Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the
combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and
brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) II. To evaluate the complete
response (CR) rate for the regimens of brentuximab vedotin and nivolumab compared to
brentuximab vedotin, ipilimumab, and nivolumab. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate complete response (CR) rate, partial response (PR) rate and overall response
rate (ORR), for the combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin
and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) II. To evaluate
the duration of remission (DOR) to these combinations and compare with the DOR achieved with
the most recent prior systemic therapy. (Phase I) III. To evaluate the progression-free
survival (PFS) and the overall survival (OS) in patients receiving the combination of
brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab
vedotin, ipilimumab, and nivolumab. (Phase I) IV. To evaluate the ORR, PR, and stable disease
(SD) rate for the combinations of brentuximab vedotin and nivolumab and brentuximab vedotin,
ipilimumab, and nivolumab. (Phase II) V. To evaluate the DOR to these combinations and
compare with the DOR achieved with the most recent prior systemic therapy. (Phase II) VI. To
evaluate the 5 year PFS and OS in patients receiving the combinations of brentuximab vedotin
and nivolumab and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II) VII. To further
evaluate the safety and characterize the toxicity for the combinations of brentuximab vedotin
and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II)

CORRELATIVE STUDY OBJECTIVES:

I. To evaluate the ability of these combinations to alter tumor specific T cell immunity.
(Phase I) II. To evaluate the effects of these combinations on systemic immunity. (Phase I)
III. To evaluate a panel of cytokine and T cell specific biomarkers from the peripheral blood
as a potential immune signature of treatment response to therapy with these combinations for
patients with relapsed/refractory Hodgkin lymphoma (HL). (Phase I) IV. To evaluate using gene
expression profiling (GEP) a signature of response to these novel combinations of an antibody
drug conjugate with immunomodulatory therapy. (Phase I) V. To evaluate the ability of these
combinations to alter tumor specific T cell immunity, and circulating T cell phenotypes, in
patients as a function of treatment response at multiple timepoints during therapy. (Phase
II) VI. To evaluate peripheral blood cytokine profiles in responding and resistant patients
at multiple timepoints during therapy. (Phase II) VII. To evaluate using GEP a signature of
response versus (vs.) resistance to these novel combinations of an antibody drug conjugate
with immunomodulatory therapy. (Phase II) VIII. To evaluate the influence of human gut
microbiome dysbiosis on HL lymphomagenesis and the systemic immune response. (Phase II)

IMAGING CORRELATIVE STUDY OBJECTIVES:

I. To evaluate atypical response patterns with currently available response evaluation
criteria. (Phase II) II. To correlate response evaluated using currently available response
evaluation criteria with duration of response (PFS, event free survival [EFS], failure free
survival [FFS]). (Phase II) III. To evaluate response patterns in different immunotherapy
treatment schemes and correlate with historical data using chemotherapy. (Phase II) IV. To
correlate imaging changes in all treatment schemes quantitatively with PFS. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin, ipilimumab, and
nivolumab followed by a phase II study.

PHASE I: Patients are assigned into 1 of 3 arms.

ARM I: Patients receive brentuximab vedotin intravenously (IV) over 90 minutes on day 1 and
ipilimumab IV over 30 minutes on day 1 of cycles 1-4, 8, 12, and 16. Treatment repeats every
21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and
nivolumab IV over 30 minutes on day 1 of cycles 1-46. Treatment repeats every 21 days for up
to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of
disease progression or unacceptable toxicity.

ARM III: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16,
nivolumab IV over 30 minutes on day 1 of cycles 1-46, and ipilimumab IV over 30 minutes on
day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 cycles
and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease
progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and
nivolumab IV over 30 minutes on day 1 of cycles 1-34. Treatment repeats every 21 days for up
to 34 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16,
nivolumab IV over 30 minutes on day 1 of cycles 1-34, and ipilimumab IV over 30 minutes on
day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 34 cycles
in the absence of disease progression or unacceptable toxicity.

After completion of phase I study treatment, patients are followed up every 3 months for 1
year, then every 6 months for 2 years. After completion of phase II study treatment, patients
are followed up for 5 years.

Inclusion Criteria:

- PHASE I (ARMS A, B, C, D, E, F, G, H, I, X, Y, Z)

- Patients must have pathologically confirmed relapsed or refractory classical Hodgkin
lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including
lymphocyte predominant (LP) HL are not permitted

- Patients must have relapsed after first line chemotherapy; may have relapsed after
autologous or allogeneic stem cell transplant, or have primary refractory disease; no
upper limit for number of prior therapies; if status post allogeneic stem cell
transplant, no active graft versus host disease

- Patients may have received prior brentuximab vedotin, but must not have received
brentuximab vedotin within 6 months prior to registration, and must not have relapsed
within 6 months of receiving previous brentuximab vedotin; patients may not have
received prior nivolumab or PD1/PDL1 axis agents; patients in the
nivolumab/brentuximab cohorts ONLY (D, E, F, Y) may have received prior ipilimumab

- Patients may have received other prior activating immunotherapies (i.e. checkpoint
inhibitors), but must not have received them within 6 months prior to registration,
and there must be no serious unresolved complication of therapy at the time of
registration; for the purposes of this study monoclonal antibodies and antibody drug
conjugates are not considered to be activating immunotherapies and there are no
additional time restrictions on prior exposure to these agents (except prior
brentuximab vedotin)

- Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging
Network (ACRIN) performance status between 0-2

- Patients must have measurable disease; baseline measurements and evaluations must be
obtained within 4 weeks of registration to the study; abnormal positron emission
tomography (PET) scans will not constitute evaluable disease unless verified by a
diagnostic quality computed tomography (CT) scan; patients must use the same imaging
modality (CT or PET/CT) throughout the study

- Women must not be pregnant or breast-feeding due to risk of fetal harm by the
chemotherapeutic agents prescribed in this protocol; all females of childbearing
potential must have a blood test or urine study within 2 weeks prior to registration
to rule out pregnancy; a female of childbearing potential is any woman, regardless of
sexual orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has
had menses at any time in the preceding 24 consecutive months)

- Women of childbearing potential (WOCBP) and sexually active males must either abstain
from sexual intercourse for the duration of their participation in the study or agree
to use both double barrier contraception and birth control pills or implants for at
least one week prior to the start of the study drug and continuing for 5 months after
the last dose of study drug (for female patients) and for 7 months after the last dose
of study drug (for male patients who are sexually active with WOCBP); should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she (or the participating partner) should inform the treating physician
immediately

- Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while
breathing room air

- Patients must have forced expiratory volume in 1 second (FEV1)/forced vital capacity
(FVC) > 60% by pulmonary function test (PFT), unless due to large mediastinal mass
from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted
value; all pulmonary function tests must be obtained within one month prior to
registration

- Absolute neutrophil count (ANC) >= 1500/mcL (1.5 x 10^9/L) (obtained within 2 weeks
prior to registration)

- Platelets >= 75,000/mcL (75 x 10^9/L) (obtained within 2 weeks prior to registration)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN) (obtained within 2 weeks prior to registration)

- Bilirubin =< 2 x upper limit of normal (ULN) (unless documented Gilbert's syndrome,
for which bilirubin =< 3 x upper limit of normal [ULN] is permitted) (obtained within
2 weeks prior to registration)

- Calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min (obtained
within 2 weeks prior to registration)

- No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in
situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously
disease free for >= 5 years so as not to interfere with interpretation of radiographic
response

- Patient must have no current or prior history of central nervous system (CNS)
involvement

- All prior therapy must have been completed at least 21 days prior to enrollment; no
concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose
of treatment of lymphoma are allowed; topical steroids are allowed

- No history of Steven's Johnson's syndrome, toxic epidermal necrolysis (TEN)s syndrome,
or motor neuropathy

- Human immunodeficiency virus (HIV) positive patients are allowed on this study if they
have a CD4 count > 400, and are on a stable antiviral regimen; patients with poorly
controlled HIV or other chronic active viral infections will be excluded

- Patients must not have autoimmune disorders or conditions of immunosuppression that
require current ongoing treatment with systemic corticosteroids (or other systemic
immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or
continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
history of occasional (but not continuous) use of steroid inhalers is allowed

- Replacement doses of steroids for patients with adrenal insufficiency are
allowed; patients who discontinue use of these classes of medication for at least
2 weeks prior to initiation of study treatment are eligible if, in the judgment
of the treating physician investigator, the patient is not likely to require
resumption of treatment with these classes of drugs during the study

- Exclusion from this study also includes patients with a history of symptomatic
autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
[scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune
vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of
autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other
CNS autoimmune disease (e.g., Multiple sclerosis); patients with autoimmune
hypothyroid disease or type I diabetes on replacement treatment are eligible

- Patients must not have grade 2 or greater peripheral sensory neuropathy

- Patients must not have New York Heart Association (NYHA) class III or IV heart
failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
electrocardiographic evidence of acute ischemia

- Patients must not have previously existing hypersensitivity to brentuximab vedotin or
ipilimumab

- Patients must not have a serious medical or psychiatric illness likely to interfere
with study participation

- Patients must not be participating in any other clinical trial or taking any other
experimental medications within 21 days prior to registration

- Routine vaccinations, including seasonal influenza, should be given at least 2 weeks
prior to study treatment; vaccines are not prohibited on study, but must be given at
least 6 weeks after cycle 1 and not within 7 days of treatment

- Patients registering to Arms D, E, F, G, H, I, X, Y must not currently be smoking
tobacco or other substances and must not have smoked within the past 6 months

- RANDOMIZED PHASE II (ARMS K AND L): Patients must have pathologically confirmed
relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is
acceptable; other histologies including lymphocyte predominant (LP) HL are not
permitted

- RANDOMIZED PHASE II (ARMS K AND L): Patients must have relapsed after first line
chemotherapy; may have relapsed after autologous stem cell transplant, or have primary
refractory disease; no upper limit for number of prior therapies; patient must not
have received a prior allogeneic stem cell transplant

- RANDOMIZED PHASE II (ARMS K AND L): Patients may have received prior brentuximab
vedotin, but must not have received brentuximab vedotin within 6 months prior to
registration, and must not have relapsed within 6 months of receiving previous
brentuximab vedotin; patients may not have received prior nivolumab or PD1/PDL1 axis
agents; patients may not have received prior ipilimumab

- RANDOMIZED PHASE II (ARMS K AND L): Patients may not have received other prior
activating immunotherapies (i.e. checkpoint inhibitor therapies); for the purposes of
this study monoclonal antibodies and antibody drug conjugates are not considered to be
activating immunotherapies and there are no additional time restrictions on prior
exposure to these agents (except prior brentuximab vedotin)

- RANDOMIZED PHASE II (ARMS K AND L): ECOG-ACRIN performance status between 0-2

- RANDOMIZED PHASE II (ARMS K AND L): Patients must have measurable disease; baseline
measurements and evaluations must be obtained within 4 weeks of registration to the
study; abnormal PET scans will not constitute evaluable disease unless verified by a
diagnostic quality CT scan; patients must use the same imaging modality (CT or PET/CT)
throughout the study

- RANDOMIZED PHASE II (ARMS K AND L): Women must not be pregnant or breast-feeding due
to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol; all
females of childbearing potential must have a blood test or urine study within 24
hours prior to enrollment to rule out pregnancy; a female of childbearing potential is
any woman, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months)

- RANDOMIZED PHASE II (ARMS K AND L): Women of childbearing potential (WOCBP) and
sexually active males must either abstain from sexual intercourse for the duration of
their participation in the study or agree to use both double barrier contraception and
birth control pills or implants for at least one week prior to the start of the study
drug and continuing for 5 months after the last dose of study drug (for female
patients) and for 7 months after the last dose of study drug (for male patients who
are sexually active with WOCBP); should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she (or the
participating partner) should inform the treating physician immediately

- RANDOMIZED PHASE II (ARMS K AND L): Patients must have no evidence of dyspnea at rest
and a pulse oximetry > 92% while breathing room air

- RANDOMIZED PHASE II (ARMS K AND L): Patients must have FEV1/FVC > 60% by pulmonary
function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide
diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted value; all pulmonary
function tests must be obtained within one month prior to registration

- RANDOMIZED PHASE II (ARMS K AND L): ANC >= 1500/mcL (1.5 x 0^9/L) (obtained within 2
weeks prior to registration)

- RANDOMIZED PHASE II (ARMS K AND L): Platelets >= 75,000/mcL (75 x 10^9/L) (obtained
within 2 weeks prior to registration)

- RANDOMIZED PHASE II (ARMS K AND L): AST/ALT =< 2.5 x upper limit of normal (ULN)
(obtained within 2 weeks prior to registration)

- RANDOMIZED PHASE II (ARMS K AND L): Bilirubin =< 2 x upper limit of normal (ULN)
(unless documented Gilbert's syndrome, for which Bilirubin =< 3 x upper limit of
normal [ULN] is permitted) (obtained within 2 weeks prior to registration)

- RANDOMIZED PHASE II (ARMS K AND L): Calculated creatinine clearance by Cockroft-Gault
formula >= 30 ml/min (obtained within 2 weeks prior to registration)

- RANDOMIZED PHASE II (ARMS K AND L): No evidence of prior malignancy except adequately
treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or
radiation-cured malignancy continuously disease free for >= 5 years so as not to
interfere with interpretation of radiographic response

- RANDOMIZED PHASE II (ARMS K AND L): Patient must have no current or prior history of
CNS involvement

- RANDOMIZED PHASE II (ARMS K AND L): All prior therapy must have been completed at
least 21 days prior to enrollment (6 weeks for nitrosoureas or mitomycin C); no
concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose
of treatment of lymphoma are allowed; topical steroids are allowed

- RANDOMIZED PHASE II (ARMS K AND L): No history of Steven's Johnson's syndrome, TENs
syndrome, or motor neuropathy

- RANDOMIZED PHASE II (ARMS K AND L): HIV positive patients are eligible provided they
meet the other protocol criteria including the following:

- Long term survival expected were it not for the cHL

- HIV viral loads undetectable by standard clinical HIV testing

- Willing to adhere to effective combination antiretroviral therapy

- RANDOMIZED PHASE II (ARMS K AND L): Patients must not have autoimmune disorders or
conditions of immunosuppression that require current ongoing treatment with systemic
corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e.,
prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or
ophthalmologic steroids; a history of occasional (but not continuous) use of steroid
inhalers is allowed; replacement doses of steroids for patients with adrenal
insufficiency are allowed; patients who discontinue use of steroid medication for at
least 2 weeks prior to initiation of therapy are eligible if, in the judgment of the
treating physician investigator, the patient is not likely to require resumption of
treatment with these classes of drugs during the study; exclusion from this study also
includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid
arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus,
Sjogren's syndrome, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor
neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and
Myasthenia Gravis); other CNS autoimmune disease (e.g., Multiple sclerosis); patients
with autoimmune hypothyroid disease or type I diabetes on replacement treatment are
eligible

- RANDOMIZED PHASE II (ARMS K AND L): Patients must not have grade 2 or greater
peripheral sensory ne