Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma
Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma
This phase III trial compares immunotherapy drugs (nivolumab or brentuximab vedotin) when
 given with combination chemotherapy in treating patients with newly diagnosed stage III or IV
 classic Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may
 help the body's immune system attack the cancer, and may interfere with the ability of tumor
 cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked
 to a toxic agent called vedotin. Brentuximab attaches to cancer cells in a targeted way and
 delivers vedotin to kill them. Chemotherapy drugs, such as doxorubicin, vinblastine, and
 dacarbazine, work in different ways to stop the growth of cancer cells, either by killing the
 cells, by stopping them from dividing, or by stopping them from spreading. The addition of
 nivolumab or brentuximab vedotin to combination chemotherapy may shrink the cancer or extend
 the time without disease symptoms coming back.
PRIMARY OBJECTIVE:

 I. To compare the progression-free survival (PFS) in patients with newly diagnosed advanced
 stage classical Hodgkin lymphoma randomized to N-AVD (nivolumab, doxorubicin hydrochloride
 [doxorubicin], vinblastine sulfate [vinblastine], dacarbazine) versus that obtained with
 BV-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine).

 SECONDARY OBJECTIVES:

 I. To compare overall survival (OS) in patients randomized to N-AVD versus BV-AVD.

 II. To compare event-free survival (EFS) in patients randomized to N-AVD versus BV-AVD.

 III. To compare the metabolic complete response (CR) rate at the end of treatment in patients
 randomized to N-AVD versus BV-AVD.

 IV. To compare the physician-reported treatment-related adverse event rates between arms
 stratified by age groups.

 V. To compare patient-reported symptoms using selected Patient Reported Outcome Common
 Toxicity Criteria for Adverse Events (PRO-CTCAE) items between arms stratified by age groups.

 VI. To compare the safety and tolerability of N-AVD versus that of BV-AVD.

 QUALITY OF LIFE OBJECTIVE:

 I. To compare between arms patient-reported fatigue, neuropathy and health-related quality of
 life over time (baseline, beginning of cycle 3, 4-8 weeks after the last dose of protocol
 therapy [following last dose of study drug or radiation therapy, whichever is later], and 1
 and 3 years after randomization) using the Patient Reported Outcomes Measurement Information
 System (PROMIS)-Fatigue, the Functional Assessment of Cancer Therapy/Gynecologic Oncology
 Group-Neurotoxicity (FACT/GOG-Ntx), and the PROMIS Global, respectively.

 BANKING OBJECTIVES:

 I. To bank specimens for future correlative studies. II. To bank positron emission tomography
 (PET)-computed tomography (CT) images for future correlative studies.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I: Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV,
 dacarbazine IV, and nivolumab IV over 30 minutes on days 1 and 15. Patients may receive
 pegfilgrastim subcutaneously (SC) on days 2 and 16, or filgrastim SC or IV on days 6-10 and
 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or
 unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5
 days per week for approximately 4 weeks at the discretion of the treating physician.

 ARM II: Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine
 IV, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Patients may receive
 pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment
 repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable
 toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week
 for approximately 4 weeks at the discretion of the treating physician.

 After completion of study treatment and prior to disease progression, patients are followed
 up every 3 months for the first year, every 6 months for years 2 and 3, then annually until
 10 years after registration. Patients are followed up at the time of progression and then
 annually until 10 years after registration. Patients who receive radiation therapy are
 followed up at 8-12 weeks after completion of radiation therapy.
Inclusion Criteria:

 -  All patients must have histologically confirmed newly diagnosed, previously untreated
 stage III or IV classical Hodgkin lymphoma (nodular sclerosing, mixed cellularity,
 lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified [NOS]). Nodular
 lymphocyte predominant Hodgkin lymphoma is not eligible.

 -  Patients must have bidimensionally measurable disease (at least one lesion with
 longest diameter >= 1.5 cm) documented on the Lymphoma Baseline Tumor Assessment Form
 in Rave.

 -  Patients must have a whole body or limited whole body PET-CT scan performed within 42
 days prior to registration. (A contrast-enhanced [diagnostic] CT, MRI or MR-PET is
 acceptable in event that PET-CT is contra-indicated, however if it is later possible
 to administer a PET-CT, then PET-CT is strongly preferred for the interim scan (after
 cycle 2) (if performed) and the EOT assessment. Otherwise, if PET-CT is not
 subsequently possible, then the same modality as baseline must be used throughout the
 trial.) NOTE: All images from PET-CT, CT, MRI or MR-PET scans performed as standard of
 care to assess disease (within 42 days prior to registration) must be submitted and
 associated radiology reports must be submitted.

 -  Patients must not have received any prior chemotherapy, radiation, or antibody-based
 treatment for classical Hodgkin lymphoma. Steroid pre-treatment is permitted.

 -  Patients must not have had prior solid organ transplant.

 -  Patients must not have had prior allogeneic stem cell transplantation.

 -  Patients must not have received a live vaccine within 30 days prior to planned day 1
 of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies,
 Bacillus Calmette-Guerin [BCG], oral polio vaccine, and oral typhoid).

 -  At registration, investigator must declare intent-to-treat with residual PET radiation
 therapy (residual PET RT- RPRT) to be administered after patient completes 6 cycles of
 therapy if, after end of treatment, the patient meets criteria specified for receiving
 RT). Patients will be stratified by investigator's intent-to-treat with residual PET
 RT.

 -  All pediatric patients (< 18 years of age) will be considered intent-to-treat
 with Residual PET RT at time of registration.

 -  Patients must have a performance status corresponding to Zubrod scores of 0, 1 or 2.
 Use Lansky for patients =< 17 years of age. *The conversion of the Lansky to Eastern
 Cooperative Oncology Group (ECOG) scales is intended for National Cancer Institute
 (NCI) reporting purposes only.

 -  Adults (age 18 or older): Creatinine clearance >= 30 mL/min, as estimated by the
 Cockcroft and Gault formula. The creatinine value used in the calculation must have
 been obtained within 28 days prior to registration. Estimated creatinine clearance is
 based on actual body weight.

 Pediatric Patients (age 12-17), the following must have been obtained within 14 days prior
 to registration:

 -  Measured or calculated creatinine clearance or radioisotope glomerular filtration rate
 (GFR) >= 70 ml/min/1.73 m^2, or

 -  Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a serum
 creatinine (SCr) based on age/gender as follows:

 -  Age < 13 maximum serum creatinine: Male 1.2 mg/dL; Female 1.2 mg/dL

 -  Age 13 to < 16 maximum serum creatinine: Male 1.5 mg/dL; Female 1.4 mg/dL

 -  Age 16-17 maximum serum creatinine: Male 1.7 mg/dL; Female 1.4 mg/dL

 -  Total bilirubin =< 2 x IULN (must be documented within 28 days prior to
 registration for adults [age 18 or older]; must be documented within 14 days
 prior to registration for pediatric patients [age 12-17]).

 -  Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile
 duct syndrome

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x IULN
 (must be documented within 28 days prior to registration for adults [age 18 or
 older]; must be documented within 14 days prior to registration for pediatric
 patients [age 12-17]).

 -  Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile
 duct syndrome

 -  Patients must have an echocardiogram (ECHO), multigated acquisition (MUGA), or
 functional cardiac imaging scan with a left ventricular ejection (LVEF) fraction
 >= 50% or a shortening fraction of >= 27%. For all patients, the ECHO, MUGA, or
 functional cardiac imaging scan must be performed within 42 days prior to
 registration.

 -  Patients with known human immunodeficiency virus (HIV) infection must be
 receiving anti-retroviral therapy and have an undetectable or unquantifiable
 viral load at their most recent viral load test within 6 months prior to
 registration.

 -  Patients must not have known active hepatitis B (HBV) or hepatitis C virus (HCV)
 at date of registration. Patients with previously treated HBV or HCV that have an
 undetectable viral load within 6 months prior to registration and no residual
 hepatic impairment are eligible.

 -  Patients must not have any known central nervous system lymphoma.

 -  Patients must not have a history of or active interstitial pneumonitis or
 interstitial lung disease.

 -  Patients must not have had a diagnosis of inherited or acquired immunodeficiency.

 -  Patients must not have any known uncontrolled intercurrent illness including, but
 not limited to symptomatic congestive heart failure, unstable angina pectoris,
 hemodynamically unstable cardiac arrhythmia, or psychiatric illness/social
 situations that would limit compliance with study requirements.

 -  Patients must not have a condition requiring systemic treatment with either
 corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
 medications within 14 days prior to registration. Inhaled or topical steroids,
 and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted
 in the absence of active autoimmune disease. Steroid use for the control of
 Hodgkin lymphoma symptoms is allowable, but must be discontinued prior to cycle
 1, day 1.

 -  Patients with peripheral neuropathy must have < grade 2 at date of registration.

 -  Patients must not have active autoimmune disease that has required systemic
 treatment in past 2 years (i.e., with use of disease modifying agents,
 immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10
 mg or equivalent). Autoimmune diseases include but are not limited to autoimmune
 hepatitis, inflammatory bowel disease (including ulcerative colitis and Crohn's
 disease), as well as symptomatic disease (e.g.: rheumatoid arthritis, systemic
 progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
 vasculitis [e.g., Wegener's granulomatosis]); central nervous system (CNS) or
 motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome
 and myasthenia gravis, multiple sclerosis or glomerulonephritis). Vitiligo,
 alopecia, hypothyroidism on stable doses of thyroid replacement therapy,
 psoriasis not requiring systemic therapy within the past 2 years are permitted.

 -  No second prior malignancy is allowed except for adequately treated basal (or
 squamous cell) skin cancer, any in situ cancer or other cancer for which the
 patient has been disease free for two years.

 -  Females of childbearing potential must not be pregnant or nursing, and have a
 negative pregnancy test within 28 days prior to registration. Women/men of
 reproductive potential must have agreed to use an effective contraceptive method
 while receiving study drug and for women until 6 months after receiving the last
 dose of study drug or, for men, until 7 months after receiving the last dose of
 study drug. A woman is considered to be of "reproductive potential" if she has
 had menses at any time in the preceding 12 consecutive months. In addition to
 routine contraceptive methods, "effective contraception" also includes
 heterosexual celibacy and surgery intended to prevent pregnancy (or with a
 side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
 oophorectomy or bilateral tubal ligation. However, if at any point a previously
 celibate patient chooses to become heterosexually active during the time period
 for use of contraceptive measures outlined in the protocol, he/she is responsible
 for beginning contraceptive measures.

 -  Patients must have one formalin-fixed paraffin embedded (FFPE) diagnostic tumor
 block or at least 1 diagnostic, 4-5 micron, hematoxylin and eosin (H&E) slide
 collected prior to registration and available for submission.

 -  Patients must be offered participation in banking for planned translational
 medicine and future research. With patient consent, any residuals from the
 mandatory tissue submission will also be banked for future research.

 -  Patients who can complete Patient-Reported Outcome instruments in English,
 Spanish, or French must complete the PROMIS Fatigue, the FACT/GOG-Ntx, and the
 PROMIS Global prior to registration.

 -  Patients who can complete Patient-Reported Outcome instruments in English,
 Spanish, or French must also agree to complete the PROMIS Fatigue, the
 FACT/GOG-Ntx, the PROMIS Global, and the PRO-CTCAE (or Ped PRO-CTCAE) at the
 scheduled on-study assessment timepoints.

 -  Patients must be informed of the investigational nature of this study and all
 patients and/or their parents or legal guardians (for patients < 18 years of age)
 must sign and give informed consent and assent (where appropriate) in accordance
 with institutional and federal guidelines. For participants with impaired
 decision-making capabilities, legally authorized representatives may sign and
 give informed consent on behalf of study participants in accordance with
 applicable federal, local, and Central Institutional Review Board Initiative
 (CIRB) regulations.

 -  Note: As a part of the Oncology Patient Enrollment Network (OPEN) registration process
 the treating institution's identity is provided in order to ensure that the current
 (within 365 days) date of institutional review board approval for this study has been
 entered in the system.