Vanderbilt-Ingram Cancer Center

The purpose of this study is to compare the effects, good and/or bad, of ipilimumab with interferon alfa-2b on patients who have had their melanoma surgically removed to find out which is better. In this study, patients will get either ipilimumab or the interferon alfa-2b. The study plans to determine whether ipilimumab stops or delays melanoma from returning in comparison to interferon alfa-2b. High doses of interferon alfa-2b can reduce the risk of melanoma returning, but only some patients benefit from interferon. This interferon is commercially available. The study aims to find a more effective and long-lasting treatment . Ipilimumab is a biological agent that has been shown to have anti-tumor activity in advanced melanoma. Interferon alfa-2b is FDA-approved as an adjuvant treatment to surgery in adult patients with melanoma who are free of disease but at high risk for recurrence. Ipilimumab is investigational and has not been approved by the FDA for use in this cancer.

Criteria
 Inclusion Criteria:

 • Diagnosis of melanoma of a cutaneous origin or unknown primary

 • No ocular melanoma or melanoma of mucosal origin

 • Stage IIIB, IIIC, or IV (M1a or M1b) disease

 • Patients with stage IV melanoma must have normal LDH and distant skin, subcutaneous, lymph node, or lung metastases

 • No other visceral metastases allowed

 • Disease that has been completely resected with negative margins on resected specimens within the past 12 weeks

 • 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 PET-CT scan (with or without brain) and brain MRI or CT (if MRI is contraindicated) (if PET-CT cannot be done, CT scan of neck, chest, abdomen, and pelvis should be done)

 • Patients rendered free of disease by non-surgical means not allowed

 • Disease recurrence after adequate surgical excision of original primary cutaneous melanoma allowed provided one of the following criteria are met:

 • 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 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

 • ECOG performance status 0-1

 • WBC ≥ 3,000/μL

 • ANC ≥ 1,500/μL

 • Platelet count ≥ 100,000/μL

 • Hemoglobin ≥ 10 g/dL

 • Serum creatinine ≤ 1.8 mg/dL

 • AST and ALT ≤ 2.5 times upper limit of normal (ULN)

 • Serum bilirubin < 2 times ULN (< 3 mg/dL in case of Gilbert syndrome)

 • Not pregnant or nursing

 • Negative pregnancy test

 • Fertile patients must use adequate method of contraception throughout the study and for up to 26 weeks after the last dose of high-dose recombinant interferon alpha-2b (HDI)

 • No active infection requiring concurrent treatment with parenteral antibiotics

 • None of the following:

 • Other significant medical, surgical, or psychiatric conditions

 • Requirement for 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, such as a condition associated with frequent diarrhea

 • 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 IFNα or ipilimumab hazardous, should not be enrolled on this protocol; the risks and benefits of being treated with standard adjuvant IFNα should be weighed very carefully in consultation with behavioral health or psychiatry

 • No documented history of inflammatory bowel disease, including ulcerative colitis and Crohn disease, or diverticulitis

 • History of diverticulosis allowed

 • No autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids or continuous use of topical steroid creams or ointments or ophthalmologic steroids

 • History of occasional (but not continuous) use of steroid inhalers allowed

 • None of the following:

 • History of symptomatic autoimmune disease

 • Rheumatoid arthritis

 • Systemic progressive sclerosis (scleroderma)

 • Systemic lupus erythematosus

 • Sjögren syndrome

 • Autoimmune vasculitis (e.g., Wegener granulomatosis)

 • Motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis)

 • Other CNS autoimmune disease (e.g., poliomyelitis, multiple sclerosis)

 • Autoimmune hypothyroid disease or type 1 diabetes allowed provided replacement therapy is administered

 • Not incarcerated or compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

 • No other current malignancies except any prior in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas, basal or squamous skin cancer, or other malignancies for which the patient has been disease free for > 5 years

 • No active or chronic infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)

 • Patients must have negative testing for HIV, hepatitis B antigen, and HCV within the past 4 weeks

 • No other concurrent anticancer or investigational agent

 • No prior adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after resection

 • At least 30 days since prior radiotherapy, including after surgical resection

 • No prior or concurrent anti-CTLA4 monoclonal antibodies, CTLA-4 inhibitor or agonist, CD137 agonist, or prior interferon-α

 • At least 4 weeks since prior aldesleukin (IL-2), anti-tumor vaccine, or chemotherapy given before randomization

 • No infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, meningococcal, or tetanus toxoid) within the past 4 weeks

 • No concurrent systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or ophthalmologic steroids

 • Occasional but not continuous use of steroid inhalers allowed

 • Systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or ophthalmologic steroids within the past 2 weeks allowed provided, in judgment of the treating physician investigator, that the patient is not likely to require resumption of treatment with these classes of drugs during the study

 • Replacement doses of steroids for patients with adrenal insufficiency allowed

 • No concurrent chemotherapy or radiotherapy