A Phase II/III Trial of Chemotherapy + Cetuximab vs Chemotherapy + Bevacizumab vs Atezolizumab + Bevacizumab Following Progression on Immune Checkpoint Inhibition in Recurrent/Metastatic Head and Neck Cancers

Plain English Summary

Testing the Use of Investigational Drugs Atezolizumab and/or Bevacizumab With or Without Standard Chemotherapy in the Second-Line Treatment of Advanced-Stage Head and Neck Cancers is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Lip and Oral Cavity Carcinoma, Metastatic Nasal Cavity Squamous Cell Carcinoma, Metastatic Nasopharyngeal Squamous Cell Carcinoma, Metastatic Pharyngeal Squamous Cell Carcinoma, Metastatic Sinonasal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma. This trial compares chemotherapy with different combinations of immunotherapy drugs to treat advanced head and neck cancers. It's for patients who have had their cancer spread or return after initial treatment with immunotherapy. Participants will receive infusions of drugs and have blood samples taken. They will also continue their current cancer treatments. Alternative treatments include standard chemotherapy and immunotherapy. The trial aims to enroll 430 participants.

Official Summary

This phase II/III compares the standard therapy (chemotherapy plus cetuximab) versus adding bevacizumab to standard chemotherapy, versus combination of just bevacizumab and atezolizumab in treating patients with head and neck cancer that has spread to other places in the body (metastatic or advanced stage) or has come back after prior treatment (recurrent). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Cisplatin and carboplatin are in a class of chemotherapy medications known as platinum-containing compounds. They work by killing, stopping, or slowing the growth of cancer cells. Docetaxel is in a class of chemotherapy medications called taxanes. It stops cancer cells from growing and dividing and may kill them. The addition of bevacizumab to standard chemotherapy or combination therapy with bevacizumab and atezolizumab may be better than standard chemotherapy plus cetuximab in treating patients with recurrent/metastatic head and neck cancers.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible patients must be 18 years or older, have advanced head and neck cancer, and have previously received immunotherapy. Patients cannot have had prior antiangiogenic treatments or severe infections. Health requirements include no uncontrolled hypertension and no history of bleeding or thrombosis. This trial is studying Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Lip and Oral Cavity Carcinoma, Metastatic Nasal Cavity Squamous Cell Carcinoma, Metastatic Nasopharyngeal Squamous Cell Carcinoma, Metastatic Pharyngeal Squamous Cell Carcinoma, Metastatic Sinonasal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures focus on how long patients can live without their cancer getting worse and their overall survival. The specific primary outcome measures are: Progression free survival (PFS) (Phase II) (Time from treatment initiation until disease progression or death, assessed up to 5 years from randomization); Overall survival (OS) (Phase III) (Time from treatment initiation until death from any cause, assessed up to 5 years from randomization). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill a treatment gap by evaluating new combinations of immunotherapy drugs for advanced head and neck cancers. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Lip and Oral Cavity Carcinoma, Metastatic Nasal Cavity Squamous Cell Carcinoma, Metastatic Nasopharyngeal Squamous Cell Carcinoma, Metastatic Pharyngeal Squamous Cell Carcinoma, Metastatic Sinonasal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, where improved treatment options are needed.

Investor Insight

The large market size and competitive landscape make this trial significant, with a high probability of approval if successful. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if you have advanced head and neck cancer and have tried immunotherapy. Understand that you will receive infusions of drugs and have blood samples taken. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 430 participants

Interventions

• BIOLOGICAL: Atezolizumab — Given IV
• BIOLOGICAL: Bevacizumab — Given IV
• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• DRUG: Carboplatin — Given IV
• BIOLOGICAL: Cetuximab — Given IV

Primary Outcomes

• Progression free survival (PFS) (Phase II) (Time from treatment initiation until disease progression or death, assessed up to 5 years from randomization)
• Overall survival (OS) (Phase III) (Time from treatment initiation until death from any cause, assessed up to 5 years from randomization)

Secondary Outcomes

• OS in the subset of patients with high PD-L1 expression (Phase III) (Up to 5 years from randomization)
• Incidence of adverse events (Phase III) (Up to 30 days after completion of treatment)
• Correlation between fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET) and computed tomography (CT) neck imaging biomarkers (Up to 5 years from randomization)
• Prediction of treatment response (Baseline up to 12 weeks)

Full Eligibility Criteria

Inclusion Criteria:

* Patient must have histologically confirmed squamous cell carcinoma of the head and neck (HNSCC) (excluding squamous cell carcinoma \[SCC\] of salivary glands, Epstein-Barr virus \[EBV\]-associated nasopharynx and skin)
* Patient must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Measurements must be obtained within 4 weeks prior to randomization
* Patient must be \>= 18 years of age
* Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Patient must have disease progression after prior therapy with an immune checkpoint inhibitor (ICI) in the first-line setting for recurrent/metastatic disease. Patient must have received first-line immune checkpoint inhibition for at least 6 weeks. Patients who have recurred or progressed within 12 weeks of immune checkpoint inhibition administered in the definitive setting for locally advanced disease (for e.g., in the context of a clinical trial) will also be eligible if local therapies are not feasible
* Prior combination immunotherapies are permitted, but patient must not have had prior antiangiogenic treatment (e.g., bevacizumab, ziv-aflibercept, ramucirumab, sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, etc.). Patient must have completed any prior investigational therapy at least 28 days prior to randomization.

  * NOTE: Patients who received platinum/taxanes in the locally-advanced or recurrent/metastatic setting and did not progress for at least 4 months thereafter, will be eligible for this study. Patients who received cetuximab in the locally-advanced setting and did not progress for at least 4 months thereafter, will also be eligible for this study
* Patient must not have a history of \>= grade 3 immune-related adverse event on prior ICI therapy (except those that could be managed with steroids \[e.g., dermatologic toxicity, asymptomatic elevation of pancreatic enzymes, etc.\]) and ICI could eventually be resumed. Patients who developed grade 3 endocrinopathies but are now stable on hormone supplementation and/or a daily prednisone dose of =\< 10 mg (or equivalent doses of another glucocorticoid), will be permitted on this trial
* Patient must not have a history of PD-1 inhibitor-induced hyper-progression, defined as 100% increase in tumor burden within 8 weeks (or 50% within 4 weeks) of initiating ICI and associated with clinical deterioration
* Patient must not have any of the following criteria due to the possibility of increased risk for tumor bleeding with bevacizumab therapy:

  * Prior carotid bleeding,
  * Tumors that invade major vessels (e.g., the carotid) as shown unequivocally by imaging studies,
  * Central (e.g., within 2 cm from the hilum) lung metastases that are cavitary as shown unequivocally by imaging studies,
  * Any prior history of bleeding related to the current head and neck cancer,
  * History of gross hemoptysis (bright red blood of 1/2 teaspoon or more per episode of coughing) within 3 months prior to randomization
* Patient must not have uncontrolled hypertension, a history of hypertensive crisis or hypertensive encephalopathy, or a history of grade 4 thromboembolism
* Patient must not have a history of coagulopathy or hemorrhagic disorders
* Patient must not have a history of thrombosis (e.g., pulmonary embolism or deep venous thrombosis) currently requiring therapeutic anticoagulation (prophylactic use of anticoagulation is allowed)
* Patient must not be receiving chronic daily treatment with aspirin (\> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAID's) known to inhibit platelet function. The use of anti-platelet agents \[e.g., dipyridamole (Persatine), ticlopidine (Ticlid), clopidogrel (Plavix)\] is allowed only if patient is not receiving concurrent aspirin or NSAID's known to inhibit platelet function
* Patient must have PD-L1 expression \>= 1% by CPS in the tumor and/or immune cells

  * NOTE: Enrolling centers should test for PD-L1 CPS preferably using the SP263 assay. Where this is not feasible, using their preferred Clinical Laboratory Improvement Act (CLIA)-certified or similar assay will be accepted. It is preferred for standard of care (SOC) PD-L1 assessments to be done on post-first line ICI samples if available, but SOC PD-L1 assessments on pre-ICI samples will be accepted for eligibility
* Patient must not have a severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Patients must not have active tuberculosis
* Patient must not have a history of non-infectious pneumonitis requiring steroids at doses greater than or equal to 10 mg per day of prednisone or the equivalent on first line immunotherapy
* Patient must not have a history of solid organ transplantation or stem-cell transplant
* Patient must not be on immunosuppressive medication within 7 days prior to random

Trial Locations

• University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States
• Epic Care-Dublin, Dublin, California, United States
• Epic Care Partners in Cancer Care, Emeryville, California, United States
• UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care, Irvine, California, United States
• Contra Costa Regional Medical Center, Martinez, California, United States
• UC Irvine Health/Chao Family Comprehensive Cancer Center, Orange, California, United States
• Stanford Cancer Institute Palo Alto, Palo Alto, California, United States
• VA Palo Alto Health Care System, Palo Alto, California, United States
• Smilow Cancer Hospital-Derby Care Center, Derby, Connecticut, United States
• Smilow Cancer Hospital Care Center-Fairfield, Fairfield, Connecticut, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Related conditions include other types of head and neck cancers, such as oropharyngeal, laryngeal, and nasopharyngeal carcinomas.
• Therapeutic areas include oncology and immunotherapy.

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