VELOCITY-HNSCC Substudy-01: a phase 2 study of novel combination therapies in participants with previously untreatedrecurrent or metastatic head and neck squamous cell carcinoma regardless of PD-L1 expression status

PI: Prof. Lisa Licitra 

The 01/VELOCITY HNSCC study is a clinical trial evaluating the activity of the immunotherapy drugs Zimberelimab and Domvanalimab in combination with Paclitaxel and Carboplatin-based chemotherapy in patients with locally recurrent and/or distant metastatic squamous cell carcinoma of the head and neck, who have not yet received treatment for recurrent disease. 

Zimberelimab and Domvanalimab are drugs known as inhibitors designed to act by targeting specific parts of immune cells. Specifically, Zimberelimab acts on a protein called Programmed cell Death Protein 1 (PD-1), which is located on the surface of immune cells and prevents the immune system from attacking cancer cells. Domvanalimab targets a specific immune cell receptor known as TIGIT. By targeting these proteins, Zimberelimab and Domvanalimab help the immune system improve its ability to attack and destroy cancer cells. 

This study, conducted in accordance with international ethical guidelines, is considered experimental, as Zimberelimab and Domvanalimab have not been approved by health authorities for the treatment of head and neck cancer. However, the potential impact of Zimberelimab and Domvanalimab has already been demonstrated in previous clinical studies, supporting the biological and clinical rationale that immune checkpoint inhibitors may improve prognosis in this patient population. 

By contrast, Paclitaxel and Carboplatin have long been approved by the Food and Drug Administration (FDA) in the United States and by the AIFA (Italian Medicines Agency) for the treatment of certain types of cancer. 

The objective of this study is therefore to achieve greater oncological responses to the experimental drugs Zimberelimab and Domvanalimab in combination with the chemotherapeutic agents Paclitaxel and Carboplatin, and to improve progression-free survival in these patients. 

This is an open-label, randomized study. 
The term "open-label" means that the patient, the doctor, and the study staff all know which study drugs are being administered. 
The term "randomized" means that the study drugs are assigned randomly, like flipping a coin. Assignment to one treatment group or the other will occur through a computerized system called "randomization", which randomly allocates patients to treatment groups, without any decision-making by the investigator or the patient. There will be a 50% chance of being assigned to Group A and a 50% chance of being assigned to Group B: 

• Group A: will receive Zimberelimab, Domvanalimab, Paclitaxel, and Carboplatin 
• Group B: will receive Zimberelimab, Paclitaxel, and Carboplatin 

The feasibility of enrollment in the study depends on: patient characteristics (demographics, oncological history, and comorbidities), laboratory tests, and radiological parameters, which will be assessed through specific screening examinations before starting treatment. These assessments will be performed at this institution according to well-defined timelines. 

The treatment schedule will be as follows: 

• Zimberelimab, with or without Domvanalimab, administered via intravenous infusion every 3 weeks, for up to 35 cycles (approximately 2 years) 
• Paclitaxel and Carboplatin, administered via intravenous infusion every 3 weeks, for up to 6 cycles 

Treatment will continue until maximum response is achieved and in accordance with the study protocol. Treatment will be discontinued in case of disease progression, unacceptable toxicity, or, as always in clinical trials, if decided by either the investigator or the patient (who will nonetheless continue to have access to medical care and will not forfeit any legal rights or benefits to which they are entitled). 

Patients will also be monitored for adverse events caused by chemotherapy and for immune-related toxicities induced by immunotherapy, as a result of immune system overactivity. In fact, it can happen that immunotherapy treatment causes adverse events—many of which are already known—because the immune system may attack not only diseased cells but also healthy ones, being no longer able to recognize them. In such cases, the investigators will propose symptomatic therapies and implement targeted strategies to reduce the intensity of these side effects (e.g., therapeutic pauses, dose reductions, corticosteroid-based treatments, etc.). To ensure patient safety from the toxicities of chemotherapy and immunotherapy, study participants will be closely monitored. 

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