Ipilimumab With or Without High-Dose Recombinant Interferon Alfa-2b in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Test the hypothesis that the combination of ipilimumab and high-dose interferon-alpha 2b
(HDI [recombinant interferon alfa-2b]) will improve progression free survival (PFS) of
patients with advanced metastatic melanoma as compared to ipilimumab alone (across ipilimumab
treatment status).

SECONDARY OBJECTIVES:

I. Test the hypothesis that the combination of ipilimumab and HDI will prove to be safe and
tolerable.

II. Within the constraints of the sample size, attempt to test the hypotheses that (1)
ipilimumab 10 mg/kg will lead to improved PFS in comparison to ipilimumab 3 mg/kg (across HDI
treatment status); (2) the combination of ipilimumab and HDI will improve overall survival
(OS) of patients with advanced metastatic melanoma as compared to ipilimumab alone (across
ipilimumab treatment status) and (3) ipilimumab 10 mg/kg will lead to improved OS in
comparison to ipilimumab 3 mg/kg (across HDI treatment status).

OUTLINE: Patients are randomized to 1 of 4 treatment arms.

ARM A:

INDUCTION PHASE: Patients receive higher dose ipilimumab intravenously (IV) over 90 minutes
once every 3 weeks for 4 doses and recombinant interferon alfa-2b IV over 20 minutes 5 days a
week for 4 weeks and then subcutaneously (SC) 3 times weekly for 8 weeks.

MAINTENANCE PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 12
weeks for 4 doses beginning in week 24 and recombinant interferon alfa-2b SC 3 times weekly
for 48 weeks.

ARM B:

INDUCTION PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 3
weeks for 4 doses.

MAINTENANCE PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 12
weeks for 4 doses beginning in week 24.

ARM C:

INDUCTION PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 3 weeks
for 4 doses and recombinant interferon alfa-2b IV over 20 minutes 5 days a week for 4 weeks
and then SC 3 times weekly for 8 weeks.

MAINTENANCE PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 12
weeks for 4 doses beginning in week 24 and recombinant interferon alfa-2b SC 3 times weekly
for 48 weeks.

ARM D:

INDUCTION PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 3 weeks
for 4 doses.

MAINTENANCE PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 12
weeks for 4 doses beginning in week 24.

In all arms, treatment continues in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually for up to 5 years.

Inclusion Criteria:

- Patients must have unresectable stage III or stage IV melanoma, either initial
presentation or recurrent, that is of cutaneous origin or unknown primary origin and
that is histologically diagnosed

- No more than one prior systemic therapeutic regimen for unresectable stage III or
stage IV melanoma; this includes chemotherapy, biologic therapy, biochemotherapy, or
investigational treatment; this does not include any therapies given in the adjuvant
setting; however, patients are excluded if they have a history of prior treatment for
melanoma (either adjuvant or metastatic disease) with ipilimumab or other cytotoxic
T-lymphocyte antigen 4 (CTLA-4) inhibitor, or prior interferon-alpha treatment for
metastatic disease (history of adjuvant interferon-alpha is allowed); there should be
a 4-week washout period between last treatment administration and initiation of study
therapy

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

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

- Patients must not have a history of inflammatory bowel disease or diverticulitis
(history of diverticulosis is allowed)

- 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; one exception are patients treated with a curative
intent and are continuously disease free for > 3 years; these patients would be
considered eligible:

- 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 Clark I melanoma in situ are eligible

- Patients with prior history of basal or squamous skin cancer are eligible

- 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 (e.g., 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, 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
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

- Due to the possible effect of treatment with ipilimumab on the immunologic response to
infectious disease vaccines, patients must not have had any infectious disease
vaccination (e.g, standard influenza, H1N1 influenza, pneumococcal, meningococcal,
tetanus toxoid) within 4 weeks prior to randomization

- 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: 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); for the purposes of this study, post-menopause
is defined as:

- Amenorrhea >= 24 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
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 or must abstain from sexual intercourse 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

- White blood cells (WBC) >= 3000/uL

- Absolute neutrophil count (ANC) >= 1500/uL

- Platelets >= 100 x 10^3/uL

- Hemoglobin >= 10 g/dL

- Serum creatinine =< 1.8 mg/dl

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
of normal (ULN) for patients with liver metastases and =< 2.0 x ULN for patients
without liver metastases

- Serum bilirubin < 2 x ULN for patients with liver metastases and =< 1.5 x ULN for
patients without liver metastases, (except patients with Gilbert's syndrome, who must
have a total bilirubin < 3.0 mg/dL)

- No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B,
or hepatitis C

- Patients must be free of brain metastasis by contrast-enhanced computed tomography
(CT)/magnetic resonance imaging (MRI) scans within 4 weeks prior to enrollment; if
known to have prior brain metastases, must not have evidence of active brain disease
after definitive therapy (surgery, radiation therapy or stereotactic radiosurgery) on
two successive MRI evaluations at least 3 months apart (one of which is =< 4 weeks
prior to starting the study drugs)

- All sites of disease must be evaluated within 4 weeks prior to randomization; patients
must have measurable disease as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) version (v)1.1