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

36 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Zanzalintinib, Pembrolizumab, and Cetuximab for head and neck cancer?

Research shows that Pembrolizumab and Cetuximab are effective in treating head and neck cancer, especially when used together or with chemotherapy. Pembrolizumab, an immune therapy, has shown improved responses in patients with certain cancer markers, and combining it with other treatments like Cetuximab, which targets cancer cell growth, may enhance effectiveness. ^{1 2 3 4 5}

What safety information is available for the combination of Zanzalintinib, Pembrolizumab, and Cetuximab in head and neck cancer treatment?

Pembrolizumab and cetuximab have been studied for head and neck cancer, showing manageable side effects. Common side effects include skin issues like rashes and dry skin, and more severe reactions are rare. These drugs have been used safely in humans, but specific safety data for Zanzalintinib is not provided in the available research. ^{5 6 7 8 9}

What makes the combination of Zanzalintinib, Pembrolizumab, and Cetuximab unique for head and neck cancer?

This treatment is unique because it combines Zanzalintinib, a novel drug, with Pembrolizumab and Cetuximab, which are antibodies that target different pathways in cancer cells. This combination may offer a new approach for patients with head and neck cancer, especially those who are resistant to standard treatments like cisplatin. ^{1 5 10 11 12}

What is the purpose of this trial?

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).

Research Team

Ari Rosenberg, MD

Principal Investigator

University of Chicago Medicine Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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

Findings from Research

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 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 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]

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]

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 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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

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2. Switzerland pubmed.ncbi.nlm.nih.gov

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers. [2022]

3. England 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. [2023]

4. United States 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. [2023]

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Pembrolizumab plus cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. [2021]

6. England 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. [2019]

7. England 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. [2022]

8. England 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. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Dermatologic Toxicities of Targeted Therapy and Immunotherapy in Head and Neck Cancers. [2021]

10. Switzerland 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. [2022]

11. United States 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. [2022]

12. United States 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. [2020]