Classical Hodgkin Lymphoma Clinical Trials

• Documented informed consent of the participant and/or legally authorized representative

‣ Assent, when appropriate, will be obtained per institutional guidelines

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies

‣ If unavailable, exceptions may be granted with study principal investigator (PI) approval

• Meets at least one of the following criteria indicating unsuitability for conventional anthracycline-based frontline chemotherapy, as determined by the investigator:

‣ Age ≥ 75 years

⁃ Eastern Cooperative Oncology Group (ECOG) 2-4

⁃ Left ventricular ejection fraction (LVEF) \< 50%

⁃ Creatinine clearance \< 60 mL/min, using Cockcroft-Gault formula or equivalent

⁃ Pulmonary function impairment: forced expiratory volume in 1 second (FEV1) \< 50% and/or diffusion capacity of the lung for carbon monoxide (DLCO) \< 50%

• ECOG ≤ 2

• Age ≥ 18 years

• Histologically confirmed new diagnosis of classical Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) according to the World Health Organization (WHO) classification, with hematopathology review at the participating institution

• No prior systemic treatment for classical Hodgkin lymphoma with the following exceptions: a course of systemic corticosteroids for palliation of symptoms related to the classical Hodgkin lymphoma is allowed but must be stopped by cycle 1 day 1 (C1D1) as well as prior treatment with P-G as part of this clinical trial for patients will receive P-BV-D

• Measurable disease (at least one non-bone fludeoxyglucose F-18 \[FDG\]-avid lesion ≥ 1.5 cm in long axis)

• Absolute neutrophil count (ANC) ≥ 1,000/mm\^3

‣ NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement

• Platelets ≥ 50,000/mm\^3

‣ NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement

• Total bilirubin ≤ 2 × upper limit of normal (ULN) or direct bilirubin ≤ 2 × ULN for patients with Gilbert's disease

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN

• AST and ALT ≤ 3 x ULN unless there is liver involvement by lymphoma in which case AST and ALT \< 5 x ULN

• For patients for whom P-BV-D therapy is planned, creatinine clearance of ≥ 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula

• If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN

‣ If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants

• If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN

‣ If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants

• Seronegative for hepatitis C virus (HCV), hepatitis B virus (HBV) (surface antigen negative) OR

‣ If seropositive for HBV or HCV, nucleic acid quantitation must be performed. Viral load must be undetectable. Patients with occult or prior HBV infection (defined as negative hepatitis B virus surface antigen \[HBsAg\] and positive hepatitis B core antibody \[HBcAb\]) may be included if HBV DNA is undetectable, if they are willing to undergo DNA testing on day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

‣ If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• A male participant must agree to use a contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

‣ Not a woman of childbearing potential (WOCBP) OR

⁃ A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least (X days/weeks \[corresponding to time needed to eliminate any study treatment(s)\] \[pembrolizumab and/or any active comparator/combination\] plus 30 days \[a menstruation cycle\] for study treatments with risk of genotoxicity) after the last dose of study treatment

• TO PROCEED WITH SALVAGE TREATMENT: ECOG ≤ 2

• TO PROCEED WITH SALVAGE TREATMENT: Resolution of treatment-related adverse events (AEs) to baseline or grade 1, whichever is higher

• TO PROCEED WITH SALVAGE TREATMENT: Measurable disease (at least one non-bony FDG-avid lesion ≥ 1.5 cm in long axis)

• TO PROCEED WITH SALVAGE TREATMENT: Peripheral neuropathy ≤ grade 2

• TO PROCEED WITH SALVAGE TREATMENT: ANC ≥ 1,000/mm\^3

‣ NOTE: Growth factors are permitted

• TO PROCEED WITH SALVAGE TREATMENT: Platelets ≥ 50,000/mm\^3

‣ NOTE: Platelet transfusions are permitted

• TO PROCEED WITH SALVAGE TREATMENT: Hemoglobin ≥ 8 g/dL (no transfusion allowed within 3 days prior to screening)

• TO PROCEED WITH SALVAGE TREATMENT: Total bilirubin ≤ 2 x ULN or direct bilirubin ≤ 2 x ULN for patients with Gilbert's disease

• TO PROCEED WITH SALVAGE TREATMENT: AST ≤ 3 x ULN, or less then 5 x ULN for patients with liver involvement by lymphoma

• TO PROCEED WITH SALVAGE TREATMENT: ALT ≤ 3 x ULN, or less then 5 x ULN for patients with liver involvement by lymphoma

• TO PROCEED WITH SALVAGE TREATMENT: Creatinine clearance of ≥ 30 mL/min per 24-hour urine test or the Cockcroft-Gault formula