RADAR: A randomised phase III trial with a PET response adapted design comparing ABVD +/- ISRT with A2VD +/- ISRT in patients with previously untreated stage IA/IIA Hodgkin lymphoma

The primary objective of this study is to evaluate whether substituting A2VD for ABVD in a **PET**-response adapted design can improve the **Progression Free Survival (PFS)** in patients with previously untreated stage IA/IIA **Hodgkin lymphoma**. This is clinically relevant as improving PFS could potentially lead to better long-term outcomes and reduce the need for more aggressive treatments in the future.

Secondary objectives include:

• Assessing the prognostic value of baseline metabolic tumor volume and/or tumor lesion glycolysis on PET.
• Evaluating the prognostic power of PET after 1 and 2 cycles of ABVD/A2VD compared with EORTC and GHSG pre-treatment risk factors.
• Determining the prognostic power of PET after 1 and 2 cycles using a quantitative extension to the Deauville score.
• Correlating response to treatment and side-effects with radiomic features on PET-CT.
• Evaluating the use of automated methods to measure uptake in and segment tumor and non-tumor tissue on FDG PET-CT scans.
• Monitoring changes in pulmonary function tests.
• Investigating the relationship between maximum tumor dimension at baseline and end of treatment with PFS.
• Improving the PET Complete Metabolic Response (CMR) rate.
• Enhancing Overall Survival (OS).
• Reducing late toxicity by decreasing the proportion of patients receiving radiotherapy and the incidence of second cancers and cardiovascular disease.
• Improving Event Free Survival (EFS).

The clinical trial involves a total of **342 participants** diagnosed with **stage IA/IIA Hodgkin lymphoma**. The study population includes both male and female subjects, aged between 16 and 69 years, with specific age criteria for certain centers. Participants are required to have adequate bone marrow function, a haemoglobin level of at least 8g/dl, and an ECOG performance status of 0-2. They must be fit to receive anthracycline-based chemotherapy, with specific cardiac function criteria for those with a history of ischaemic heart disease or hypertension. The trial population was selected based on their ability to comply with the protocol requirements, including providing written informed consent. Participants must not have received any previous treatment for Hodgkin lymphoma. Lifestyle considerations such as diet and physical activity are not specified, but participants must meet certain health criteria, including creatinine clearance and liver function tests within defined limits. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of substituting A2VD for ABVD in a PET-response adapted design for patients with stage IA/IIA **Hodgkin lymphoma**. The primary objective is to assess the improvement in Progression-Free Survival (PFS). Secondary endpoints include PET Complete Metabolic Response (CMR) rate after two cycles of ABVD/A2VD, Event-Free Survival (EFS), Overall Survival (OS), incidence of second cancers and cardiovascular disease, and the safety and toxicity of ABVD and A2VD as assessed by CTCAE v5.0. The trial is expected to run from June 15, 2023, to October 15, 2032, with a maximum treatment period of 16 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, bone marrow function, and disease stage. Following the screening, participants will be randomized to receive either ABVD or A2VD, with or without involved-site radiotherapy (ISRT), depending on PET scan results. Follow-up visits will occur at regular intervals to monitor treatment response and adverse events. The end-of-study visit will evaluate the overall treatment outcomes and collect final safety data.

The expected length of participant involvement is approximately 16 weeks, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. Participants must meet specific inclusion criteria, such as being between 16 and 69 years of age, having adequate organ function, and no prior treatment for Hodgkin lymphoma. Exclusion criteria are not explicitly detailed in the provided data. The trial aims to provide valuable insights into the potential benefits of a PET-response adapted treatment strategy in early-stage Hodgkin lymphoma.

The clinical trial involves the administration of several **chemotherapy medications**. **Vinblastine Sulfate** is provided as a 1 mg/ml solution for injection, manufactured by Hospira UK Ltd. It is administered intravenously with a maximum daily dose of 6 mg/m² and a total dose not exceeding 48 mg/m² over a treatment period of 16 weeks.

**Dacarbazine** is available in multiple formulations by Medac Gesellschaft für klinische Spezialpräparate MBH (Wedel), including 100 mg, 200 mg, 500 mg, and 1000 mg powders for solution for injection/infusion. All formulations are administered intravenously with a maximum daily dose of 375 mg/m² and a total dose of 3000 mg/m² over 16 weeks.

**Bleomycin** is provided as a 15000 IU powder for solution for injection/infusion by Accord Healthcare Limited. It is administered intravenously with a maximum daily dose of 10000 IU and a total dose of 80000 IU over the treatment period.

**Doxorubicin Hydrochloride** is available as a 2 mg/ml solution for infusion, produced by Medac Gesellschaft für klinische Spezialpräparate MBH (Wedel). It is administered intravenously with a maximum daily dose of 25 mg/m² and a total dose of 200 mg/m² over 16 weeks.

**Brentuximab Vedotin** is provided as ADCETRIS 50 mg powder for concentrate for solution for infusion by Takeda Pharma A/S. It is administered intravenously with a maximum daily dose of 120 mg and a total dose of 960 mg over the treatment period.

**Filgrastim** is administered subcutaneously with a maximum daily dose of 480 µg and a total dose of 26880 µg over 16 weeks. It is used as an auxiliary treatment to support the primary chemotherapy regimen.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy of these treatments in patients with previously untreated stage IA/IIA **Hodgkin lymphoma**.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which will measure the length of time during and after the treatment that a patient lives with the disease without it getting worse. Secondary endpoints include the PET Complete Metabolic Response (CMR) rate after 2 cycles of ABVD/A2VD, Event-Free Survival (EFS), Overall Survival (OS), the incidence of second cancers and cardiovascular disease, and the safety and toxicity of ABVD and A2VD as assessed by CTCAE v5.0.

Data collection for these endpoints will occur at specified intervals throughout the trial. The PET CMR rate will be evaluated after 2 cycles of treatment, while PFS, EFS, and OS will be monitored continuously throughout the study duration. Safety and toxicity assessments will be conducted using the CTCAE v5.0 criteria. The trial is designed to compare the efficacy of substituting A2VD for ABVD in a PET-response adapted design for patients with early-stage Hodgkin lymphoma, aiming to improve PFS.