Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery
Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery
This randomized phase III trial studies ipilimumab to see how well it works compared to
 high-dose interferon alfa-2b in treating patients with high-risk stage III-IV melanoma that
 has been removed by surgery. Monoclonal antibodies, such as ipilimumab, may interfere with
 the ability of tumor cells to grow and spread. Interferon alfa-2b may interfere with the
 growth of tumor cells and slow the growth of melanoma and other cancers. It is not yet known
 whether ipilimumab is more effective than interferon alfa-2b in treating patients with
 melanoma.
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