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

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ClinicalTrials.gov Identifier: NCT01274338
Recruitment Status : Active, not recruiting
First Posted : January 11, 2011
Results First Posted : May 27, 2021
Last Update Posted : May 27, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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. 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.

Condition or disease Intervention/treatment Phase
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 Biological: Ipilimumab Biological: Alfa Interferon Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1673 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Actual Study Start Date : May 25, 2011
Actual Primary Completion Date : February 15, 2019
Estimated Study Completion Date : June 26, 2035


Arm Intervention/treatment
Experimental: Arm A (HIP)
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 12 weeks 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)
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • MDX-010
  • MDX-CTLA4

Experimental: Arm B (HDI)
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. (adult accrual has completed to Arms A, B, and C as of 8/15/2014)
Biological: Alfa Interferon
Given IV and SC
Other Names:
  • Interferon Alfa - 2b
  • Intron A
  • IFN-alpha 2b
  • NSC #377523

Experimental: Arm C (LIP)
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 12 weeks 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)
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • MDX-010
  • MDX-CTLA4

Experimental: Arm D (HIP; Pediatric)
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 12 weeks for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (ages 12-17)
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • MDX-010
  • MDX-CTLA4

Experimental: Arm E (HDI; Pediatric)
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. (ages 12-17)
Biological: Alfa Interferon
Given IV and SC
Other Names:
  • Interferon Alfa - 2b
  • Intron A
  • IFN-alpha 2b
  • NSC #377523

Experimental: Arm F (LIP; Pediatric)
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 12 weeks for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity. (ages 12-17)
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • MDX-010
  • MDX-CTLA4




Primary Outcome Measures :
  1. Recurrence-free Survival (RFS; Arm B [HDI] vs. Arm C [LIP]) [ Time Frame: 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.


  2. 5-year Overall Survival (OS) Rate (Arm B [HDI] vs. Arm C [LIP]) [ Time Frame: 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.

  3. Recurrence-free Survival (RFS; Arm A [HIP] vs. Arm B [HDI]) [ Time Frame: 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.


  4. 5-year Overall Survival (OS) Rate (Arm A [HIP] vs. Arm B [HDI]) [ Time Frame: 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 Outcome Measures :
  1. Change in FACT-G (Functional Assessment of Cancer Therapy - General) Total Score From Baseline to 3 Months [ Time Frame: 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.

  2. Change in FACIT-D (Functional Assessment of Cancer Therapy - Diarrhea) Diarrhea Subscale Score From Baseline to 3 Months [ Time Frame: 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.

  3. Change in FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifiers) Total Score From Baseline to 3 Months [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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
  • All females of childbearing potential must have a blood test or urine study during screening to rule out pregnancy
  • Woman of childbearing potential (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
  • 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)

Exclusion Criteria:

  • Prior 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

    • 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
  • Active infection requiring current treatment with parenteral antibiotics
  • 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 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
  • Documented history of inflammatory bowel disease (including ulcerative colitis and Crohn's disease) or diverticulitis (history of diverticulosis is allowed)
  • 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
  • Prior infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, meningococcal, or tetanus toxoid) within 4 weeks prior to randomization
  • Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
  • 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
  • Pregnant or breast-feeding

    • 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 ; men or WOCBP who are unwilling or unable to strictly follow this requirement are not eligible
  • A positive pregnancy test at baseline
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01274338


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ahmad Tarhini ECOG-ACRIN Cancer Research Group
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01274338    
Other Study ID Numbers: NCI-2011-02649
NCI-2011-02649 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
E1609 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
P50CA121973 ( U.S. NIH Grant/Contract )
U10CA180820 ( U.S. NIH Grant/Contract )
U10CA021115 ( U.S. NIH Grant/Contract )
U24CA196172 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2011    Key Record Dates
Results First Posted: May 27, 2021
Last Update Posted: May 27, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Cancer Institute (NCI):
Ipilimumab
Interferon Alfa-2b
Melanoma
Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Interferons
Interferon-alpha
Ipilimumab
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs