Nivolumab and Ipilimumab in Treating Patients With HIV Associated Relapsed or Refractory Classical Hodgkin Lymphoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To demonstrate safety and feasibility of ipilimumab and nivolumab at the standard doses of
drug in solid tumor and relapsed refractory HIV-classical Hodgkin lymphoma (cHL) participants
with human immunodeficiency virus (HIV) infection given the possibility of increased toxicity
based on immune activation, co-morbidity, or interference with highly active antiretroviral
therapy (HAART) therapy. (Dose De-escalation and Dose Expansion Cohorts)

SECONDARY OBJECTIVES:

I. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab, on immune function (HIV viral load in plasma using conventional assay, CD4+ and
CD8+ cells). (Dose De-escalation Cohort) II. To preliminarily assess objective response rates
associated with treatment for commonly represented tumors (Kaposi sarcoma, anal cancer, and
lung cancer) and relapsed refractory HIV-cHL. (Solid Tumor Dose Expansion and cHL Cohorts)
III. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab, on immune function (HIV viral load in plasma using conventional HIV assay, CD4+,
and CD8+ cells). Only single agent nivolumab will be utilized in the cHL cohort. (Solid Tumor
Dose Expansion and cHL Cohorts)

TERTIARY OBJECTIVES:

I. Understand the immune response to agent in the context of antiretroviral therapy (ART), of
altered immune function, and repertoire due to prior HIV infection.

II. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab, on intratumor immune cells by immunohistochemistry (IHC) such as PD1, programmed
cell death 1 ligand 1 (PDL-1), and others.

III. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab on circulating cytokine markers by multiplex assay, such as: interleukin (IL)-2,
IL-4, IL-6, IL-10, IL-8, interferon gamma-induced protein 10 (IP10), chemokine (C-X-C motif)
ligand 13 (CXCL13), interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, soluble IL-2
receptor (sIL2R)-alpha, sCD27, soluble TNF receptor (sTNFR)1, and sTNFR2.

IV. To understand the response of human tumor viruses (human papillomavirus [HPV],
Epstein-Barr virus [EBV], Kaposi's sarcoma-associated herpesvirus [KSHV]) to agent.

V. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab on herpesvirus loads (EBV, KSHV, cytomegalovirus [CMV]) in plasma.

VI. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab on latent herpesvirus (EBV, KSHV, CMV) in peripheral blood mononuclear cells
(PBMC).

VII. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab on herpesvirus specific CD8 and CD4 T cells in PBMC.

VIII. In cases of Kaposi sarcoma, to evaluate the effects of single agent nivolumab, and the
combination of ipilimumab and nivolumab on viral transcription in tumor biopsies.

IX. In cases of anal cancer, to evaluate the effects of single agent nivolumab, and the
combination of ipilimumab and nivolumab on HPV types in anal swabs, when feasible.

X. Understand the response of HIV to agent. XI. To evaluate the effects of single agent
nivolumab, and the combination of ipilimumab and nivolumab on latent HIV loads in PBMC using
outgrowth assay.

XII. To evaluate the effects of single agent nivolumab, and the combination of ipilimumab and
nivolumab on HIV reactive T cells.

OUTLINE: This is a dose escalation study of nivolumab.

Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Patients in dose
level 2 also receive ipilimumab IV over 90 minutes on day 1 of every third course of
nivolumab, and patients in dose level -2 also receive ipilimumab IV over 90 minutes on day 1
of every sixth course of nivolumab. Courses repeat every 14 days for up to 46 courses of
nivolumab (with ipilimumab if receiving dose level 2 or -2) in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 16 weeks or 112 days (based
on 5 half lives).

Inclusion Criteria:

- Participants must have histologically confirmed solid tumor malignancy that is
metastatic or unresectable and for which standard curative or palliative measures do
not exist or are no longer effective; participants with uncontrolled Kaposi sarcoma
are permitted (KS must be increasing despite HAART and HIV suppression for greater
than or equal to 2 months, or stable KS despite HAART for greater than or equal to 3
months)

- For participants in the 24 participant solid tumor cohort, only those histologies
not known to respond to single agent nivolumab (such as pancreas, prostate, and
microsatellite stable [MSS] colorectal cancer) will be excluded

- For participants in the relapsed refractory HIV-cHL expansion cohort,
participants must have histologically confirmed, relapsed/refractory (defined as
relapsed/refractory to one or greater lines of therapy) HIV-associated classical
Hodgkin lymphoma

- HIV-1 infection, as documented by any federally approved, licensed HIV rapid test
performed in conjunction with screening (or enzyme linked immunosorbent assay [ELISA],
test kit, and confirmed by Western blot or other approved test); alternatively, this
documentation may include a record demonstrating that another physician has documented
the participant's HIV status based on either: 1) approved diagnostic tests, or 2) the
referring physician's written record that HIV infection was documented, with
supporting information on the participant's relevant medical history and/or current
management of HIV infection

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic
resonance imaging (MRI), or calipers by clinical exam; scans must have been performed
within 4 weeks prior to registration; Note: for participants with Kaposi sarcoma, the
following apply: at least five measurable cutaneous KS lesions or any number of
lesions with systemic unresectable disease with no previous local radiation, surgical,
or intralesional cytotoxic therapy that would prevent response assessment

- Prior therapy for metastatic disease permitted; at least 4 weeks must have elapsed
since prior chemotherapy or biological therapy, 6 weeks if the regimen included
carmustine (BCNU) or mitomycin C; radiotherapy must be completed at least 4 weeks
prior to registration

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Leukocytes >= 2,000/mm^3,
within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Absolute neutrophil count
>= 1,000/mm^3, within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Platelets >= 75,000/mm^3,
within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Total bilirubin =< 1.5 x
institutional upper limit of normal (ULN) =< 3 x ULN for subjects with Gilbert's
disease or with atazanavir- or indinavir-induced unconjugated hyperbilirubinemia
without aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation
and must have a total bilirubin less than 3.0 mg/dL, within 2 weeks prior to
enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum lipase and amylase <
1.5 x ULN, within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: AST (serum glutamic
oxaloacetic transaminase [SGOT])/ALT (serum glutamate pyruvate transaminase [SGPT]) =<
3 X ULN, within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Creatinine < 1.5 UNL or
creatinine clearance (CrCl) > 50 ml/min, within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Hemoglobin >= 9 g/dL,
within 2 weeks prior to enrollment

- PARTICIPANTS NOT ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum albumin >= 2.8 g/dL,
within 2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Leukocyte count: no lower
limit, within 2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Absolute neutrophil count: >
500/mcL, within 2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Platelets: > 50,000/mcL, within
2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Hemoglobin: >= 9 g/dL unless
bone marrow involvement secondary to Hodgkin lymphoma is present, within 2 weeks prior
to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum albumin: >= 2.8 g/dL,
within 2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Total bilirubin: =<1.5 ×
institutional upper limit of normal (ULN), or =< 3 x ULN for participants with
Gilbert's disease or with atazanavir- or indinavir-induced unconjugated
hyperbilirubinemia without AST or ALT elevation, and must have a total bilirubin less
than 3.0 mg/dL), within 2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum lipase and amylase < 1.5
x ULN, within 2 weeks prior to enrollment

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: AST (SGOT) / ALT (SGPT): =< 3 x
ULN

- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Creatinine: < 1.5 x upper
normal limit (UNL) or CrCl > 50ml/min, within 2 weeks prior to enrollment

- HIV plasma HIV-1 ribonucleic acid (RNA) below detected limit obtained by Food and Drug
Administration (FDA)-approved assays (limit of detection: 75) within 4 weeks prior to
registration

- CD4 counts:

- For Stratum 1: CD4+ cell count greater than 200 cells/mm^3 obtained within 2
weeks prior to enrollment at any United States (U.S.) laboratory that has a
clinical laboratory improvement amendments (CLIA) certification or its equivalent

- For Stratum 2: CD4 cell count between 100-200 cells/mm^3 obtained within 2 weeks
prior to enrollment at any U.S. laboratory that has a clinical laboratory
improvement amendments (CLIA) certification or its equivalent

- Expansion Cohort: CD4 cell count for this cohort will be specified once Stratum 1
and Stratum 2 have completed enrollment

- Solid Tumor Expansion Cohort: CD4+ cell count greater than 200 cells/mm^3
obtained within 2 weeks prior to enrollment at any U.S. laboratory that has a
clinical laboratory improvement amendments (CLIA) certification or its equivalent

- cHL Cohort: CD4 cell count of at least 100 cells/mm^3

- Participants must be purified protein derivative (PPD) negative; alternatively, the
QuantiFERON-TB Gold In-Tube (QFT-GIT) assay can be used; an individual is considered
positive for M. tuberculosis infection if the IFN-gamma response to tuberculosis (TB)
antigens is above the test cut-off (after subtracting the background IFN-gamma
response in the negative control); the result must be obtained within 12 weeks prior
to enrollment; PPD positive (or Quantiferon assay positive) participants are permitted
if prophylaxis has been completed prior to enrollment

- Women of childbearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation; WOCBP should use an adequate method
to avoid pregnancy for 6 months after the last dose of investigational drug; women of
childbearing potential must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic [HCG]) within
72 hours prior to the start of nivolumab; women must not be breastfeeding; men who are
sexually active with WOCBP must use any contraceptive method with a failure rate of
less than 1% per year; men receiving nivolumab and who are sexually active with WOCBP
will be instructed to adhere to contraception for a period of 31 weeks after the last
dose of investigational product; women who are not of childbearing potential (i.e.,
who are postmenopausal or surgically sterile as well as azoospermic men) do not
require contraception; WOCBP receiving nivolumab will be instructed to adhere to
contraception for a period of 6 months after the last dose of investigational product;
men receiving nivolumab and who are sexually active with WOCBP will be instructed to
adhere to contraception for a period of 31 weeks after the last dose of
investigational product; 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

- Participants MUST receive appropriate care and treatment for HIV infection, including
antiretroviral medications when clinically indicated, and should be under the care of
a physician experienced in HIV management; participants will be eligible regardless of
antiretroviral medication (including no antiretroviral medication) provided there is
no intention to initiate therapy or the regimen has been stable for at least 4 weeks
with no intention to change the regimen within 12 weeks following enrollment

- Participants who have hepatitis C (both reactive anti-hepatitis C virus [HCV] antibody
and detectable HCV RNA) and hepatitis B (hepatitis B surface antigen [HBsAg] positive
and anti-hepatitis B core [HBc]-total positive), may be enrolled, provided total
bilirubin is =< 1.5 x institutional ULN, and AST (SGOT) and ALT (SGPT) must be =< 3 X
institutional upper limit of normal, and hepatitis B virus (HBV) deoxyribonucleic acid
(DNA) < 100 IU/mL (if hepatitis B positive) within 2 weeks prior to enrollment

- Ability to understand and to sign a written informed consent document

- Criteria for Solid Tumor Expansion and Lymphoma Cohorts:

- Inclusion and exclusion criteria for this cohort are the same as above, with the
following rule for CD4 count based on tolerability in Phase I; if, participants
with lymphocyte T CD4 count between 100-200/mm^3 (Stratum 2) are shown to
tolerate treatment in the Phase I dose de-escalation portion at the same dose
level as those with CD4 counts > 200/mm^3 (Stratum 1), participants in the
expansion cohort with CD4 counts >= 100/mm^3 are permitted; otherwise, the
expansion is open to all solid tumor patients except those whose tumors are known
not to respond to nivolumab (pancreas, prostate and MSS colon cancer); for the
relapsed refractory HIV-cHL cohort, participants with CD4 count >= 100/mm^3 are
permitted

Exclusion Criteria:

- Participants who have received any other investigational agents within the 4 weeks
prior to enrollment; concurrent radiation therapy is not permitted, except palliative
(limited-field) radiation therapy, if all of the following criteria are met:

- Repeat imaging demonstrates no new sites of bone metastases

- The lesion being considered for palliative radiation is not a target lesion

- Participants with known brain metastases or leptomeningeal metastases must be excluded
unless they qualify for enrollment as described below because of poor prognosis and
concerns regarding progressive neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events; participants with brain metastases
are permitted if metastases have been treated and there is no magnetic resonance
imaging (MRI) evidence of progression for at least 4 weeks or more after treatment is
complete and within 4 weeks prior to the first dose of nivolumab administration

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ipilimumab, nivolumab, or other agents used in study, or history of
severe hypersensitivity reaction to any monoclonal antibody

- Participants should be excluded if they have a condition requiring systemic treatment
with either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 2 weeks of study drug administration; these drugs
may interfere with the activity of ipilimumab and nivolumab if administered at the
time of the first ipilimumab dose; inhaled or topical steroids and adrenal replacement
doses =< 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease; participants are permitted to use topical, ocular,
intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
absorption); physiologic replacement doses of systemic corticosteroids are permitted,
even if >= 10 mg/day prednisone equivalents; a brief course of corticosteroids for
prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions
(e.g., delayed-type hypersensitivity reaction caused by contact allergen) is
permitted; use of anabolic steroids is permitted

- Participants with clinical or radiographic evidence of pancreatitis are excluded

- 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

- Participants should be excluded if they have had prior treatment with an anti-PD-1,
anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death ligand 2
(PD-L2), anti-CTLA-4 antibody, or any other antibody or drug specifically targeting
T-cell co-stimulation or immune checkpoint pathways; prior immune modulating therapy
including vaccines may be eligible; prior immune events must be evaluated and the risk
for new events which may represent continued sub clinical disease or a new process at
previously damaged site or immune potentiation (e.g. ipilimumab followed by IL2
causing bowel perforation, ipilimumab followed by indoleamine 2,3-dioxygenase [IDO]
inhibitor resulting in clinical hypophysitis); please keep in mind that inflammatory
events may occur weeks to months following the last dose of ipilimumab and possibly
nivolumab; assessment of potential effects of prior therapy should include:

- Immune status

- Organ damage

- Risk of autoimmunity

- Immunopotentiation

- The participant has not recovered to baseline or Common Terminology Criteria for
Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except =<
grade 2 alopecia, neuropathy, and other non-clinically significant adverse events
(AEs)

- The participant has a primary brain tumor

- Participant has >= grade 2 diarrhea (participants with grade 1 diarrhea are eligible
provided stool for ova/parasites and stool cryptosporidium studies are negative)

- Opportunistic infection within the last 3 months

- Participants with active autoimmune disease or h