Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate recurrence-free survival (RFS) between patients randomized to receive
post-operative adjuvant ipilimumab given at either 10 mg/kg (high dose ipilimumab; HIP) or 3
mg/kg (low dose ipilimumab: LIP) versus those randomized to receive high-dose interferon
alfa-2b (HDI) utilizing a hierarchical design assessing HIP versus HDI first and LIP versus
HDI second (if the first comparison is significant).

II. To evaluate overall survival (OS) between patients randomized to receive post-operative
adjuvant ipilimumab given at either 10 mg/kg (HIP) or 3 mg/kg (LIP) versus those randomized
to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus
HDI second (if the first comparison is significant).

SECONDARY OBJECTIVES:

I. To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at
either 10 mg/kg (HIP) or 3 mg/kg (LIP).

II. Among patients enrolled by Clinical Community Oncology programs (CCOPs), to compare the
global quality of life (QOL) between the ipilimumab arms versus HDI using Functional
Assessment of Cancer Therapy (FACT)-General (G) form and to evaluate the effect of
treatment-related side effects that may have an impact on the health-related domains of QOL
using Functional Assessment of Chronic Illness Therapy (FACIT)-diarrhea (D) and
FACT-biological response modifiers (BRM).

OUTLINE: Patients age >= 18 are randomized to Arms A, B, or C and patients ages 12-17 are
randomized to Arms D, E, or F.

ARM A: Patients receive induction high-dose ipilimumab intravenously (IV) over 90 minutes on
day 1. Treatment repeats every 21 days for a total of 4 courses in the absence of disease
progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance
high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a
maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (closed
accrual as of 4/4/14) (adult accrual has completed to Arms A, B, and C as of 8/15/2014)

ARM B: Patients receive induction high-dose recombinant interferon alfa-2b IV over 20 minutes
on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable
toxicity. Patients then receive maintenance high-dose recombinant interferon alfa-2b
subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the
absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms
A, B, and C as of 8/15/2014)

ARM C: Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment
repeats every 21 days for a total of 4 courses in the absence of disease progression or
unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab
IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in
the absence of disease progression or unacceptable toxicity. (adult accrual has completed to
Arms A, B, and C as of 8/15/2014)

ARM D: Patients receive induction high-dose ipilimumab IV over 90 minutes on day 1. Treatment
repeats every 21 days for a total of 4 courses in the absence of disease progression or
unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose
ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4
courses in the absence of disease progression or unacceptable toxicity.

ARM E: Patients receive induction high-dose recombinant interferon alfa-2b IV over 20 minutes
on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable
toxicity. Patients then receive maintenance high-dose recombinant interferon alfa-2b SC on
days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease
progression or unacceptable toxicity

ARM F: Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment
repeats every 21 days for a total of 4 courses in the absence of disease progression or
unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab
IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years, every
6 months for 3 years, and then yearly for up to 15 years.

Inclusion Criteria:

- All patients must have disease-free status documented by a complete physical
examination and imaging studies within 4 weeks prior to randomization; imaging studies
must include a total body positron emission tomography (PET)-computed tomography (CT)
scan (with or without brain) and brain magnetic resonance imaging (MRI) or CT (if MRI
is contraindicated); if PET-CT cannot be done, CT of neck, chest, abdomen, and pelvis
should be done

- If for some reason a CT cannot be done, an MRI may be done instead; any other
imaging studies if performed (eg, bone scan) must show no evidence of disease

- Patients must have primary cutaneous melanoma that belong to one of the following
American Joint Commission on Cancer (AJCC) stages (2009 AJCC Melanoma Staging System):

- Stage IIIB

- T1-4b N1a M0

- T1-4b N2a M0

- T1-4b N1b M0

- T1-4b N2b M0

- T1-4b N2c M0

- Stage IIIC

- T1-4b N1b M0

- T1-4b N2b M0

- T1-4b N2c M0

- Any T N3 M0

- Stage IV

- M1a

- M1b

- NOTE: patients with stage IV melanoma must have normal lactate dehydrogenase
(LDH) and either distant skin, subcutaneous, lymph node, or lung metastases,
but no other visceral metastases in order to be eligible; for patients with
resected stage IV melanoma, LDH within the institutional upper limit of
normal (ULN) must be documented within 4 weeks prior to randomization

- Patients with disease recurrence after adequate surgical excision of the original
primary cutaneous/unknown primary melanoma are allowed even if they don't fit the
strict staging criteria, but only as follows:

- Recurrence in a regional lymph node basin after a prior complete lymph node
dissection; relapsed disease must be completely surgically resected with free
margins

- Recurrence in the form of in-transit or satellite metastases or distant
skin/subcutaneous, nodal, or lung metastases that are completely surgically
resected with free margins

- Recurrence in a regional lymph node basin; relapsed disease must be completely
surgically resected with free margins

- Patients with unknown primary melanoma (Tx) who present with cutaneous, subcutaneous,
nodal and/or lung metastases that are completely surgically resected with free margins
are allowed; these patients are allowed even if they don't fit the strict staging
criteria; for stage IV patients LDH within the institutional ULN must be documented
within 4 weeks prior to randomization (M1c is not eligible)

- NOTE: all subjects should be classified as IIIB, IIIC, M1a or M1b including
subjects with disease recurrence after adequate surgical excision of the original
primary melanoma; that is the treating team/physician investigator should review
an overall TNM status (that includes primary tumor presentation and disease
recurrence status) and provide a designation of IIIB, IIIC, M1a or M1b

- Patients must be randomized within 84 days (12 weeks) of surgical resection; if more
than one surgical procedure is required to render the patient disease-free, the
patient must be randomized within 12 weeks of the last surgery

- NOTE: patients with clinically positive lymph nodes for melanoma involvement or
those with positive lymph nodes identified through lymphoscintigraphic and/or dye
lymphographic techniques in the groin, axilla, or neck should have additional
lymphadenectomy in those sites; the complete lymph node dissection procedure
would be considered as the last surgery in counting the 84 days unless a
subsequent surgical procedure(s) was clinically required to ensure the disease
free status

- Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or
limb perfusion) after the resection(s) that make(s) them eligible for this trial

- NOTE: previous radiation therapy, including after the surgical resection, is
allowed as long as 21 days have elapsed between the radiation and initiation of
this adjuvant systemic therapy

- Prior treatment with anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) monoclonal
antibodies or prior CTLA-4 inhibitor or agonist or prior clusters of differentiation
(CD)137 agonist or prior interferon-alfa is not allowed; other forms of prior
treatment for melanoma (e.g., aldesleukin [IL-2], anti-tumor vaccine, chemotherapy)
are allowed if given before the resection(s) that make(s) the patient eligible for
this trial, but these must have been completed at least 4 weeks prior to randomization

- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Patients must not have an active infection requiring current treatment with parenteral
antibiotics

- Patients must not have other significant medical, surgical, or psychiatric conditions
or require any medication or treatment that in the opinion of the investigator may
interfere with compliance, make the administration of ipilimumab or HDI hazardous or
obscure the interpretation of adverse events (AEs), such as a condition associated
with frequent diarrhea; patients with a baseline of frequent diarrhea (e.g. irritable
bowel syndrome) are not eligible

- Patients should be carefully screened for depression at baseline and if there are
indications or a history of depression it is strongly recommended that these patients
be closely followed together with behavioral health or psychiatric medical support;
patients with an established diagnosis of depression that, in the assessment of the
investigator may make the administration of interferon (IFN)-alfa or ipilimumab
hazardous, should not be enrolled on this protocol; the risks and benefits of being
treated with standard adjuvant IFN-alfa should be weighed very carefully in
consultation with behavioral health or psychiatry

- Patients must not have a documented history of inflammatory bowel disease (including
ulcerative colitis and Crohn's disease) or diverticulitis (history of diverticulosis
is allowed)

- 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 randomization 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, Sjögren's syndrome, autoimmune
vasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered of
autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other
central nervous system (CNS) autoimmune disease (e.g., poliomyelitis, multiple
sclerosis)

- Patients with autoimmune hypothyroid disease or type I diabetes on replacement
treatment are eligible

- Patients must not have had any infectious disease vaccination (e.g., standard
influenza, H1N1 influenza, pneumococcal, meningococcal, or tetanus toxoid) within 4
weeks prior to randomization

- Patients must not be prisoners or subjects who are compulsorily detained
(involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g.,
infectious) illness

- Patients who have other current malignancies are not eligible; patients with other
malignancies are eligible if they have been continuously disease free for > 5 years
prior to the time of randomization; patients with prior history at any time of any in
situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ,
atypical melanocytic hyperplasia or melanoma in situ are eligible; patients with prior
history of basal or squamous skin cancer are eligible; patients who have had multiple
primary melanomas are eligible

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study during screening to rule out pregnancy

- NOTE: a woman of childbearing potential (WOCBP) 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); post-menopause is defined as:

- Amenorrhea >= 12 consecutive months without another cause, or

- For women with irregular menstrual periods and taking hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
>= 35 mIU/mL

- WOCBP must be using an adequate method of contraception to avoid pregnancy throughout
the study and for up to 26 weeks after the last dose of ipilimumab or HDI, in such a
manner that the risk of pregnancy is minimized; women who are using oral
contraceptives, other hormonal contraceptives (vaginal products, skin patches, or
implanted or injectable products), or mechanical products such as an intrauterine
device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or
are practicing abstinence or where their partner is sterile (e.g., vasectomy) should
be considered to be of childbearing potential

- Men of fathering potential and WOCBP must be using an adequate method of
contraception to avoid conception/pregnancy throughout the study and for up to 26
weeks after the last dose of ipilimumab or HDI in such a manner that the risk of
pregnancy is minimized; men or WOCBP who are unwilling or unable to strictly
follow this requirement are not eligible

- WOCBP are not eligible if they satisfy any of the following:

- A positive pregnancy test at baseline

- Pregnant or breastfeeding

- White blood cell (WBC) >= 3,000/uL (obtained within 4 weeks prior to randomization)

- Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 4 weeks prior to
randomization)

- Platelets >= 100 x 10^3/uL (obtained within 4 weeks prior to randomization)

- Hemoglobin >= 10 g/dL (obtained within 4 weeks prior to randomization)

- Serum creatinine =< 1.5 mg/dL (obtained within 4 weeks prior to randomization)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (obtained
within 4 weeks prior to randomization)

- Serum bilirubin =< 1.5 x ULN, (except patients with Gilbert's syndrome, who must have
a total bilirubin less than 3.0 mg/dL) (obtained within 4 weeks prior to
randomization)

- No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B,
or hepatitis C; patients must have negative testing for HIV, hepatitis B virus (HBV),
hepatitis C virus (HCV) within 4 weeks prior to randomization