Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

PRIMARY OBJECTIVES:

I. To evaluate the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
overall response rate (ORR) in subsets of patients with advanced rare cancers treated with
ipilimumab plus nivolumab combination immunotherapy.

SECONDARY OBJECTIVES:

I. To evaluate toxicities in each cohort. II. To estimate overall survival (OS),
progression-free survival (PFS), clinical benefit rate; and to estimate immune-related ORR
(irORR), and immune-related PFS (irPFS) by unidimensional immune-related response criteria.

TERTIARY OBJECTIVES:

I. To evaluate the association of tumor mutational burden measured by tissue sequencing with
durable response (complete response [CR] or partial response [PR] lasting 24 weeks or more).

II. To describe the mutational load and targeted sequencing of well-known oncogenes and
changes in these markers of patients at up to three time points (baseline, cycle 2, and
progression), and across strata to describe associations with survival outcomes.

III. To describe the presence of germline mutations, and across strata to evaluate
association with outcome.

IV. Within strata, to describe patient risk category as defined by the biodesix protein
signature and change over time at up to three time points (baseline, cycle 2, progression),
and across strata to evaluate associations with outcomes.

V. Within strata, to evaluate the association of PD-L1 expression (positive versus negative)
with response and survival outcomes, and within strata, to characterize baseline PD-L1
prevalence.

VI. To collect specimens for banking for use in future correlative biomarker research
studies.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and
ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 10 years from registration.

Inclusion Criteria:

- Patients are eligible under ONE of the following criteria:

- Patients must have histologically confirmed rare cancer and must be able to
submit specimens; NOTE: Subsequent to site's Institutional Review Board (IRB)
approval of revision 3, patients are NOT required to participate in EAY131
"National Cancer Institute (NCI)-Molecular Analysis for Therapy Choice (MATCH)"
to register to this study

- FOR PATIENTS ENROLLED IN EAY131 "NCI-MATCH" PRIOR TO EAY131 ADDENDUM 10 ONLY:
Patients must have histologically confirmed rare cancer that did not have a match
to a molecularly-guided therapy on EAY131 "NCI-MATCH" protocol or who are off
protocol treatment on EAY131, "NCI-MATCH" and have no further molecularly-matched
treatment recommendations per EAY131, "NCI-MATCH" or who are otherwise unable to
receive EAY131, "NCI-MATCH" therapy

- Patients that do not qualify for one of the histologic cohorts may be considered for
registration in the "Not Otherwise Categorized" Rare Tumors cohort with confirmation
of at least one of the study chairs via email

- Patients that are determined to have a rare cancer with unknown primary site are
eligible under cohort #32 (tumor of unknown primary [cancer of unknown primary; CuP]),
provided that there is histologic documentation of metastatic malignancy with no
discernible primary site identified from histopathologic review, physical exam and
associated cross-sectional imaging of the chest, abdomen, and pelvis

- Patients must have progressed following at least one line of standard systemic therapy
and there must not be other approved/standard therapy available that has been shown to
prolong overall survival (i.e. in a randomized trial against another standard
treatment or by comparison to historical controls); patients who cannot receive other
standard therapy that has been shown to prolonged survival due to medical issues will
be eligible, if other eligibility criteria are met; OR

- Patients for whose disease no standard treatment exists that has been shown to
prolong overall survival

- Patients must have a diagnostic quality computed tomography (CT) scan or magnetic
resonance imaging (MRI), performed within 28 days prior to registration, which
demonstrates measurable disease, as defined in RECIST v. 1.1; all disease must be
assessed and documented on the S1609 Baseline Tumor Assessment Form

- No other prior malignancy is allowed except for the following:

- Adequately managed stage I or II cancer from which the patient is currently in
complete remission

- Any other cancer from which the patient has been disease free for one year

- Adequately managed stage I or II follicular thyroid or prostate cancer is also
eligible, wherein patient is not required to be in complete remission

- Patients may have received prior anti-CTLA4 or other anti-PD-1/anti-PD-L1 therapy, not
both, provided that it is completed >= 4 weeks prior to registration

- Patients who had prior grade 3 or higher immune-related adverse event (e.g.
pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer
vaccine, cytokine, etc.) are not eligible

- Patients with clinically controlled thyroiditis or pituitary disorders on stable
replacement therapy are eligible

- Patients are not eligible if they have had or are planned for solid organ transplant;
patients who have received allogeneic hematopoietic stem cell transplant are eligible
if:

- The transplant occurred at least 90 days prior to registration,

- Patient has no prior acute graft versus host disease (GVHD), and

- Within 48 hours of registration, patient demonstrates at least 90% engraftment,
defined as: absolute neutrophil count (ANC) >= 500 mcl, measured over 3
consecutive days or 1 day with an ANC >= 1,000 mcl, or platelets >= 50,000 mcl
measured, wherein the patient did not receive any platelet transfusions within 7
days prior to laboratory assessment

- Patients with autoimmune disease who are otherwise eligible must not have received
steroid and immunosuppressive therapy within 28 days prior to registration

- Patients with brain metastases or primary brain tumors must have completed treatment,
surgery or radiation therapy >= 28 days prior to registration and have stable disease
at time of registration; metastatic brain parenchymal disease must have been treated
and patient must be off steroids for 7 days prior to registration; patients must have
a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease
within 42 days prior to registration

- Patients must not currently be receiving any other investigational agents or any other
systemic anti-cancer therapy (including radiation, excluding RANKL inhibitors and
bisphosphonates); in event patient recently received any other systemic anti-cancer
therapy, patient must be off therapy at least 7 days prior to registration and any
therapy-induced toxicity must have recovered to =< grade 1, except alopecia and =<
grade 2 neuropathy which are allowed; any planned radiation therapy must be completed
before enrollment onto S1609

- Patients must not have prior history of allergy or known hypersensitivity to nivolumab
or ipilimumab

- Patients must have a Zubrod performance status of 0-2

- Within 28 days prior to registration: ANC >= 1,000/mcL

- Within 28 days prior to registration: Platelets >= 75,000/mcL

- Within 28 days prior to registration: Hemoglobin >= 8 g/dL

- Within 28 days prior to registration: Total bilirubin =< 2.0 x institutional upper
limit of normal (IULN) or for documented/suspected Gilbert's disease, total bilirubin
=< 3.0 x IULN

- Within 28 days prior to registration: Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) both =< 3 x IULN

- Within 28 days prior to registration: Serum creatinine =< 2.0 x IULN

- Within 28 days prior to registration: Creatinine clearance (CrCl) >= 50 mL/min., as
estimated by the Cockcroft and Gault formula; estimated creatinine clearance is based
on actual body weight

- Patients must have adequate thyroid function, as evidenced by either
thyroid-stimulating hormone (TSH) or, free thyroxine (T4) serum tests demonstrating
values within the normal range, within 28 days prior to registration; Note: TSH, with
reflex T4 is allowable if per institutional standard; otherwise, both TSH and free-T4
must be obtained

- Patients must have adequate adrenal axis function, as evidenced by adrenocorticotropic
hormone (ACTH) values within the institutional normal ranges OR cortisol levels within
institutional normal ranges (ante meridiem [AM] cortisol preferred), within 28 days
prior to registration

- Females of childbearing potential must have negative serum or urine pregnancy test 7
days prior to registration and agree to use birth control throughout study and for 23
weeks after completion of protocol therapy; patients must not be pregnant or nursing;
women/men of reproductive potential must have agreed to use an effective contraceptive
method; 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

- Men of reproductive potential must have agreed to use birth control throughout the
study and for 31 weeks after completion of protocol therapy; in addition to routine
contraceptive methods, "effective contraception" also includes heterosexual celibacy
and surgery intended to prevent pregnancy (vasectomy); 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 is responsible
for beginning contraceptive measures

- Patients must not have known active hepatitis B virus (HBV) or hepatitis virus (HCV)
infection at time of registration; patients with HBV or HCV that have an undetectable
viral load, or in the opinion of the treating investigator is well-controlled, are
eligible

- Patients who are known to be human immunodeficiency virus (HIV)-positive at
registration are eligible at the time of registration:

1. Cluster of differentiation (CD)4+ cell count greater or equal to 250 cells/mm^3

2. If patient is on antiretroviral therapy, there must be minimal interactions or
overlapping toxicity of the antiretroviral therapy with the experimental cancer
treatment; once daily combinations that use pharmacologic boosters may not be
used

3. No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining
conditions other than historical low CD4+ cell counts

- 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 10mg or equivalent); replacement
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment; autoimmune diseases include but are not limited to autoimmune hepatitis,
inflammatory bowel disease (including ulcerative colitis and Chron'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]); 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
is permitted; short-term steroid premedication for contrast allergy is permitted

- Patients must not have any uncontrolled intercurrent illness including (not limited
to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA]
III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks
prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of
NCI Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4 grade >= 2),
known psychiatric illness that would limit study compliance, intra-cardiac
defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>=
grade 3)

- Note: Patients with history of CHF or patients who are deemed at risk because of
underlying cardiovascular disease or exposure to cardiotoxic drugs should have an
electrocardiogram (EKG) and echocardiogram (ECHO), as clinically indicated, at
baseline and at the start of each cycle; patients who have evidence at baseline
(or subsequently) of CHF, myocardial infarction (MI), cardiomyopathy, or myositis
cardiac evaluation (NYHA I/II) should have additional consult by a cardiologist,
including review of EKG, creatine phosphokinase (CPK), troponin, echocardiogram,
as clinically indicated

- Patients must have amylase or lipase within =< 1.5 x IULN without symptoms of
pancreatitis at registration, within 28 days prior to registration

- Patients must not have symptomatic interstitial lung disease or pneumonitis

- Patients must have fully recovered from any adverse effects of major surgery (to =<
grade 1) at least 14 days prior to registration