before the first dose of study treatment

Pregnancy or breastfeeding at screening

I do not have any infections needing treatment or major health problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive Zanzalintinib, Cetuximab, and Pembrolizumab in 42-day cycles to determine the maximally tolerated dose (MTD) and recommended Phase II dose (RP2D).

42 days per cycle

3 visits (in-person) per cycle

Dose Expansion

Participants receive the combination of Zanzalintinib, Cetuximab, and Pembrolizumab at the recommended Phase II dose in 42-day cycles.

42 days per cycle

3 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival (PFS) and overall survival (OS).

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cetuximab
• Pembrolizumab
• Zanzalintinib

Trial Overview The trial tests Zanzalintinib combined with Pembrolizumab and Cetuximab in patients. It aims to find the safest high dose (MTD) and suggest a Phase II dose (RP2D), while checking how well it works by measuring time without disease progression (PFS) and survival time (OS).

How Is the Trial Designed?

Group I: Dose Expansion Experimental Treatment 3 Interventions

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 II: Dose Escalation (Dose Level 1) Experimental Treatment 3 Interventions

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 III: Dose Escalation (Dose Level 0) Experimental Treatment 3 Interventions

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 IV: Dose Escalation (Dose Level -1) Experimental Treatment 3 Interventions

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

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

In a study of 46 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, the combination of weekly paclitaxel and cetuximab showed a promising overall response rate of 54%, with 22% achieving complete responses.

The treatment was well tolerated, with a disease control rate of 80% and median overall survival of 8.1 months, making it a potential option for patients who cannot receive platinum-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the combination of cetuximab and weekly paclitaxel in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Hitt, R., Irigoyen, A., Cortes-Funes, H., et al.[2022]

The combination of pembrolizumab and vorinostat showed some effectiveness in treating recurrent/metastatic head and neck cancers, with 32% of patients experiencing a partial response, although no complete responses were observed.

Patients experienced higher toxicity levels compared to pembrolizumab alone, with 54% reporting grade 1 or higher adverse events, indicating that while the treatment has potential, it may come with increased risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer. Rodriguez, CP., Wu, QV., Voutsinas, J., et al.[2020]

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

In a study with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., et al.[2023]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

The study evaluated the effectiveness of pembrolizumab and cetuximab, both alone and in combination, on head and neck squamous cell carcinoma (HNSCC) using the FLAVINO assay, revealing significant variability in patient responses, particularly in those with cisplatin-resistant cases.

An 'IP-10 score' was developed to predict patient outcomes based on their response to treatment, indicating that higher levels of IP-10 release in response to interferon gamma (IFN-γ) stimulation may correlate with better outcomes for certain HNSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel Biomarker. Berszin, M., Michaelides, I., Siemert, J., et al.[2022]

In a study involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

In a phase 1b trial involving 60 patients with recurrent or metastatic squamous cell carcinoma of the head and neck, pembrolizumab was found to be well tolerated, with only 17% experiencing severe drug-related adverse events and no drug-related deaths.

The treatment showed clinically meaningful antitumor activity, with an overall response rate of 18%, and particularly higher in HPV-positive patients at 25%, indicating its potential as a viable therapy for advanced head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Seiwert, TY., Burtness, B., Mehra, R., et al.[2022]

Citations

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STELLAR-305: A randomized phase 2/3 study of ... Zanzalintinib + ICI combination has shown promising antitumor activity and manageable safety in a phase 1 study in solid tumors. To further ...

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Press Release - Exelixis, Inc. Zanzalintinib in combination with nivolumab demonstrated an objective response rate of 63% and a disease control rate of 90%.

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Exelixis and Merck Sign Clinical Development ... In the U.S., it is estimated there will be more than 58,450 new cases of head and neck cancer diagnosed and more than 12,230 deaths from the disease in 2024.

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long-term survival update with a biomarker analysis Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic ...

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Zanzalintinib with Pembrolizumab and Cetuximab for the ... Giving zanzalintinib with pembrolizumab and cetuximab may be safe, tolerable and/or effective in treating patients with recurrent and/or metastatic squamous ...

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Metastatic Head and Neck Cancer: Immunotherapy and ... KEYNOTE-B10 results showed similar efficacy with a response rate of 49% (95% CI 38.4-58.7), median PFS 5.6 months (95% CI 5.1-6.7), and OS 13.1 months (95% CI ...