Evaluation of BrECADD Versus Escalated BEACOPP in First-Line Treatment of Advanced Hodgkin Lymphoma: A Randomized Controlled Trial

The primary objective of this study is to demonstrate the reduced toxicity of the BrECADD treatment regimen compared to the escalated BEACOPP regimen in patients with **advanced stage Hodgkin lymphoma**. This is measured by treatment-related morbidity (TRMB). Additionally, the study aims to establish the non-inferior efficacy of 6 cycles of BrECADD compared to 6 cycles of escalated BEACOPP, each followed by radiotherapy to PET-positive residual lesions, in terms of progression-free survival. These objectives are clinically relevant as they address the need for effective treatment options with minimized adverse effects, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include further exploration of the efficacy, safety, and feasibility of the treatment regimen. This exploration is crucial for understanding the broader implications of the treatment in clinical practice and ensuring its applicability and safety for a wider patient population.

The clinical trial involves a total of **265 participants** diagnosed with an **advanced stage of Hodgkin Lymphoma**. The study population includes both male and female subjects, with an age range of 18 to 75 years. Participants are categorized into two groups: those aged 18 to 60 years and a cohort of older patients aged 61 to 75 years. The trial population was selected based on specific criteria, including a histologically proven diagnosis of classical Hodgkin lymphoma, with no previous treatment, and classified as stage IIB with large mediastinal mass and/or extranodal lesions, stage III, or IV. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy and safety across different age groups.

The clinical trial is designed to evaluate the efficacy and safety of two treatment regimens for **advanced stage Hodgkin lymphoma**. This is a randomized, double-blind, controlled trial comparing 4-6 cycles of escalated BEACOPP with 4-6 cycles of BrECADD, each followed by radiotherapy to PET-positive residual lesions. The primary objective is to demonstrate reduced toxicity of the BrECADD treatment compared to escalated BEACOPP, as measured by treatment-related morbidity. Additionally, the trial aims to establish the non-inferior efficacy of 6 cycles of BrECADD in terms of progression-free survival. The trial is expected to run from March 2016 to December 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven classical Hodgkin lymphoma, first diagnosis, and specific disease stages. The trial includes a cohort of patients aged 18 to 60 years and a separate cohort for older patients aged 61 to 75 years. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the primary and secondary endpoints, including progression-free survival, overall survival, and quality of life.

The expected length of participant involvement varies depending on the treatment regimen, with a maximum treatment period of 6 cycles for escalated BEACOPP and BrECADD. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **ADCETRIS** (brentuximab vedotin), a **powder for concentrate for solution for infusion**. This experimental medication is administered via **intravenous infusion**. The maximum daily dose is 180 mg, with a total maximum dose of 1080 mg over a treatment period of up to 6 cycles. Brentuximab vedotin is a monoclonal antibody against human CD30, covalently linked to the cytotoxin monomethylauristatin E, and is classified as an immunological/biological product.

**Doxorubicin hydrochloride** is used as a comparator treatment in the study. It is provided as a **concentrate for solution for infusion** and administered through **intravenous infusion**. The maximum daily dose is 40 mg/m², with a total maximum dose of 240 mg/m² over a 6-cycle treatment period. Doxorubicin hydrochloride is of chemical origin.

**Dexamethasone** is included in the trial as a non-experimental treatment. It is administered orally in **tablet** form. The maximum daily dose is 40 mg, with a total maximum dose of 960 mg over a 24-cycle treatment period. Dexamethasone is of chemical origin.

**Procarbazine hydrochloride** is administered orally in **capsule** form. The maximum daily dose is 100 mg/m², with a total maximum dose of 4200 mg/m² over a 42-cycle treatment period. This medication is of chemical origin.

**Bleomycin sulfate** is provided as a **solution for injection** and administered via **intravenous bolus use**. The maximum daily dose is 10 mg/m², with a total maximum dose of 60 mg/m² over a 6-cycle treatment period. Bleomycin sulfate is of chemical origin.

**Vincristine sulfate** is administered as an **injection** via **intravenous bolus use**. The maximum daily dose is 1.4 mg/m², with a total maximum dose of 8.4 mg/m² over a 6-cycle treatment period. Vincristine sulfate is of chemical origin.

**Prednisone** is administered orally in **tablet** form. The maximum daily dose is 40 mg/m², with a total maximum dose of 3360 mg/m² over an 84-cycle treatment period. Prednisone is of chemical origin.

**Dacarbazine** is provided as a **powder for solution for injection/infusion** and administered via **intravenous infusion**. The maximum daily dose is 250 mg/m², with a total maximum dose of 3000 mg/m² over a 12-cycle treatment period. Dacarbazine is of chemical origin.

**Etoposide phosphate** is administered as a **solution for injection/infusion** via **intravenous infusion**. The maximum daily dose is 200 mg/m², with a total maximum dose of 3600 mg/m² over an 18-cycle treatment period. Etoposide phosphate is of chemical origin.

**Cyclophosphamide monohydrate** is provided as a **powder for solution for injection/infusion** and administered via **intravenous infusion**. The maximum daily dose is 1250 mg/m², with a total maximum dose of 7500 mg/m² over a 6-cycle treatment period. Cyclophosphamide monohydrate is of chemical origin.

**Etoposide** is administered as a **solution for infusion** via **intravenous infusion**. The maximum daily dose is 250 mg/m², with a total maximum dose of 3000 mg/m² over an 18-cycle treatment period. Etoposide is of chemical origin.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **treatment-related morbidity (TRMB)** and progression-free survival (PFS) for the randomized main study, as well as the complete remission (CR) rate after chemotherapy for the cohort of older patients. Secondary endpoints for the randomized main study encompass tumor response (CR rate), overall survival (OS), infertility rate at 1 year, second malignancies, quality of life (QoL), frequency of adverse events, therapy adherence, and event-free survival (EFS). For the cohort of older patients, secondary endpoints include TRMB, PFS, OS, time to progression (PFSHL), and Hodgkin lymphoma-specific survival (OSHL).

The trial aims to demonstrate reduced toxicity of the BrECADD treatment compared to escalated BEACOPP treatment, measured by TRMB, and to establish non-inferior efficacy of 6 cycles of BrECADD compared to 6 cycles of escalated BEACOPP, each followed by radiotherapy to PET-positive residual lesions, in terms of PFS. The trial is designed to optimize treatment for advanced stage Hodgkin lymphoma, comparing 4-6 cycles of escalated BEACOPP with 4-6 cycles of BrECADD.