A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AV-299 in Combination with Cetuximab in Participants with Recurrent or Metastatic (R/M) HPV-Negative Head and Neck Squamous Cell Carcinoma

PI: Prof.ssa Lisa Licitra 

The study is designed to compare the efficacy and safety of ficlatuzumab in combination with cetuximab (experimental arm) versus placebo plus cetuximab (control arm) in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who are HPV (Human Papillomavirus) negative. 

Ficlatuzumab (AV-299) is a humanized monoclonal antibody that: 

• Binds to hepatocyte growth factor (HGF), inhibiting tumor cell proliferation, migration, and invasion; 
• Prevents activation of the c-MET signaling pathway, which is associated with tumor growth and metastatic spread; 
• Promotes the death of tumor cells. 

Cetuximab (C225) is a monoclonal antibody that: 

• Acts by binding to the epidermal growth factor receptor (EGFR) on tumor cells, thereby blocking its action; 
• Inhibits tumor cell proliferation and the formation of new blood vessels that support tumor growth; 
• Induces tumor cell death. 

This study aims to compare the anti-tumor activity of the combination therapy versus the current standard of care (cetuximab alone), with the hypothesis that the combination may lead to improvements in patient quality of life, tumor response, and progression-free survival. This hypothesis is strongly supported by encouraging results from previous clinical trials. 

Eligibility for enrollment in the study depends on: patient characteristics (demographic data and cancer history), laboratory values, and radiologic findings, which will be assessed through specific screening tests conducted before the start of treatment. These procedures will take place at this Institution, following a defined schedule. 

Additionally, eligible patients must: 

• Have previously received immunotherapy with anti-PD-1 (Programmed Cell Death Protein 1) or PD-L1 (Programmed Death Ligand 1) drugs, as well as platinum-based chemotherapy, either in combination or sequentially; 
• Not have received more than two prior lines of treatment for recurrent disease; 
• Not have been previously treated with cetuximab for recurrent and/or metastatic disease. 

Randomization, a computerized process, will determine assignment to one of the two study arms (ficlatuzumab + cetuximab vs. placebo + cetuximab). This ensures a random allocation without any decision-making power from the investigator or the patient. 

Ficlatuzumab and cetuximab will be administered intravenously every two weeks, until maximum response is achieved. 

When the two drugs are combined, patients will be monitored for potential toxicities, particularly: 

• Rash resembling acne, 
• Reduced albumin levels in the blood, 
• Edema (swelling in certain parts of the body). 

The treatment may also cause other, more common side effects. In such cases, the study team will adopt strategies to reduce their severity (e.g., dose reductions or treatment breaks) and manage symptoms (e.g., with symptomatic therapies). 

Treatment will continue until maximum response and will be discontinued only in case of: 

• Disease progression; 
• Unacceptable toxicity; 
• Or, as in any clinical trial, decision by the patient (who will continue to receive medical care and will not lose any legal rights or benefits) or by the investigator. 

The study staff is available for more detailed information (email: amo@istitutotumori.mi.it). 

* Placebo: A placebo is an inert substance administered during a clinical trial to serve as a comparison with a potentially active drug. In this study, the placebo will be a saline solution with no active ingredient, designed to look identical to the investigational drug.