Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients With High-Risk Stage III-IV Melanoma That Has Been Removed by Surgery
Condition: Melanoma of Unknown Primary; Recurrent Melanoma; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7
MeSH terms: Melanoma; Skin Neoplasms
Intervention: Ipilimumab; Quality-of-Life Assessment; Recombinant Interferon Alfa-2b
Intervention description: Given IV; Ancillary studies; Given IV and SC
Intervention MeSH terms: Interferons; Interferon-alpha; Interferon alpha-2; Ipilimumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1673.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No

Summary:

      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. Immunotherapy with monoclonal antibodies, such as ipilimumab,
      may help the body's immune system attack the cancer, and 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.
    

Eligibility criteria:

        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 have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Given that serious adverse events may occur with ipilimumab and IFN-alpha and that
             these may impact a patient's wellbeing, it is possible that the occurrence of other
             serious adverse events (SAEs) may seriously impact an underlying state of mental
             depression and lead to suicidal ideation; therefore, 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 IFN-alpha or ipilimumab hazardous, should not be enrolled on this
             protocol; the risks and benefits of being treated with standard adjuvant IFN-alpha
             should be weighed very carefully in consultation with behavioral health or psychiatry

          -  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

          -  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 due to the unknown effects of ipilimumab; patients must have negative
             testing for HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) within 4 weeks prior
             to randomization

        Exclusion Criteria:

          -  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 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 because of the difficulty in interpreting later
             expected GI toxicities that may lead to suboptimal management and complications

          -  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, 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

          -  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 and compliance with
             study procedures

          -  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 due to the unknown effects of ipilimumab
             and HDI on conception and the fetus; 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