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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01274338
First received: January 8, 2011
Last updated: June 23, 2014
Last verified: April 2014
  Purpose

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, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. 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.


Condition Intervention Phase
Recurrent Melanoma
Stage IIIB Melanoma
Stage IIIC Melanoma
Stage IV Melanoma
Biological: ipilimumab
Biological: recombinant interferon alfa-2b
Other: quality-of-life assessment
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected High Risk Melanoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Recurrence-free survival [ Time Frame: From randomization to the time of disease recurrence or death from any cause, assessed up to 20 years ] [ Designated as safety issue: No ]
    Will be performed using the log-rank test.

  • Overall survival [ Time Frame: From randomization to date of death, assessed up to 20 years ] [ Designated as safety issue: No ]
    Will be performed using the log-rank test.


Secondary Outcome Measures:
  • Incidence of toxicity assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 70 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    Will be summarized by treatment group and NCI CTCAE worst grade. Toxicity incidence rate and 95% confidence interval for each type will be presented.

  • Change in global quality of life assessed using the FACT-G [ Time Frame: Baseline to up to 1 year ] [ Designated as safety issue: No ]
    The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.

  • Change in health-related domains of quality of life assessed using symptom and functioning subscales [ Time Frame: Baseline to up to 1 year ] [ Designated as safety issue: No ]
    The two-sample t-test will be used to compare continuous measurements and Chi-square test will be used to compare the categorical outcomes between the two treatment groups. Longitudinal regression models will also be used to address the overall change over time during which the QOL data is collected.


Estimated Enrollment: 1500
Study Start Date: May 2011
Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (high-dose ipilimumab)
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.
Biological: ipilimumab
Given IV
Other Names:
  • anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
  • MDX-010
  • MDX-CTLA-4
  • monoclonal antibody CTLA-4
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Experimental: Arm B (recombinant interferon alfa-2b)
Patients receive high-dose recombinant interferon alpha-2b IV 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 alpha-2b SC on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity.
Biological: recombinant interferon alfa-2b
Given IV and SC
Other Names:
  • Alfatronol
  • Glucoferon
  • Heberon Alfa
  • IFN alpha-2B
  • Intron A
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment
Experimental: Arm C (low-dose ipilimumab)
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.
Biological: ipilimumab
Given IV
Other Names:
  • anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody
  • MDX-010
  • MDX-CTLA-4
  • monoclonal antibody CTLA-4
Other: quality-of-life assessment
Ancillary studies
Other Name: quality of life assessment

Detailed Description:

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 are randomized to 1 of 3 treatment arms.

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.

ARM B: Patients receive induction high-dose recombinant interferon alfa-2b IV 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.

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.

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 15 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All patients must have disease that is completely surgically resected in order to be eligible; patients must have been surgically rendered free of disease with negative margins on resected specimen; patients rendered free of disease by non-surgical means are not eligible
  • 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 belongs to one of the following American Join Commission on Cancer (AJCC) (2009 AJCC Melanoma Staging System) stages:

    • 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 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 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
  • White blood cell (WBC) >= 3,000/uL
  • Absolute neutrophil count (ANC) >= 1,500/uL
  • Platelets >= 100 x 10^3/uL
  • Hemoglobin >= 10 g/dL
  • Serum creatinine =< 1.5 mg/dL
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
  • Serum bilirubin =< 1.5 ULN, (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01274338

  Show 806 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Ahmad Tarhini Eastern Cooperative Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01274338     History of Changes
Other Study ID Numbers: NCI-2011-02649, NCI-2011-02649, ECOG-E1609, CDR0000692568, E1609, E1609, U10CA180820, U10CA021115
Study First Received: January 8, 2011
Last Updated: June 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Interferon-alpha
Interferons
Antibodies, Monoclonal
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 01, 2014