| Eligibility |
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
- Age > 18 years, because no dosing or AE data are currently available on the use of
ipilimumab in combination with nivolumab in participants <18 years of age, children
are excluded from this study.
- 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 may receive granulocyte colony
stimulating factor [GCSF] and transfusions to meet these parameters)
- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Absolute neutrophil count: >=
1,000/mm^3, unless decreased due to bone marrow involvement with lymphoma (within 2
weeks prior to enrollment) (participants may receive GCSF and transfusions to meet
these parameters)
- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Platelets: >= 75,000/mm^3,
unless decreased due to bone marrow involvement with lymphoma (within 2 weeks prior to
enrollment) (participants may receive GCSF and transfusions to meet these parameters)
- 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 may receive GCSF and transfusions to meet these
parameters)
- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Total bilirubin: =< 1.5 x
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 may receive GCSF
and transfusions to meet these parameters)
- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: Serum lipase and amylase < 1.5
x ULN (within 2 weeks prior to enrollment) (participants may receive GCSF and
transfusions to meet these parameters)
- PARTICIPANTS ON THE HODGKIN LYMPHOMA EXPANSION COHORT: AST (SGOT)/ALT (SGPT): =< 3 x
ULN (within 2 weeks prior to enrollment) (participants may receive GCSF and
transfusions to meet these parameters)
- 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)
(participants may receive GCSF and transfusions to meet these parameters)
- HIV viral load should be well suppressed, defined as below the limit of detection of
the local assay or below 75 copies/mL by Food and Drug Administration (FDA)-approved
assays, 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-tuberculosis (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 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
- The effects of nivolumab and ipilimumab on the developing human fetus are unknown; for
this reason and because other therapeutic agents used in this trial are known to be
teratogenic, 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 enrollment and 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 ribonucleic acid [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 history of autoimmune disease that
might recur, which may affect vital organ function or require immune suppressive
treatment including systemic corticosteroids, should be excluded; these include but
are not limited to patients with a history of immune related neurologic disease,
multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,
myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus
(SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),
Crohn's, ulcerative colitis, hepatitis; and participants with a history of toxic
epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should
be excluded because of the risk of recurrence or exacerbation of disease; participants
with vitiligo, endocrine deficiencies including thyroiditis managed with replacement
hormones including physiologic corticosteroids are eligible; participants with
rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis
controlled with topical medication and participants with positive serology, such as
antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the
presence of target organ involvement and potential need for systemic treatment but
should otherwise be eligible; participants 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
(precipitating event)
- Participants who have had evidence of Clostridium (C.) difficile infection, active or
acute diverticulitis, intra-abdominal abscess, intra-abdominal abscess,
gastrointestinal (GI) obstruction and abdominal carcinomatosis, which are known risk
factors for bowel perforation, should be evaluated for the potential need for
additional treatment before coming on study
- cHL COHORT ONLY: history of allogeneic transplant
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