Evaluation of Non-Irritant Concentrations of Atezolizumab, Daratumumab, and Nivolumab in Skin Tests for Biotherapy Hypersensitivity in Oncology Patients

The primary objective of the study is to determine the maximum non-irritant concentration of biotherapy that can be utilized in allergologic **skin tests** (prick tests and intradermal tests) for patients suspected of hypersensitivity to the biotherapy, specifically in non-allergic patients treated with biotherapy. This is clinically relevant as it aims to establish a safe concentration threshold for skin testing, which is crucial for accurately diagnosing hypersensitivity reactions without causing undue irritation or false positives.

The secondary objective is to assess the possible occurrence of a delayed reaction at 48 hours and one week post-testing. This evaluation is important for understanding the temporal dynamics of hypersensitivity reactions, which can inform clinical management and patient monitoring strategies following skin testing.

The clinical trial involves participants diagnosed with various medical conditions, including **Chronic lymphocytic leukemia (CLL)**, AL amyloidosis, esophageal squamous cell carcinoma, myeloma, cholangiocarcinoma, Hodgkin lymphoma, non-small cell lung carcinoma, deficient mismatch repair (dMMR) colorectal adenocarcinoma, small cell lung carcinoma, follicular lymphoma, melanoma, hepatocellular carcinoma, gastric cardia cancer, locally advanced cutaneous squamous cell carcinoma, deficient mismatch repair (dMMR) colorectal cancer, and pleural mesothelioma. The study population includes both male and female subjects aged 18 years and older. Participants are required to have been treated with one of the specified biotherapies, such as Atezolizumab, Nivolumab, Obinutuzumab, Durvalumab, Pembrolizumab, Daratumumab, or Cemiplimab, and must have received at least two injections without suspected allergic side effects. The trial does not involve a vulnerable population. Participants must have medical care assurance rights and provide written informed consent. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations include the potential discontinuation of systemic corticosteroids and H1 antihistamines at least one week before testing, although inhaled corticosteroids are permitted.

The clinical trial is designed to evaluate the maximum non-irritant concentration of biotherapies used in allergologic skin tests for patients suspected of hypersensitivity. The trial employs a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. The trial is expected to commence on April 14, 2025, and conclude by May 20, 2027, with an estimated duration of approximately two years. Participants will be involved in the study for a maximum treatment period of one day, with the possibility of early termination if they experience any adverse reactions or fail to meet the inclusion criteria.

The sequence of study visits includes an initial **screening** visit to assess eligibility based on criteria such as age (≥18 years), prior treatment with the biotherapies under study, and the absence of suspected allergic side effects. Following the screening, participants will undergo skin tests using the biotherapies, including **atezolizumab**, **nivolumab**, **obinutuzumab**, **durvalumab**, **pembrolizumab**, **daratumumab**, and **cemiplimab**. The primary endpoint is to determine the maximum concentration that does not produce a skin reaction in at least 90% of patients. Secondary endpoints include monitoring for delayed reactions at the injection sites or systemic reactions post-administration. Follow-up visits will involve phone consultations to confirm the presence or absence of delayed reactions, with photographic evidence if necessary. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any adverse events are addressed.

Participants are expected to adhere to the study protocol, including discontinuation of corticosteroids and H1 antihistamines at least one week before testing, unless inhaled corticosteroids are used. Conditions leading to early termination include non-compliance with the protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial aims to provide valuable insights into the safe use of biotherapies in allergologic testing, contributing to improved patient care and management of hypersensitivity reactions.

The clinical trial involves the administration of several **experimental medications**. **Atezolizumab** is utilized in this study, presented in a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 0.5 ml, with a total dose not exceeding 0.5 ml per day. The administration route is categorized as "OTHER USE," and the treatment period is limited to one day. The active substance, atezolizumab, is a protein of non-human origin, and its role in the trial is as a test substance.

**Daratumumab** is another experimental medication used in the trial, also in the form PHF00231MIG. The dosing schedule mirrors that of atezolizumab, with a maximum daily and total dose of 0.5 ml. The administration route is similarly classified as "OTHER USE," and the treatment duration is one day. Daratumumab is a protein-based substance, serving as a test agent in the study.

**Nivolumab** is included in the trial, provided in the pharmaceutical form PHF00230MIG. The dosing parameters are consistent with the other medications, with a maximum daily and total dose of 0.5 ml. The administration route is "OTHER USE," and the treatment period is one day. Nivolumab, a protein of non-human origin, is utilized as a test substance.

**Durvalumab** is administered in the trial, also in the form PHF00230MIG. The dosing schedule is identical to the other medications, with a maximum daily and total dose of 0.5 ml. The administration route is "OTHER USE," and the treatment period is one day. Durvalumab is a protein-based substance, serving as a test agent in the study.

**Cemiplimab** is another experimental medication, provided as a solution for infusion. The dosing parameters are consistent with the other medications, with a maximum daily and total dose of 0.5 ml. The administration route is "OTHER USE," and the treatment period is one day. Cemiplimab, a protein of non-human origin, is utilized as a test substance.

**Obinutuzumab** is included in the trial, presented in the pharmaceutical form PHF00230MIG. The dosing schedule mirrors that of the other medications, with a maximum daily and total dose of 0.5 ml. The administration route is "OTHER USE," and the treatment period is one day. Obinutuzumab, a protein-based substance, serves as a test agent in the study.

**Pembrolizumab** is administered in the trial, also in the form PHF00230MIG. The dosing parameters are consistent with the other medications, with a maximum daily and total dose of 0.5 ml. The administration route is "OTHER USE," and the treatment period is one day. Pembrolizumab, a protein of non-human origin, is utilized as a test substance.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the study. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to evaluate the maximum non-irritant concentration of these biotherapies for use in allergologic skin tests.

Efficacy in the clinical trial titled "ETCABio - Evaluation of Skin Tests in Biotherapy Allergies" will be assessed using specific primary and secondary endpoints. The primary endpoint is the determination of the maximum non-irritant concentration of each biotherapy that can be used in allergologic skin tests, such as prick tests and intradermal tests. This concentration is defined as the maximum concentration that does not produce a skin reaction in at least 9 out of 10 patients, ensuring 90% specificity.

Secondary endpoints include the assessment of delayed reactions. A delayed reaction is identified if a skin reaction occurs at the intradermal injection sites 48 hours or one week after injection, or if a systemic reaction occurs following the administration of the biotherapy. To confirm the presence or absence of a delayed local reaction, patients will be contacted by phone. If necessary, a photograph taken during a consultation with the allergologist investigator or via video consultation will be used to confirm the reaction.