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ECOG 1609: “A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High-Dose Interferon a-2b for Resected High-Risk Melanoma”

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive induction 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 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 II: 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 on days 1, 3, and 5. Treatment repeats every week for 48 weeks 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:

  • Diagnosis of melanoma of a cutaneous origin or unknown primary
  • No ocular melanoma or melanoma of mucosal origin
  • Stage IIIB, IIIC, or IV (M1a or M1b) disease
  • Patients with stage IV melanoma must have normal LDH and distant skin, subcutaneous, lymph node, or lung metastases
  • No other visceral metastases allowed
  • Disease that has been completely resected with negative margins on resected specimens within the past 12 weeks
  • 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 PET-CT scan (with or without brain) and brain MRI or CT (if MRI is contraindicated) (if PET-CT cannot be done, CT scan of neck, chest, abdomen, and pelvis should be done)
  • Patients rendered free of disease by non-surgical means not allowed
  • Disease recurrence after adequate surgical excision of original primary cutaneous melanoma allowed provided one of the following criteria are met:
  • 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 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
  • ECOG performance status 0-1
  • WBC ≥ 3,000/μL
  • ANC ≥ 1,500/μL
  • Platelet count ≥ 100,000/μL
  • Hemoglobin ≥ 10 g/dL

  • Serum creatinine ≤ 1.8 mg/dL
  • AST and ALT ≤ 2.5 times upper limit of normal (ULN)
  • Serum bilirubin < 2 times ULN (< 3 mg/dL in case of Gilbert syndrome)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use adequate method of contraception throughout the study and for up to 26 weeks after the last dose of high-dose recombinant interferon alpha-2b (HDI)
  • No active infection requiring concurrent treatment with parenteral antibiotics
  • None of the following:
  • Other significant medical, surgical, or psychiatric conditions
  • Requirement for 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, such as a condition associated with frequent diarrhea
  • 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 IFNα or ipilimumab hazardous, should not be enrolled on this protocol; the risks and benefits of being treated with standard adjuvant IFNα should be weighed very carefully in consultation with behavioral health or psychiatry
  • No documented history of inflammatory bowel disease, including ulcerative colitis and Crohn disease, or diverticulitis
  • History of diverticulosis allowed
  • No autoimmune disorders or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids or continuous use of topical steroid creams or ointments or ophthalmologic steroids
  • History of occasional (but not continuous) use of steroid inhalers allowed
  • None of the following:
  • History of symptomatic autoimmune disease
  • Rheumatoid arthritis
  • Systemic progressive sclerosis (scleroderma)
  • Systemic lupus erythematosus
  • Sjögren syndrome
  • Autoimmune vasculitis (e.g., Wegener granulomatosis)
  • Motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis)
  • Other CNS autoimmune disease (e.g., poliomyelitis, multiple sclerosis)
  • Autoimmune hypothyroid disease or type 1 diabetes allowed provided replacement therapy is administered
  • Not incarcerated or compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness
  • No other current malignancies except any prior in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas, basal or squamous skin cancer, or other malignancies for which the patient has been disease free for > 5 years
  • No active or chronic infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)
  • Patients must have negative testing for HIV, hepatitis B antigen, and HCV within the past 4 weeks
  • No other concurrent anticancer or investigational agent
  • No prior adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after resection
  • At least 30 days since prior radiotherapy, including after surgical resection

  • No prior or concurrent anti-CTLA4 monoclonal antibodies, CTLA-4 inhibitor or agonist, CD137 agonist, or prior interferon-α
  • At least 4 weeks since prior aldesleukin (IL-2), anti-tumor vaccine, or chemotherapy given before randomization
  • No infectious disease vaccination (e.g., standard influenza, H1N1 influenza, pneumococcal, meningococcal, or tetanus toxoid) within the past 4 weeks
  • No concurrent systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or ophthalmologic steroids
  • Occasional but not continuous use of steroid inhalers allowed
  • Systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or ophthalmologic steroids within the past 2 weeks allowed provided, in judgment of the treating physician investigator, that the patient is not likely to require resumption of treatment with these classes of drugs during the study
  • Replacement doses of steroids for patients with adrenal insufficiency allowed
  • No concurrent chemotherapy or radiotherapy

PRIMARY OBJECTIVES:

  1. 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 HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant).

  2. 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:

  1. To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP).

  2. Among patients enrolled by CCOPs, to compare the global QOL between the ipilimumab arms versus HDI using FACT-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 FACIT-D and FACT-BRM.

National Enrollment to Date: 1216/1500

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