PET Adapted Brentuximab Vedotin and Pembrolizumab in Combination With Doxorubicin and Dacarbazine in Classic Hodgkin Lymphoma

To learn about the effects of brentuximab vedotin and pembrolizumab in combination with doxorubicin and dacarbazine when given to patients who have Stage II cHL with bulky mediastinal disease or advanced cHL (Stage III or IV) and who have not received treatment for the disease.

Inclusion Criteria: 1. Treatment-naïve, HL subjects with Ann Arbor stage III, IV, or stage II with bulky disease (\>10 cm). 2. Histologically confirmed cHL according to the current World Health Organization Classification (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted, classical HL, or not otherwise specified). a. Subjects enrolling must submit a tumor block for analysis. Availability of tissue must be confirmed prior to enrollment. 3. Bidimensional measurable disease as documented by PET/CT or CT imaging. Must have at least one lesion \>15 mm (1.5 cm) in the longest diameter on cross-sectional imaging, measurable in 2 perpendicular dimensions on CT (or MRI), and FDG avid by PET. 4. Age 18 years or older. 5. An Eastern Cooperative Oncology Group (ECOG) performance status zero, or one. 6. Subjects of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 7 days prior to the first dose of brentuximab vedotin. Subjects with false positive results and documented verification that the subject is not pregnant are eligible for participation. Subjects of non-childbearing potential are those who are postmenopausal \>1 year or who have had a bilateral oophorectomy or hysterectomy. 7. If sexually active in a way that could result in pregnancy, subjects of childbearing potential must agree to use 2 effective contraception methods during the study and for 7 months following the last dose of study drug. Subjects who can father children and have partners of childbearing potential must agree to use 2 effective contraception methods during the study and for 7 months following the last dose of study drug. Subjects who can father children must also be willing to refrain from sperm donation during this time. 8. The subject or the subject's legally acceptable representative must provide written informed consent. Cognitive ability will be assessed according to policy CLN0547. 9. The following baseline laboratory data: * absolute neutrophil count ≥1500/μL unless there is known HL marrow involvement * platelet count ≥75,000/μL * serum bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with Gilbert's disease * estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) study equation as applicable * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN or ≤5 x ULN if there is documented hepatic involvement of HL * hemoglobin ≥8 g/dL Exclusion Criteria: 1. Nodular lymphocyte predominant HL. 2. History of another malignancy within 3 years before the first dose of study drug or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Subjects with nonmelanoma skin cancer, localized prostate cancer, or carcinoma in situ of any type are not excluded if they have undergone complete resection. 3. Prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy (e.g., immunoglobulin replacement, other monoclonal antibody therapies) within 4 weeks of first study drug dose, unless underlying disease has progressed on treatment. 4. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 5. Active cerebral/meningeal disease related to the underlying malignancy, including signs or symptoms of progressive multifocal leukoencephalopathy (PML) or history of PML. Subjects with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior CNS disease has been treated. 6. Any active Grade 3 or higher (per the National Cancer Institute's Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4.03) viral, bacterial, or fungal infection within 1 week prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted. 7. Current therapy with other systemic anti-neoplastic or investigational agents. 8. Planned consolidative radiotherapy. 9. Active interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity. 10. Grade 3 or higher pulmonary disease unrelated to underlying malignancy. 11. Idiopathic interstitial pneumonia or diffusing capacity of the lung for carbon monoxide (adjusted for hemoglobin) \