Phase III Randomized Trial of Adjuvant Nivolumab with Cisplatin-Based Chemoradiotherapy in High-Risk Resected Squamous Cell Carcinoma of the Head and Neck

The primary objective of this phase III randomized trial is to determine the **efficacy** of nivolumab in combination with cisplatin-radiotherapy (RT) compared to the standard of care (SOC) cisplatin-RT alone in patients with resected squamous cell carcinoma of the head and neck. The primary endpoint is disease-free survival (DFS) as assessed by investigator imaging. This is clinically relevant as it aims to improve post-operative outcomes in high-risk patients by potentially enhancing DFS, which is a critical measure of treatment success in oncology.

Secondary objectives include:

• Comparing overall survival (OS), local regional control, and distant metastases between the nivolumab plus cisplatin-RT group and the SOC cisplatin-RT group.
• Determining DFS through blinded independent central imaging review.
• Evaluating the overall safety and tolerability profile of nivolumab in combination with cisplatin-RT versus SOC cisplatin-RT.
• Assessing DFS by PDL-1 expression using the 28-8 assay.
• Evaluating candidate immune-related predictive biomarkers of sensitivity to nivolumab in tumor samples obtained at surgery and in blood, and exploring potential correlations between treatment outcomes and the immune landscape.

The clinical trial involves a total of **5 participants** diagnosed with **resected squamous cell carcinoma of the head and neck**. The study population includes both male and female subjects, aged between 18 and 75 years, who have undergone primary surgery for their condition. Participants were selected based on specific criteria, including a histopathological classification of pStage III or IV, or pStage II p16 positive with certain tobacco consumption levels, as per the American Joint Committee on Cancer 8th edition. All subjects must have had a complete macroscopic resection and be free of disease at the time of enrollment. The trial does not include a vulnerable population. Lifestyle factors such as alcohol consumption and smoking history are recorded, which may be relevant to the study outcomes. Participants are required to have a Performance Status (PS) ECOG of 0-1, indicating they are in relatively good health and capable of self-care. The trial aims to assess the efficacy of nivolumab combined with cisplatin-RT compared to the standard of care cisplatin-RT alone, with disease-free survival as the primary endpoint.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of **nivolumab** in combination with **cisplatin**-radiotherapy compared to the standard of care (SOC) cisplatin-radiotherapy alone in patients with resected squamous cell carcinoma of the head and neck. The primary endpoint is disease-free survival (DFS) as assessed by investigator imaging. Secondary endpoints include overall survival, DFS by blinded independent central imaging review, and safety assessments. The trial is expected to commence recruitment on June 13, 2024, and conclude by December 30, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histopathological classification, and performance status. Following randomization, participants will receive treatment over a maximum period of 32 weeks, with regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. The expected length of participant involvement is approximately 32 weeks, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent.

Inclusion criteria require participants to be between 18 and 75 years of age, have undergone primary surgery for squamous cell carcinoma of the head and neck, and meet specific histopathological and clinical criteria. Exclusion criteria are not explicitly detailed in the provided data. The trial will utilize intravenous administration of the investigational products, with **cisplatin** and **nivolumab** being administered as solutions for infusion. The study aims to provide valuable insights into the potential benefits of adding nivolumab to the existing cisplatin-radiotherapy regimen for this patient population.

The clinical trial involves the administration of **Cisplatin**, marketed as CISPLATINE ACCORD 1 mg/mL, which is a **solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous administration. The dosage is calculated based on body surface area, with a maximum daily dose of 100 mg/m² and a total maximum dose of 300 mg/m² over a treatment period of up to 3 cycles. Cisplatin is a cytostatic antineoplastic agent, and its administration is monitored to ensure compliance with the dosing schedule.

Another experimental medication used in the trial is **Nivolumab**, marketed as OPDIVO 10 mg/mL, which is a concentrate for solution for infusion. This medication is also administered intravenously. The maximum daily dose for Nivolumab is 480 mg, with a total maximum dose of 4200 mg over a treatment period of up to 32 cycles. Nivolumab is a protein-based therapeutic agent, and its administration is carefully monitored to ensure adherence to the prescribed dosing regimen.

In this study, the experimental treatments are compared against the standard-of-care therapy, which involves the administration of cisplatin in conjunction with radiotherapy (cisplatin-RT). The primary objective is to evaluate the efficacy of the combination of Nivolumab and cisplatin-RT relative to the standard cisplatin-RT alone, with disease-free survival as the primary endpoint. Compliance with the treatment protocol is monitored throughout the trial to ensure the integrity of the study results.

The efficacy of the clinical trial will be assessed primarily through **Disease-Free Survival (DFS)**, as determined by investigator imaging assessments. DFS is defined as the time from randomization to the first occurrence of loco-regional or distant recurrence, or death from any cause, whichever occurs first. This primary endpoint will provide a direct measure of the treatment's effectiveness in preventing disease progression or recurrence in patients with resected squamous cell carcinoma of the head and neck (SCCHN).

Secondary endpoints include overall survival, DFS by blinded independent central imaging review, and DFS and overall survival stratified by PD-L1 status. Additional secondary measures involve the cumulative incidence of locoregional failure, distant metastatic failure, and death without prior progression. The incidence of second primary malignancies and safety assessments, including adverse events and laboratory abnormalities graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0), will also be evaluated. The trial will further explore the correlation between the immune landscape and patient outcomes.