Randomized Non-Inferiority Trial of Hypoxia-Profile Guided Nimorazole in Radiotherapy/Chemoradiotherapy for Head and Neck Squamous Cell Carcinoma

The primary objective of the study is to demonstrate a comparable treatment response in patients with **head and neck squamous cell carcinoma (HNSCC)** who are predicted as non-responders to the hypoxic modifier **nimorazole** based on a hypoxia gene profile. These patients are randomized to receive concurrent nimorazole or not during their radiotherapy or chemoradiotherapy. This objective is clinically relevant as it aims to optimize treatment strategies for HNSCC by identifying patients who may not benefit from hypoxic modification, thereby potentially sparing them from unnecessary treatment and associated side effects.

The clinical trial involves participants diagnosed with **head and neck squamous cell carcinoma (HNSCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. The trial does not involve a vulnerable population. Participants were selected based on specific criteria, including the indication for hypoxic modification with nimorazole under primary radiotherapy, as per DAHANCA's guidelines. The trial excludes individuals with concurrent or previous malignant diseases that could impact treatment outcomes. Informed consent is required, and radiotherapy must commence within three weeks of inclusion. Additionally, a hypoxic status from gene profile testing must be available before the initiation of radiotherapy. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, non-inferiority study to evaluate the efficacy of hypoxia-profile guided hypoxic modification with **nimorazole** during radiotherapy or chemoradiotherapy in patients with head and neck squamous cell carcinoma (HNSCC). The trial aims to demonstrate comparable treatment responses in patients predicted as non-responders to nimorazole based on a hypoxia gene profile. Participants will be randomly assigned to receive either nimorazole or no hypoxic modification during their treatment. The trial is expected to run from July 2016 to December 2029, with the primary endpoint being locoregional control after radiotherapy, excluding possible salvage treatment. Secondary endpoints include local and regional control, distant metastases, overall survival, and morbidity.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as the absence of concurrent malignant diseases and the availability of hypoxic status from gene profile testing. Radiotherapy must be planned to start within three weeks from inclusion. Follow-up visits will be scheduled to monitor treatment response and adverse events, with the end-of-study visit marking the conclusion of the participant's involvement. The expected duration of participant involvement is up to six months, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the development of significant adverse events or withdrawal of consent.

The clinical trial involves the administration of **Nimorazole**, marketed as Nimoral tablets 500 mg, which is utilized as a **hypoxia modifier**. The pharmaceutical form of this experimental medication is a tablet, and it is administered orally. The dosage regimen for Nimorazole is set at a maximum daily dose of 3500 mg, with a total maximum dose of 75000 mg over a treatment period of up to 6 weeks. The active substance, Nimorazole, is chemically derived and is classified under the ATC code L01XD, which pertains to agents used in photodynamic therapy. The trial aims to evaluate the efficacy of Nimorazole in patients with head and neck cancer, specifically those predicted as non-responders to hypoxic modification based on a hypoxia gene profile.

In addition to the experimental treatment, the trial includes the administration of **Cisplatin**, a well-established **chemotherapeutic agent**. Cisplatin is administered via infusion, with a dosage of up to 40 mg/m² per day and a total maximum dose of 70 mg over the same 6-week treatment period. The active substance, Cisplatin, is also chemically derived and is classified under the ATC code L01XA01. This agent serves as a comparator treatment in the study, providing a standard-of-care reference for evaluating the efficacy of Nimorazole in the specified patient population.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is **locoregional control** after radiotherapy, excluding any potential salvage treatment. Secondary endpoints include local control at the T-site, regional control at the N-site, the presence of distant metastases, locoregional control after salvage treatment, overall survival, disease-free survival, disease-specific survival, and the assessment of acute or late morbidity. These endpoints will be measured to evaluate the treatment response in patients with head and neck cancer who are predicted as non-responders to the hypoxic modifier nimorazole based on a hypoxia gene profile. The trial aims to determine if these patients show comparable treatment responses when randomized to receive concomitant nimorazole or not. The schedule for measuring and collecting these efficacy parameters is aligned with the trial's design, although specific timepoints are not detailed in the provided data. The analysis will focus on comparing the outcomes between the treatment groups to establish non-inferiority in treatment response.