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

Inclusion Criteria:

• All patients must have disease-free status documented by a complete physicalexamination and imaging studies within 4 weeks prior to randomization; imagingstudies must include a total body positron emission tomography (PET)-computedtomography (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 otherimaging studies if performed (eg, bone scan) must show no evidence of disease

• Patients must have primary cutaneous melanoma that belong to one of the followingAmerican Joint Commission on Cancer (AJCC) stages (2009 AJCC Melanoma StagingSystem):

• 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 lactatedehydrogenase (LDH) and either distant skin, subcutaneous, lymph node, orlung metastases, but no other visceral metastases in order to be eligible;for patients with resected stage IV melanoma, LDH within the institutionalupper limit of normal (ULN) must be documented within 4 weeks prior torandomization

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

• Recurrence in a regional lymph node basin after a prior complete lymph nodedissection; relapsed disease must be completely surgically resected with freemargins

• Recurrence in the form of in-transit or satellite metastases or distantskin/subcutaneous, nodal, or lung metastases that are completely surgicallyresected with free margins

• Recurrence in a regional lymph node basin; relapsed disease must be completelysurgically resected with free margins

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

• NOTE: all subjects should be classified as IIIB, IIIC, M1a or M1b includingsubjects with disease recurrence after adequate surgical excision of theoriginal primary melanoma; that is the treating team/physician investigatorshould review an overall TNM status (that includes primary tumor presentationand disease recurrence status) and provide a designation of IIIB, IIIC, M1a orM1b

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

• NOTE: patients with clinically positive lymph nodes for melanoma involvement orthose with positive lymph nodes identified through lymphoscintigraphic and/ordye lymphographic techniques in the groin, axilla, or neck should haveadditional lymphadenectomy in those sites; the complete lymph node dissectionprocedure would be considered as the last surgery in counting the 84 daysunless a subsequent surgical procedure(s) was clinically required to ensure thedisease free status

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

• Given that serious adverse events may occur with ipilimumab and IFN-alpha and thatthese may impact a patient's wellbeing, it is possible that the occurrence of otherserious adverse events (SAEs) may seriously impact an underlying state of mentaldepression and lead to suicidal ideation; therefore, patients should be carefullyscreened for depression at baseline and if there are indications or a history ofdepression it is strongly recommended that these patients be closely followedtogether with behavioral health or psychiatric medical support; patients with anestablished diagnosis of depression that, in the assessment of the investigator maymake the administration of IFN-alpha or ipilimumab hazardous, should not be enrolledon this protocol; the risks and benefits of being treated with standard adjuvantIFN-alpha should be weighed very carefully in consultation with behavioral health orpsychiatry

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

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

• Men of fathering potential and WOCBP must be using an adequate method ofcontraception 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 therisk of pregnancy is minimized; men or WOCBP who are unwilling or unable tostrictly 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 torandomization)

• 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 musthave a total bilirubin less than 3.0 mg/dL) (obtained within 4 weeks prior torandomization)

• No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B,or hepatitis C due to the unknown effects of ipilimumab; patients must have negativetesting for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) within 4 weeksprior to randomization

Exclusion Criteria:

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

• NOTE: previous radiation therapy, including after the surgical resection, isallowed as long as 21 days have elapsed between the radiation and initiation ofthis adjuvant systemic therapy

• Prior treatment with anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) monoclonalantibodies 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 priortreatment 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 forthis trial, but these must have been completed at least 4 weeks prior torandomization

• Patients must not have an active infection requiring current treatment withparenteral antibiotics

• Patients must not have other significant medical, surgical, or psychiatricconditions or require any medication or treatment that in the opinion of theinvestigator may interfere with compliance, make the administration of ipilimumab orHDI hazardous or obscure the interpretation of adverse events (AEs), such as acondition associated with frequent diarrhea; patients with a baseline of frequentdiarrhea (e.g. irritable bowel syndrome) are not eligible because of the difficultyin interpreting later expected GI toxicities that may lead to suboptimal managementand complications

• Patients must not have a documented history of inflammatory bowel disease (includingulcerative colitis and Crohn's disease) or diverticulitis (history of diverticulosisis allowed)

• Patients must not have autoimmune disorders or conditions of immunosuppression thatrequire current ongoing treatment with systemic corticosteroids (or other systemicimmunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) orcontinuous use of topical steroid creams or ointments or ophthalmologic steroids; ahistory 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 weeksprior to randomization are eligible if, in the judgment of the treating physicianinvestigator, the patient is not likely to require resumption of treatment withthese classes of drugs during the study

• Exclusion from this study also includes patients with a history of symptomaticautoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmunevasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered ofautoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); othercentral nervous system (CNS) autoimmune disease (e.g., poliomyelitis, multiplesclerosis)

• Patients with autoimmune hypothyroid disease or type I diabetes on replacementtreatment are eligible

• 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; this is due to concerns about subject safety andcompliance with study procedures

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

• Women must not be pregnant or breast-feeding due to the unknown effects ofipilimumab and HDI on conception and the fetus; all females of childbearingpotential must have a blood test or urine study during screening to rule outpregnancy

• NOTE: a woman of childbearing potential (WOCBP) is any woman, regardless ofsexual orientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has not undergone a hysterectomy or bilateraloophorectomy; or 2) has not been naturally postmenopausal for at least 24consecutive months (i.e., has had menses at any time in the preceding 24consecutive months); post-menopause is defined as:

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

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