Phase II Study of FDG-PET-Adapted Brentuximab Vedotin-Based Regimens in Advanced Hodgkin Lymphoma

The primary objective of this study is to evaluate whether treatment adaptation based on very early **FDG-PET/CT** results can enhance efficacy while reducing treatment toxicity in patients with advanced stage **Hodgkin Lymphoma**. This is assessed primarily through modified progression-free survival, which is clinically relevant as it may lead to improved patient outcomes by tailoring therapy to individual responses, potentially minimizing unnecessary exposure to toxic treatments.

Secondary objectives include:

• Assessing the rate of FDG-PET negativity (Deauville score 1-3) after one cycle of BrAVD.
• Evaluating response according to Lugano Criteria at the end of protocol treatment, defined by FDG-PET/CT.
• Assessing the safety and tolerability of different BV-containing regimens.
• Evaluating the safety and tolerability of radiotherapy in the context of BrAVD and BrECADD.
• Assessing efficacy in terms of progression-free survival (PFS) and overall survival (OS).

The clinical trial involves participants diagnosed with **advanced stage Hodgkin Lymphoma**. The study population includes both male and female subjects, aged between 18 and 60 years, with a **WHO performance status** of 0-2, indicating they are ambulatory and capable of all self-care. Participants are required to have adequate organ function and must not belong to a vulnerable population. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Selection criteria include individuals who have not previously received treatment for classical Hodgkin lymphoma and who can comply with the study protocol and follow-up schedule. Lifestyle considerations such as diet and physical activity are not specified, but participants must demonstrate compliance with birth control measures if of childbearing potential. The trial does not include individuals with conditions that could impede adherence to the study requirements. Participation in translational research is mandatory, necessitating consent for additional blood samples and tissue availability.

The clinical trial is designed to evaluate the efficacy of very early FDG-PET-response adapted targeted therapy in patients with **advanced stage Hodgkin lymphoma**. This is a single-arm, phase II study with a primary objective to assess whether treatment adaptation based on early FDG-PET/CT results can improve efficacy while minimizing treatment toxicity. The trial employs a modified progression-free survival rate at two years as the primary endpoint, with secondary endpoints including FDG-PET results after one cycle of BrAVD, response according to Lugano Criteria, progression-free survival, overall survival, safety, and tolerability.

The trial is structured as a non-randomized, open-label study, with participants receiving a regimen containing **brentuximab vedotin**. The study is expected to run from February 2019 to August 2028, with participant involvement lasting up to four treatment cycles, depending on the specific regimen. The inclusion criteria require participants to have previously untreated, histologically confirmed classical Hodgkin lymphoma, be staged by PET with diagnostic-quality CT, and demonstrate adequate organ function. Participants must be between 18 and 60 years of age, with a WHO performance status of 0-2.

Study visits are sequenced to include an initial screening visit to confirm eligibility, followed by treatment visits corresponding to each cycle of therapy. Follow-up visits will be conducted to monitor response and safety, with an end-of-study visit to assess final outcomes. Participants are required to consent to additional blood samples and provide sufficient tissue for translational research. Conditions that may lead to early termination from the study include progression, relapse, or the initiation of new treatment for classical Hodgkin lymphoma when not in complete remission after completing protocol treatment, as well as any serious adverse events that compromise participant safety.

The clinical trial involves the administration of several **experimental medications**. **Doxorubicin** is utilized in the study as an antibiotic/chemotherapy agent. It is administered in the form of an infusion with a maximum daily dose of 550 mg and a total maximum dose of 6600 mg over a treatment period of up to 4 cycles. The pharmaceutical form is denoted as PHF00231MIG.

**Etoposide** is another chemotherapy agent used in the trial. It is administered via infusion with a maximum daily dose of 315 mg and a total maximum dose of 5670 mg over a maximum treatment period of 3 cycles. The pharmaceutical form is PHF675.

**Cyclophosphamide** is included as a chemotherapy agent, administered through infusion. The maximum daily dose is 262.5 mg, with a total maximum dose of 3150 mg over a treatment period of up to 4 cycles. The pharmaceutical form is PHF00231MIG.

**Vinblastine sulfate** is administered as a chemotherapy agent via infusion. The maximum daily dose is 7.4 mg, with a total maximum dose of 88.8 mg over a treatment period of up to 4 cycles. The pharmaceutical form is PHF00231MIG.

**Dacarbazine citrate** is used as a chemotherapy agent, administered through infusion. The maximum daily dose is 525 mg, with a total maximum dose of 6300 mg over a treatment period of up to 4 cycles. The pharmaceutical form is PHF00231MIG.

**Dexamethasone**, combined with cinchocaine hydrochloride, is administered as a corticosteroid. It is given orally with a maximum daily dose of 40 mg and a total maximum dose of 960 mg over a treatment period of up to 6 cycles. The pharmaceutical form is PHF00043MIG.

**Brentuximab vedotin** is administered as a solution for infusion. It is provided in the form of a powder for concentrate for solution for infusion, with a maximum daily dose of 550 mg and a total maximum dose of 1440 mg over a treatment period of up to 4 cycles. The pharmaceutical form is a solution for infusion, and it is marketed under the name ADCETRIS 50 mg powder for concentrate for solution for infusion.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to assess the efficacy and safety of these treatments in patients with advanced Hodgkin lymphoma, with a focus on minimizing treatment toxicity while improving efficacy.

The efficacy of the clinical trial will be primarily assessed through the **modified progression-free survival** (mPFS) rate at 2 years after the start of treatment. This primary endpoint considers events such as progression, relapse, initiation of new treatment for classical Hodgkin lymphoma (cHL) when not in complete remission (CR) after completing protocol treatment, and death from any cause. Secondary endpoints include the FDG-PET result (positive/negative) after one cycle of BrAVD, response according to Lugano Criteria at the end of protocol treatment, progression-free survival, overall survival, safety and tolerability, and response according to RECIL 2017.

The trial will utilize FDG-PET/CT scans to evaluate treatment response, with central assessment of FDG-PET results after one cycle of BrAVD. The response will be further evaluated at the end of protocol treatment, which includes both chemotherapy and radiotherapy if administered. The trial aims to determine whether treatment adaptation based on very early FDG-PET/CT results can improve efficacy while minimizing treatment toxicity in patients with advanced stage Hodgkin lymphoma treated with BV-containing regimens, BrAVD, and BrECADD.