Doxorubicin Hydrochloride, Vinblastine, Dacarbazine, Brentuximab Vedotin, and Nivolumab in Treating Patients With Stage I-II Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To estimate progression-free survival (PFS) at 3 years in patients with previously
untreated stage I or II non-bulky Hodgkin lymphoma (HL) who received doxorubicin
hydrochloride, vinblastine, dacarbazine (AVD) plus brentuximab vedotin (BV) induction therapy
followed by nivolumab (N)VB consolidation therapy.

SECONDARY OBJECTIVES:

I. To estimate the overall survival (OS) rate at 3 years in patients with previously
untreated stage I or II non-bulky HL who received AVD plus BV induction therapy followed by
NVB consolidation therapy.

II. To estimate the percentage of patients with untreated stage I or II non-bulky HL who are
positron emission tomography (PET) positive versus PET negative after 3 cycles of AVD plus BV
induction therapy.

III. To estimate PFS and OS at 3 and 5 years separately for patients who are PET negative
versus PET positive after 3 cycles of AVD plus BV induction followed by NVB consolidation
therapy.

IV. To estimate time to progression (TTP) in patients with previously untreated stage I or II
non-bulky HL who received AVD plus BV induction therapy followed by NVB consolidation
therapy.

V. To estimate the overall response rate and the number of patients who convert to complete
response (CMR) after NVB in patients with partial response (PMR) at the end of AVD plus BV
induction therapy.

VI. To evaluate the toxicity and tolerability of AVD plus BV induction followed by NVB
consolidation therapy as assessed via the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE version [v]4).

TERTIARY OBJECTIVES:

I. Optional biopsy tissue samples will be collected for future analysis. II. Optional blood
sample will be collected for future analysis.

OUTLINE:

Patients receive doxorubicin hydrochloride intravenously (IV) over 3-5 minutes, vinblastine
IV over 3-5 minutes, and darcarbazine IV over >= 30 minutes, and brentuximab vedotin IV over
30 minutes on days 1 and 15. Treatment repeats every 28 days for 3 courses in the absence of
disease progression or unacceptable toxicity. Patients with PET-positive then receive
brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment
repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable
toxicity. PET-positive patients then receive nivolumab IV over 60 minutes on day 1. Treatment
repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable
toxicity. PET-negative patients receive nivolumab IV over 60 minutes on day 1 starting after
AVD and BV treatment. Treatment repeats every 2 weeks for 8 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 and 8 weeks, every 3 or 6
months for 2 years, and then once a year for 3 years.

Inclusion Criteria:

- Measurable disease (>= 1.5 cm) as assessed by 2 dimensional measurement by computed
tomography (CT)

- Previously untreated stage I or II non-bulky (defined as a mass measuring < 10 cm in
the longest dimension by CT) Hodgkin lymphoma

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- Life expectancy >= 3 months

- Documented negative serologic testing for human immunodeficiency virus (HIV),
hepatitis B (unless serologically positive due to prior vaccination), and hepatitis C
=< 1 year prior to registration

- Carbon monoxide diffusing capability (DLCO) > 60% (hemoglobin adjusted) by pulmonary
function test (PFT)s

- White blood cell >= 2,000 /mm^3 without transfusion support > 7 days prior to
registration

- Hemoglobin >= 8.5 g/dL without transfusion support > 7 days prior to registration

- Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 without transfusion support > 7
days prior to registration

- Platelet count >= 75,000/mm^3 without transfusion support > 7 days prior to
registration

- Alanine and aspartate aminotransferase (ALT/AST) =< 2.5 x upper limit of normal (ULN)
obtained =< 14 days prior to registration

- Total serum bilirubin =< 1.5 x ULN (if documented Gilberts syndrome =< 3 x ULN)
obtained =< 14 days prior to registration

- Serum creatinine =< 1.5 x ULN or measured calculated creatinine clearance >= 40 ml/min
for subject with creatinine levels > 1.5 x institutional ULN (per Cockcroft-Gault
formula) obtained =< 14 days prior to registration

- Negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of
human chorionic gonadotropin [HCG]) within 72 hours (hrs) prior to registration in
women of child-bearing potential (WOCBP)

- Sexually active female of reproductive capability ie, WOCBP, has agreed to use a
medically accepted form of contraception from time of registration to completion of
study therapy through 24 weeks (6 months) after last dose of NVB or BV; Note: Females
of non-child-bearing potential are those who are postmenopausal for > 1 year or who
have had a bilateral tubal ligation or hysterectomy

- Male subjects agree to use an adequate method of contraception starting with the first
dose of study therapy through 31 weeks after the last dose of study therapy

- Provide informed written consent

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study)

- Note: During the active monitoring phase of a study (i.e., active treatment and
observation), participants must be willing to return to the consenting
institution for follow-up

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Prior therapies including involved field radiation therapy

- Bulky disease (defined as a nodal mass measuring >= 10 cm by CT)

- Known central nervous system (CNS) involvement

- Moderate or severe hepatic insufficiency Child-Pugh score > 6

- Severe renal impairment (i.e. creatinine clearance < 40 mL/min)

- Symptomatic cardiac disease including ventricular dysfunction, left ventricular
ejection fraction < 45%, symptomatic coronary artery disease or symptomatic
arrhythmias

- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy =< 7 days prior to registration

- Known history of active TB (Bacillus tuberculosis)

- Requires therapy with agents that have a predisposition for hepatoxicity

- Hypersensitivity to NVB or any of its excipients or to any component of AVD + BV
therapy

- Requires immunosuppressive doses of corticosteroid therapy (> 10 mg/day prednisone
equivalents) for >= 2 weeks prior to registration

- Active, known, or suspected autoimmune disease that requires systemic treatment (i.e.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs);
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment; subjects are permitted to enroll if they have vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger

- Active infection requiring systemic IV antibiotic therapy

- History of Steven?s Johnson?s syndrome, toxic epidermal necrolysis syndrome (TENs) or
motor neuropathy

- History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the subject?s participation
for the full duration of the trial, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator

- Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial

- Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Received a live vaccine =< 30 days prior to registration; Note: Seasonal influenza
vaccines for injection are generally inactivated flu vaccines and are allowed;
however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines,
and are not allowed; routine vaccinations, including seasonal influenza, must be given
>= 2 weeks prior to registration

- History of allergies and adverse drug reaction to study drug components

- History of another primary malignancy that has not been in remission for at least 3
years; (Note: The following are exempt for the 3-year limit: nonmelanoma skin cancer,
fully excised melanoma in situ [stage 0], curatively treated localized prostate
cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion
on papanicolaou [PAP] smear)

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- History of progressive promyelocytic leukemia (PML), known history of pancreatitis,
active grade 3 or higher viral, bacterial or fungal infection =< 2 weeks prior to
registration and documented history of cerebrovascular event (stroke or transient
ischemic attack [TIA]) =< 6 months prior to registration