Treatment optimisation trial in the first-line treatment of advanced stage Hodgkin lymphoma; comparison of 6 cycles of escalated BEACOPP with 6 cycles of BrECADD.

This is an international, prospective, randomised and open-label phase III trial. The aim of the main trial is to prove that the new chemotherapy regimen, BrECADD, is non-inferior to BEACOPP as first line treatment in advanced stage classical Hodgkin lymphoma. Main trial: Patients in the main trial will be randomised in a 1:1 ratio to either arm1 or arm2. Arm1 (standard group): Patients will either receive 4 cycles (if PET-negative) or 6 cycles (if PET-positive) of the escalated BEACOPP regimen as follows- Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 1); Adriamycin (35 mg/m^2, IV over 30 minute infusion, day 1); Etoposide (200 mg/m^2 per day, IV over 60 minute infusion, day 1 to day 3); Procarbazine (100 mg/m^2 per day, oral capsule, day 1 to day 7); Prednisone (40 mg/m^2 per day, oral tablet, day 1 to day 14); Vincristine (1.4 mg/m^2, IV bolus, day 8); Bleomycin (10 mg/m^2, IV bolus, day 8); Pegylated G-CSF ( 6 mg, subcutaneous injection, day 4). Each cycle is 21 days. Arm2 (experimental group): Patients will either receive 4 cycles (if PET-negative) or 6 cycles (if PET-positive) of the BrECADD regimen as follows- Brentuximab vedotin (1.8 mg/kg, IV over 30 minute infusion, day 1); Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 2); Adriamycin (40 mg/m^2, IV over 30 minute infusion, day 2); Etoposide (150 mg/m^2 per day, IV over 60 minute infusion, day 2 to day 4); Dacarbazine (250 mg/m^2 per day, IV over 120 minute infusion, day 3 to day 4); Dexamethasone (40 mg/m^2 per day, oral tablet, day 2 to day 5); Pegylated G-CSF (6 mg, subcutaneous injection, day 5). Each cycle is 21 days. Older cohort: Patients will not be randomised. Older patients will either receive 2 cycles (if PET-negative) or 4 cycles (if PET-positive) of the BrECADD regimen as follows- Brentuximab vedotin (1.8 mg/kg, IV over 30 minute infusion, day 1); Cyclophosphamide (1250 mg/m^2, IV over 60 minute infusion, day 2); Adriamycin (40 mg/m^2, IV over 30 minute infusion, day 2); Etoposide (150 mg/m^2 per day, IV over 60 minute infusion, day 2 to day 4); Dacarbazine (250 mg/m^2 per day, IV over 120 minute infusion, day 3 to day 4); Dexamethasone (40 mg/mm^2 per day, oral tablet, day 2 to day 5); Pegylated G-CSF (6 mg, subcutaneous injection, day 5). Each cycle is 21 days. In both the main study and in the older cohort, restaging will take place in the last week of the second treatment cycle (“PET-2”), at the end of chemotherapy (“PET-6”), and at the end of radiotherapy if given (restaging after radiotherapy). In both groups, PET-2 is to take place in the last week of the 2nd chemotherapy cycle (between day 17 and day 21) PET-6 is to take place within 3 weeks after day 21 of the 6th chemotherapy cycle. Patients will undergo restaging by FDG-PET with low dose CT, of the whole trunk of the body; images of the lower extremities are only required if a primary tumour was located there. Each restaging will always include an examination of all initially involved lymph nodes or organs using adequate methods. The objective of the PET-2 interim restaging is to document the response to chemotherapy and whether 4 - 6 cycles are required based on the patient's response to treatment, and to reassess if the patient is still qualified for the trial. The objective of the PET-6 restaging is to document the response to chemotherapy, and to recommend patients for radiotherapy where tumour masses are greater than or equal to 2.5 cm after chemotherapy. If a patient is scheduled for radiotherapy following PET-6 restaging, an additional FDG-PET will take place within 6 weeks after completion of radiotherapy. The decision and organisation of the radiotherapy is up to the discretion of the treating physician on site.