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

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 cycles 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 cycles 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 cycles 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 cycles 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 cycles 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 cycles 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 cycles 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 cycles 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 January 2026.

• Ipilimumab (Biological), also known as Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016, Ipilimumab Biosimilar CS1002, MDX 010, MDX-010, MDX-CTLA4, MDX010, Yervoy: Given IV
• Quality-of-Life Assessment (Other), also known as Quality of Life Assessment: Ancillary studies
• Recombinant Interferon Alfa-2b (Biological), also known as Alfatronol, Bioferon, Bioferon (TM), Glucoferon, Heberon Alfa, IFN alpha-2B, Interferon alfa 2b, Interferon Alfa-2B, Interferon Alpha-2b, Intron A, Sch 30500, Urifron, Viraferon: Given IV and SC

Primary outcomes

• Recurrence-free Survival (RFS; Arm B [HDI] vs. Arm C [LIP]) [Assessed every 3 months for 2 years, then every 6 months for years 3-5 and then annually up to 8 years]: Recurrence-free survival is defined as the time from randomization to recurrence or death, whichever occurs first. The following criteria constitute the only acceptable evidence of disease recurrence. Lung and liver: Positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease. Central Nervous System: A positive brain CT or MRI scan or CSF cytology. Cutaneous, Subcutaneous and Lymph Node Recurrence: Positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease. Bone and Other Organs: Positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease identified on two different radiologic studies: i.e., positive nuclear bone scan or PET scan and contrast GI series or ultrasound, X-ray or CT of abdomen for abdominal disease.
• 5-year Overall Survival (OS) Rate (Arm B [HDI] vs. Arm C [LIP]) [Assessed every 3 months for 2 years, then every 6 months for years 3-5]: Overall survival is defined as the time from randomization to death or date last known alive.
• Recurrence-free Survival (RFS; Arm A [HIP] vs. Arm B [HDI]) [Assessed every 3 months for 2 years, then every 6 months for years 3-5 and then annually up to 8 years]: Recurrence-free survival is defined as the time from randomization to recurrence or death, whichever occurs first. The following criteria constitute the only acceptable evidence of disease recurrence. Lung and liver: Positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease. Central Nervous System: A positive brain CT or MRI scan or CSF cytology. Cutaneous, Subcutaneous and Lymph Node Recurrence: Positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease. Bone and Other Organs: Positive cytology or biopsy in the presence of a single new lesion or the appearance of multiple lesions consistent with metastatic disease identified on two different radiologic studies: i.e., positive nuclear bone scan or PET scan and contrast GI series or ultrasound, X-ray or CT of abdomen for abdominal disease.
• 5-year Overall Survival (OS) Rate (Arm A [HIP] vs. Arm B [HDI]) [Assessed every 3 months for 2 years, then every 6 months for years 3-5]: Overall survival is defined as the time from randomization to death or date last known alive.

Secondary outcomes

• Change in FACT-G (Functional Assessment of Cancer Therapy - General) Total Score From Baseline to 3 Months [Assessed at baseline and 3 months]: The Functional Assessment of Cancer Therapy - General (FACT-G) is a 27-item questionnaire that has four areas of measurements (physical well-being, social/family well-being, emotional well-being and functional well-being) with a scale of 0-4. The FACT-G total score ranges between 0 and 108. The higher the score, the better the quality of life. Change in FACT-G total score from baseline to 3 months was calculated as month 3 score - baseline score.
• Change in FACIT-D (Functional Assessment of Cancer Therapy - Diarrhea) Diarrhea Subscale Score From Baseline to 3 Months [Assessed at baseline and 3 months]: The diarrhea subscale of The Functional Assessment of Chronic Illness Therapy - Diarrhea (FACIT-D) is an 11-item questionnaire with a scale of 0-4. The FACIT-D diarrhea subscale score ranges between 0 and 44. The higher the score, the better the quality of life. Change in FACIT-D diarrhea subscale score from baseline to 3 months was calculated as month 3 score - baseline score.
• Change in FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifiers) Total Score From Baseline to 3 Months [Assessed at baseline and 3 months]: The Functional Assessment of Cancer Therapy - Biologic Response Modifiers (FACT-BRM) is a questionnaire including FACT-G (The Functional Assessment of Cancer Therapy - General) and additional sections addressing physical and mental quality of life aspects. It is a 40-item questionnaire with a scale of 0-4. The FACT-BRM total score ranges between 0 and 160. The higher the score, the better the quality of life. Change in FACT-BRM total score from baseline to 3 months is calculated as month 3 score - baseline score.

Sex: All, ages: 12 Years to any

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 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

Participant flow

Outcome results

• Recurrence-free Survival (RFS; Arm B [HDI] vs. Arm C [LIP]) (Primary), Median, years: Arm B (HDI) 2.5 (1.7 to 3.3); Arm C (LIP) 4.5 (2.6 to NA) (p 0.065)
• 5-year Overall Survival (OS) Rate (Arm B [HDI] vs. Arm C [LIP]) (Primary), Number, proportion of participants: Arm B (HDI) 0.67 (0.62 to 0.72); Arm C (LIP) 0.72 (0.68 to 0.76) (p 0.044)
• Recurrence-free Survival (RFS; Arm A [HIP] vs. Arm B [HDI]) (Primary), Median, years: Arm A (HIP) 3.9 (2.9 to NA); Arm B (HDI) 2.4 (1.6 to 3.0)
• 5-year Overall Survival (OS) Rate (Arm A [HIP] vs. Arm B [HDI]) (Primary), Number, proportion of participants: Arm A (HIP) 0.70 (0.65 to 0.74); Arm B (HDI) 0.65 (0.60 to 0.70) (p 0.289)
• Change in FACT-G (Functional Assessment of Cancer Therapy - General) Total Score From Baseline to 3 Months (Secondary), Mean, score on a scale: Arm A (HIP) -4.9 +/- 14.1; Arm B (HDI) -12.9 +/- 14.1; Arm C (LIP) -3.4 +/- 13.2
• Change in FACIT-D (Functional Assessment of Cancer Therapy - Diarrhea) Diarrhea Subscale Score From Baseline to 3 Months (Secondary), Mean, score on a scale: Arm A (HIP) -3.7 +/- 6.9; Arm B (HDI) -0.7 +/- 2.7; Arm C (LIP) -2.2 +/- 5.1
• Change in FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifiers) Total Score From Baseline to 3 Months (Secondary), Mean, score on a scale: Arm A (HIP) -8.3 +/- 19.7; Arm B (HDI) -22.7 +/- 20.4; Arm C (LIP) -6.2 +/- 18.9

Adverse events

Time frame: Assessed every 4 weeks while on treatment and for 30 days after the end of treatment, up to 20 years

Serious adverse events by term

103 more terms not shown.

Other adverse events by term

837 more sites not listed.

• Results publication: McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. doi: 10.1007/s11136-022-03226-8. Epub 2022 Aug 27. PMID 36029412
• Results publication: Saad M, Lee SJ, Tan AC, El Naqa IM, Hodi FS, Butterfield LH, LaFramboise WA, Storkus W, Karunamurthy AD, Conejo-Garcia J, Hwu P, Streicher H, Sondak VK, Kirkwood JM, Tarhini AA. Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males. J Transl Med. 2022 Jun 3;20(1):253. doi: 10.1186/s12967-022-03450-3. PMID 35659704
• Results publication: Johnson DB, Friedman DL, Berry E, Decker I, Ye F, Zhao S, Morgans AK, Puzanov I, Sosman JA, Lovly CM. Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single Referral Center. Cancer Immunol Res. 2015 May;3(5):464-9. doi: 10.1158/2326-6066.CIR-14-0217. Epub 2015 Feb 3. PMID 25649350

• Study Protocol and Statistical Analysis Plan (PDF, 2018-10-22)

• Ahmad Tarhini, Principal investigator, ECOG-ACRIN Cancer Research Group

NIH grants: P50CA121973, U10CA021115, U10CA180820, U24CA196172