Evaluation of GR1014 Cutaneous Gel for Prevention of Radiodermatitis in Patients Undergoing Adjuvant Radiotherapy for Localized Breast Cancer

The primary objective of this study is to evaluate the **safety**, tolerability, and efficacy of GR1014-CG (4.7%; 2.4%) as a topical treatment to prevent **radiation-induced dermatitis** (radiodermatitis) associated with adjuvant ultra hypofractionated radiotherapy (RT) for localized, non-metastatic breast cancer following lumpectomy, compared to a vehicle gel. This is clinically relevant as radiodermatitis is a common and debilitating side effect of RT, impacting patient quality of life and potentially affecting treatment adherence.

Secondary objectives include: - Assessing the efficacy of GR1014-CG in reducing the severity, peak severity, emergence, and duration of radiodermatitis, as well as delaying its onset, compared to vehicle gel. - Evaluating its effectiveness in reducing severe radiodermatitis and other RT side effects, as well as patient-reported pain and pruritus intensity in the irradiated skin region. - Assessing participants' quality of life during and after RT. - Characterizing the plasma Cmax of amifostine thiol following GR1014-CG application. - Evaluating the efficacy of GR1014-CG in reducing skin hyperemia and preventing the loss of skin barrier integrity during and after RT, compared to vehicle gel.

The clinical trial involves a total of **82 participants** who are exclusively **female** and aged 18 years or older. The study population consists of patients with primary, localized breast cancer without metastases, who have undergone breast-conserving surgical excision and require adjuvant radiotherapy (RT). Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are in relatively good health. The trial specifically excludes individuals with any signs of dermatitis in the breast area to be irradiated, ensuring that participants are assessed as Grade 0 according to the CTCAE LV radiation dermatitis grading. The selection process mandates that participants have completed the appropriate washout period for any prior interventions or treatments. Additionally, participants must be able to comply with the RT and investigational treatment under medical supervision throughout the study period. The trial does not include any vulnerable populations, and all participants are affiliated with the Social Security System in France. The study aims to evaluate the safety, tolerability, and efficacy of GR1014-CG as a treatment to prevent **radiation-induced dermatitis** in patients undergoing ultra hypofractionated RT for localized, non-metastatic breast cancer after lumpectomy.

The clinical trial is designed as a **randomized**, **double-blind**, vehicle-controlled, multi-centre, parallel-group study. The primary objective is to investigate the safety, tolerability, and efficacy of GR1014 cutaneous gel as a topical radioprotector in preventing **radiation-induced dermatitis** in patients undergoing adjuvant radiotherapy for localized breast cancer post-lumpectomy. The trial is expected to commence on April 30, 2024, and conclude by April 30, 2025, with an estimated duration of one year.

Participants will be involved in the study for a period that includes the screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will involve screening to ensure participants meet the eligibility criteria, such as being female patients aged 18 years or older with localized breast cancer, and having no signs of dermatitis in the breast area to be irradiated. Follow-up visits will be scheduled to monitor the onset and progression of radiodermatitis, assess safety, and evaluate the efficacy of the treatment. The end-of-study visit will occur four weeks after the last radiotherapy session to assess the primary endpoint, which is the percentage of participants with no radiation dermatitis.

The expected length of participant involvement is approximately five weeks, corresponding to the duration of the ultra hypofractionated radiotherapy sessions and the subsequent follow-up period. Conditions that may lead to early termination from the study include the development of severe adverse reactions, inability to comply with study procedures, or withdrawal of consent by the participant. The study will adhere to rigorous ethical standards, ensuring informed consent is obtained from all participants prior to their inclusion in the trial.

The clinical trial involves the use of **GR1014 Cutaneous Gel**, which is an experimental medication formulated as a gel for **cutaneous use**. The active substance in this gel is **amifostine thiol**, a chemical compound known for its radioprotective properties. The gel is applied topically with a maximum daily dose of 50 mg/ml, and the treatment period is limited to a maximum of 5 days. The gel is manufactured by Graegis Pharmaceuticals Limited and is intended to prevent **radiodermatitis** in patients undergoing adjuvant radiotherapy for localized breast cancer following lumpectomy. The administration schedule is designed to ensure optimal efficacy and safety, with compliance monitored through regular assessments.

The study also includes a **placebo** group for comparison. The placebo is formulated to be identical to the GR1014 Cutaneous Gel in all aspects except for the absence of the active drug substance, **amifostine**, and hydrochloric acid, which is used in the hydrolysis step to convert amifostine into its active form, amifostine thiol. This ensures that any observed effects can be attributed to the active ingredient rather than other components of the gel. The placebo is administered in the same manner as the experimental gel, maintaining consistency in the application process and dosing schedule.

The efficacy of GR1014 cutaneous gel as a topical radioprotector in preventing **radiodermatitis** associated with adjuvant radiotherapy for localized breast cancer will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage of participants with no radiation dermatitis, defined as a Common Terminology Criteria for Adverse Events latest version (CTCAE LV) grade of 0, between the first radiotherapy (RT) session and four weeks after the last session. Secondary endpoints include the percentage of participants with a radiodermatitis grade ≥2 at any time during the same period, the maximum grade of radiodermatitis reached, and the time to onset and duration of radiodermatitis grade ≥2.

Additional secondary endpoints involve the assessment of severe radiodermatitis (grade ≥3), the number of cases of side effects other than radiodermatitis, and changes in skin pain and pruritus scores using a 0-10 Numeric Rating Scale. The Dermatology Life Quality Index (DLQI) will be evaluated weekly, and breast skin surface inflammation will be measured using a tristimulus colorimetric instrument. Transepidermal water loss (TEWL) will be measured from four test areas within the radiation field and a control area on the forearm. Pharmacokinetic parameters such as Cmax, Tmax, and AUClast will also be analyzed.