Recurrent Melanoma, Stage IIIA Cutaneous Melanoma AJCC v7, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7
Conditions
Brief summary
This randomized phase II trial studies how well ipilimumab with or without high-dose recombinant interferon alpha-2b works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab, may block tumor growth by targeting certain cells. Recombinant interferon alfa-2b may interfere with the growth of tumor cells. It is not yet known whether ipilimumab is more effective with or without high-dose recombinant interferon alfa-2b in treating melanoma.
Detailed description
PRIMARY OBJECTIVES: I. Test the hypothesis that the combination of ipilimumab and high-dose interferon-alpha 2b (HDI \[recombinant interferon alfa-2b\]) will improve progression free survival (PFS) of patients with advanced metastatic melanoma as compared to ipilimumab alone (across ipilimumab treatment status). SECONDARY OBJECTIVES: I. Test the hypothesis that the combination of ipilimumab and HDI will prove to be safe and tolerable. II. Within the constraints of the sample size, attempt to test the hypotheses that (1) ipilimumab 10 mg/kg will lead to improved PFS in comparison to ipilimumab 3 mg/kg (across HDI treatment status); (2) the combination of ipilimumab and HDI will improve overall survival (OS) of patients with advanced metastatic melanoma as compared to ipilimumab alone (across ipilimumab treatment status) and (3) ipilimumab 10 mg/kg will lead to improved OS in comparison to ipilimumab 3 mg/kg (across HDI treatment status). OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM A: INDUCTION PHASE: Patients receive higher dose ipilimumab intravenously (IV) over 90 minutes once every 3 weeks for 4 doses and recombinant interferon alfa-2b IV over 20 minutes 5 days a week for 4 weeks and then subcutaneously (SC) 3 times weekly for 8 weeks. MAINTENANCE PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24 and recombinant interferon alfa-2b SC 3 times weekly for 48 weeks. ARM B: INDUCTION PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses. MAINTENANCE PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24. ARM C: INDUCTION PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses and recombinant interferon alfa-2b IV over 20 minutes 5 days a week for 4 weeks and then SC 3 times weekly for 8 weeks. MAINTENANCE PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24 and recombinant interferon alfa-2b SC 3 times weekly for 48 weeks. ARM D: INDUCTION PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses. MAINTENANCE PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for up to 5 years.
Interventions
BIOLOGICALIpilimumab
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALRecombinant Interferon Alfa-2b
Given IV or SC
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have unresectable stage III or stage IV melanoma, either initial presentation or recurrent, that is of cutaneous origin or unknown primary origin and that is histologically diagnosed * No more than one prior systemic therapeutic regimen for unresectable stage III or stage IV melanoma; this includes chemotherapy, biologic therapy, biochemotherapy, or investigational treatment; this does not include any therapies given in the adjuvant setting; however, patients are excluded if they have a history of prior treatment for melanoma (either adjuvant or metastatic disease) with ipilimumab or other cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor, or prior interferon-alpha treatment for metastatic disease (history of adjuvant interferon-alpha is allowed); there should be a 4-week washout period between last treatment administration and initiation of study therapy * Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * 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 must not have an active infection requiring current treatment with parenteral antibiotics * Patients must not have a history of inflammatory bowel disease or diverticulitis (history of diverticulosis is allowed) * 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; one exception are patients treated with a curative intent and are continuously disease free for \> 3 years; these patients would be considered eligible: * 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 Clark I melanoma in situ are eligible * Patients with prior history of basal or squamous skin cancer are eligible * 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 (e.g., 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 * 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 * 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: 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); for the purposes of this study, post-menopause is defined as: * Amenorrhea \>= 24 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 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 or must abstain from sexual intercourse 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 * White blood cells (WBC) \>= 3000/uL * Absolute neutrophil count (ANC) \>= 1500/uL * Platelets \>= 100 x 10\^3/uL * Hemoglobin \>= 10 g/dL * Serum creatinine =\< 1.8 mg/dl * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN) for patients with liver metastases and =\< 2.0 x ULN for patients without liver metastases * Serum bilirubin \< 2 x ULN for patients with liver metastases and =\< 1.5 x ULN for patients without liver metastases, (except patients with Gilbert's syndrome, who must have a total bilirubin \< 3.0 mg/dL) * No active or chronic infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C * Patients must be free of brain metastasis by contrast-enhanced computed tomography (CT)/magnetic resonance imaging (MRI) scans within 4 weeks prior to enrollment; if known to have prior brain metastases, must not have evidence of active brain disease after definitive therapy (surgery, radiation therapy or stereotactic radiosurgery) on two successive MRI evaluations at least 3 months apart (one of which is =\< 4 weeks prior to starting the study drugs) * All sites of disease must be evaluated within 4 weeks prior to randomization; patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years | Progression-free survival (PFS) was defined as time from randomization to any documented disease progression or death from any cause, whichever occurred first (event), or censored at last date known alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years | Progression-free survival (PFS) was defined as time from randomization to any documented disease progression or death from any cause, whichever occurred first (event), or censored at last date known alive. |
| Overall Survival (OS) | Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years | Time from randomization to death (event), or censored at last date known alive |
| Overall Survival | Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years | Time from randomization to death (event), or censored at last date known alive. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAhmad Tarhini
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
Participants were recruited from ECOG-ACRIN member institutions between 1/18/2013 and 11/30/2015.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Higher Dose Ipilimumab, HDI) INDUCTION PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses and recombinant interferon alfa-2b IV over 20 minutes 5 days a week for 4 weeks and then SC 3 times weekly for 8 weeks.
MAINTENANCE PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24 and recombinant interferon alfa-2b SC 3 times weekly for 48 weeks.
Ipilimumab: Given IV
Recombinant Interferon Alfa-2b: Given IV or SC | 18 |
| Arm B (Higher Dose Ipilimumab) INDUCTION PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses.
MAINTENANCE PHASE: Patients receive higher dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24.
Ipilimumab: Given IV | 22 |
| Arm C (Lower Dose Ipilimumab + HDI) INDUCTION PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses and recombinant interferon alfa-2b IV over 20 minutes 5 days a week for 4 weeks and then SC 3 times weekly for 8 weeks.
MAINTENANCE PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24 and recombinant interferon alfa-2b SC 3 times weekly for 48 weeks.
Ipilimumab: Given IV
Recombinant Interferon Alfa-2b: Given IV or SC | 19 |
| Arm D (Lower Dose Ipilimumab) INDUCTION PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 3 weeks for 4 doses.
MAINTENANCE PHASE: Patients receive lower dose ipilimumab IV over 90 minutes once every 12 weeks for 4 doses beginning in week 24.
Ipilimumab: Given IV | 22 |
| Total | 81 |
Baseline characteristics
| Characteristic | Arm A (Higher Dose Ipilimumab, HDI) | Arm B (Higher Dose Ipilimumab) | Arm C (Lower Dose Ipilimumab + HDI) | Arm D (Lower Dose Ipilimumab) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 60 years | 57 years | 65 years | 57 years | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 22 Participants | 18 Participants | 22 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 18 Participants | 22 Participants | 18 Participants | 21 Participants | 79 Participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 6 Participants | 9 Participants | 33 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 13 Participants | 13 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 11 / 18 | 13 / 22 | 14 / 21 | 13 / 22 |
| other Total, other adverse events | 18 / 18 | 21 / 22 | 20 / 21 | 20 / 22 |
| serious Total, serious adverse events | 17 / 18 | 12 / 22 | 16 / 21 | 10 / 22 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression-free survival (PFS) was defined as time from randomization to any documented disease progression or death from any cause, whichever occurred first (event), or censored at last date known alive.
Time frame: Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years
Population: Assessed among eligible patients who started treatment. The primary objective of the study is to compare PFS on the combination of ipilimumab + HDI (Arms A \& C) versus ipilimumab alone (Arms B \& D), across ipilimumab treatment status. Thus data across arms are combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab + HDI | Progression-free Survival (PFS) | 7.5 months |
| Ipilimumab Alone | Progression-free Survival (PFS) | 4.4 months |
Comparison: The primary comparison was ipilimumab + HDI versus ipilimumab alone, across ipilimumab dose (Arms A \& C versus Arms B \& D)p-value: 0.49Log Rank
Secondary
Overall Survival
Time from randomization to death (event), or censored at last date known alive.
Time frame: Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years
Population: Eligible patients who started treatment; OS comparison of higher dose ipilimumab versus lower dose ipilimumab across HDI status (Arms A \& B versus Arms C \& D)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab + HDI | Overall Survival | 20.1 months |
| Ipilimumab Alone | Overall Survival | 23.5 months |
Comparison: Comparison of higher dose ipilimumab versus lower dose ipilimumab across HDI status (Arms A \& B versus Arms C \& D)p-value: 0.868Log Rank
Secondary
Overall Survival (OS)
Time from randomization to death (event), or censored at last date known alive
Time frame: Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years
Population: Eligible patients who started treatment; OS comparison of ipilimumab + HDI versus ipilimumab alone, across ipilimumab doses (Arms A \& C versus Arms B \& D)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab + HDI | Overall Survival (OS) | 20.1 months |
| Ipilimumab Alone | Overall Survival (OS) | 24.7 months |
p-value: 0.691Log Rank
Secondary
Progression-free Survival
Progression-free survival (PFS) was defined as time from randomization to any documented disease progression or death from any cause, whichever occurred first (event), or censored at last date known alive.
Time frame: Assessed every 3 months for two years, then every 6 months for 3 years, then every 12 months for up to 10 years
Population: Eligible patients who started treatment; PFS comparison of higher dose ipilimumab versus lower dose ipilimumab across HDI status (Arms A \& B versus Arms C \& D)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipilimumab + HDI | Progression-free Survival | 6.5 months |
| Ipilimumab Alone | Progression-free Survival | 3.8 months |
Comparison: PFS comparison of higher dose ipilimumab versus lower dose ipilimumab (Arms A \& B versus Arms C \& D)p-value: 0.144Log Rank
Other Pre-specified
Clinical Response Rate
Defined as the number of complete responses and partial responses per RECIST version 1.1 divided by the total number of evaluable cases
Time frame: Assessed every 12 weeks for 3 years
Other Pre-specified
Immune-related Response Rate Per Immune-related Response Criteria
Defined as the number of complete and partial responses per immune-related response criteria (irRC) divided by the total number of evaluable patients
Time frame: Assessed every 12 weeks for 3 years