The main aim of this study is to check how safe brentuximab vedotin is in adults with untreated Hodgkin Lymphoma (HL) when given together with doxorubicin (Adriamycin), vinblastine and dacarbazine therapy ('AVD'). Another aim is to learn how well treatment of brentuximab vedotin plus AVD works.

All participants will receive brentuximab vedotin plus AVD for approximately 6 months. Participants will undergo tests like Echocardiography (ECHO) and pulmonary function testing (PFT) during the study. ECHO is a test that uses ultrasound to show how the heart muscle and valves are working; PFT is a test to check how well a participant's lungs work.

Each participant will undergo a final health status check 2 months after the last treatment with brentuximab vedotin plus AVD.

Inclusion Criteria

1. Treatment-naïve, Hodgkin lymphoma (HL) participants with Ann Arbor Stage 3 or 4 disease.

   Note: Participants must have histologically confirmed classical HL according to the current world health organization classification.

2. Participants must have bidimensional measurable disease as documented by radiographic technique (spiral computed tomography [CT] preferred) per the international working group revised criteria for response assessment for malignant lymphoma.

3. Male or female participants 18 years or older.

4. Eastern cooperative oncology group (ECOG) performance status less than or equal to (≤)2.

5. Female participants who:

   • Are postmenopausal for at least 1 year before the screening visit, OR
   • Are surgically sterile, OR
   • If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception at the same time, from the time of signing of the informed consent form (ICF) through 6 months after the last dose of study drug, OR
   • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

6. Male participants, even if surgically sterilized (i.e., status post-vasectomy), who:

   • Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR
   • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).

7. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

8. Clinical laboratory values as specified below within 7 days before the first dose of study drug:

   • Absolute neutrophil count greater than or equal to (≥)1,000 per microliter (1,000/μL) unless there is known HL marrow involvement
   • Platelet count ≥75,000/μL unless there is known HL marrow involvement
   • Total bilirubin must be lesser than (<)1.5 x upper limit of the normal range (ULN) unless the elevation is known to be due to Gilbert syndrome.
   • Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) must be <3.0 x ULN. An AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of HL in liver.

Note: Moderate or severe hepatic disease patients will be excluded based upon Child-Pugh criteria.

• Serum creatinine must be <2.0 milligrams per deciliter (mg/dL) and/or creatinine clearance or calculated creatinine clearance >30 mL/minute (Cockcroft-Gault Equation).
• Hemoglobin must be ≥8 grams per deciliter (g/dL).

Exclusion Criteria

1. Female participants who are both lactating and breastfeeding or who have a positive serum pregnancy test during the screening period or a positive pregnancy test on Day 1 before first dose of study drug.

2. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

3. Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of progressive multifocal leukoencephalopathy (PML).

4. Symptomatic neurologic disease compromising normal activities of daily living or requiring medications.

5. Any sensory or motor peripheral neuropathy.

6. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to first study drug dose.

7. Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy (e.g., immunoglobulin replacement, other monoclonal antibody therapies) within 12 weeks of first study drug dose.

8. Previously treated with brentuximab vedotin.

9. Any contraindications to the concomitant chemotherapy regimens (doxorubicin, vinblastine, and dacarbazine).

10. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin or any component of doxorubicin, vinblastine, and dacarbazine (AVD).

11. Known human immunodeficiency virus (HIV) positive.

12. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.

13. Diagnosed or treated for another malignancy within 3 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

14. Any of the following cardiovascular conditions or values within 6 months before the first dose of study drug:

    1. A left-ventricular ejection fraction <50%
    2. Myocardial infarction within 2 years of enrollment
    3. New York Heart Association (NYHA) Class 3 or 4 heart failure. Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.