Phase 3 Evaluation of Intratumoral NBTXR3 with Radiotherapy ± Cetuximab in Platinum-Ineligible Elderly Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma

The primary objective of this Phase 3 study is to evaluate **survival outcomes** in elderly patients with **Locally Advanced Head & Neck Squamous Cell Carcinoma** who are ineligible for platinum-based chemotherapy. The study compares the efficacy of intratumorally injected JNJ-90301900 (NBTXR3), activated by the investigator's choice of radiotherapy (RT) alone or in combination with **cetuximab**, against the investigator's choice of RT with or without cetuximab. This evaluation is clinically relevant as it aims to provide alternative therapeutic options for a patient population with limited treatment choices due to chemotherapy ineligibility.

The clinical trial involves a total of **307 participants** diagnosed with **locally advanced head and neck squamous cell carcinoma**. The study population includes both male and female subjects, with an age range starting from 60 years and above. Participants were selected based on specific inclusion criteria, such as having squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx, and being candidates for definitive radiation therapy with or without cetuximab. The trial excludes individuals eligible for platinum-based chemotherapy, focusing instead on those with certain health conditions, such as reduced creatinine clearance, hearing loss, or peripheral neuropathy, and those with an ECOG Performance Status of 2. The study does not involve a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria.

The clinical trial is designed to evaluate the **survival outcomes** in elderly patients with **Locally Advanced Head & Neck Squamous Cell Carcinoma** who are ineligible for platinum-based chemotherapy. This Phase III study employs a **randomized, controlled** trial design, comparing the efficacy of intratumorally injected JNJ-90301900 (NBTXR3) activated by the investigator's choice of radiotherapy, with or without the addition of **cetuximab**, against radiotherapy with or without cetuximab alone. The trial is expected to commence recruitment on June 1, 2025, and conclude by June 30, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥60 years), specific cancer staging, and ineligibility for platinum-based chemotherapy. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The primary endpoint is **progression-free survival**, defined as the time from randomization to loco-regional recurrence, progression, distant progression, or death from any cause. The end-of-study visit will occur upon completion of the treatment period or upon early termination.

The expected duration of participant involvement is approximately two years, contingent upon individual response and disease progression. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation for the participant's safety. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Erbitux**, a **solution for infusion** containing the active substance **cetuximab**. Cetuximab is a protein-based therapeutic agent, specifically classified under the ATC code L01FE01. The pharmaceutical form of Erbitux is a 5 mg/mL solution intended for **intravenous use**. The administration schedule and dosage are determined based on the patient's body surface area, expressed in mg/m². The maximum treatment period for Erbitux is set at 999 days, with no specified maximum daily or total dose amount. Erbitux is provided by Merck Europe B.V. and is not formulated for pediatric use.

Another experimental treatment in the study is **JNJ-90301900**, also known as **NBTXR3**, which contains the active substance **hafnium oxide**. This compound is a chemically derived agent and is administered as an **injection**. The route of administration for JNJ-90301900 is **intratumoral use**, targeting the tumor directly. The dosage is measured in milligrams, with no specified maximum daily or total dose amount, and the treatment period is also set at a maximum of 999 days. JNJ-90301900 is provided by Janssen-Cilag International N.V. and is not intended for pediatric use.

The trial evaluates the efficacy of JNJ-90301900 activated by the investigator's choice of radiotherapy, either alone or in combination with cetuximab, compared to radiotherapy with or without cetuximab. The study aims to assess survival outcomes in elderly patients with locally advanced head and neck squamous cell carcinoma who are ineligible for platinum-based chemotherapy. Participant compliance with the treatment regimen is monitored throughout the study to ensure adherence to the dosing schedules and administration routes.

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. This endpoint is defined as the time from randomization to the occurrence of loco-regional recurrence, loco-regional progression, distant progression, or death from any cause, whichever occurs first. The trial involves the administration of JNJ-90301900 (NBTXR3) activated by the investigator's choice of radiotherapy alone or in combination with **cetuximab**, compared to the investigator's choice of radiotherapy alone or with cetuximab. The study targets elderly patients with locally advanced head and neck squamous cell carcinoma who are ineligible for platinum-based chemotherapy. The efficacy parameters will be collected and analyzed to determine the survival outcomes of the participants, providing insights into the potential benefits of the treatment regimen under investigation.