Please select the eligibility criteria that correspond to the clinical trial below.
Title: Neoadjuvant Combination Biotherapy With Ipilimumab and Nivolumab or Nivolumab Alone in Patients With Locally/Regionally Advanced/Recurrent Melanoma: A Randomized Efficacy, Safety and Biomarker Study
Brief Summary: This study plans to test the pathologic complete response (pCR) rate of the combination biotherapy regimen consisting of nivolumab plus ipilimumab versus nivolumab alone in patients with advanced but operable melanoma. Evaluation of the presence of tumor-infiltrating CD8+ T cells as well as that of PDL1 expression and IDO expression will be associated with clinical response (pathologic and/or radiologic). The study will test the radiologic/clinical preoperative response rate, recurrence free survival (RFS) and overall survival (OS). It will evaluate the safety of neoadjuvant nivolumab and neoadjuvant nivolumab-ipilimumab. Up to 66 patients will be randomized in 1:1 ratio.


Options:
A: Inclusion Criteria:

* Adults at least 18 years of age
* World Health Organization (WHO) Performance Status 0 or 1
* Histologically confirmed stage IIIB metastatic cutaneous melanoma, palpable disease (non-transit only) of the axilla or groin
* Patient willing to undergo triple tumor biopsies during screening and in case of disease progression
* No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
* No immunosuppressive medications within 6 months prior study inclusion
* Presence of at least two of the defined HLA alleles (Table 1, see appendix)
* Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils

  ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN
* normal LDH
* Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab+nivolumab
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product
* Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception

Exclusion Criteria:

* Distantly metastasized melanoma
* Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy
* Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy
* Radiotherapy prior or post surgery within this trial
* Patients will be excluded if they are positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
* Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
* Allergies and Adverse Drug Reaction

  * History of allergy to study drug components
  * History of severe hypersensitivity reaction to any monoclonal antibody
* Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
* Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
* Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
* Pregnant or nursing.
B: Inclusion Criteria:

1. Signed ICF
2. Age ≥ 18 years
3. Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIC (locally advanced) melanoma, as defined by the AJCC, 7th revised edition

   1. Naïve to prior systemic anti-cancer therapy for melanoma, with the following exceptions: Adjuvant treatment with IFN, IL-2, or vaccine therapies, if discontinued at least 28 days prior to initiation of study treatment
   2. Adjuvant treatment with herbal therapies, if discontinued at least 7 days prior to initiation of study treatment
4. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
5. ECOG of 0 or 1
6. Decision of eligibility for neoadjuvant combined vem+cobi+atezo treatment by in-terdisciplinary tumor board. Patient with limited numbers of metastases and few organ systems involved should be selected, making surgical resection after neo-adjuvant treatment probable.
7. Measurable disease by RECIST V1.1 criteria (must be outside the CNS)
8. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, with the exception of amylase, lipase, and LDH where up to 28 days is acceptable

   * ANC ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support
   * WBC count ≥ 2.5 × 109/L
   * Lymphocyte count ≥ 0.5 × 109/L
   * Platelet count ≥ 100 × 109/L without transfusion
   * Hemoglobin ≥ 9 g/dL without transfusion
   * Serum albumin ≥ 2.5 g/dL
   * Total bilirubin ≤ 1.5 × ULN
   * AST and ALT ≤ 2.0 x ULN
   * Amylase and lipase ≤ 1.5 x ULN
   * ALP ≤ 2.5 × ULN or, for patients with documented liver or bone metastases, ALP ≤ 5 × ULN
   * Serum creatinine ≤ 1.5 × ULN or CrCl ≥ 40mL/min on the basis of measured CrCl from a 24-hour urine collection or Crockcroft-Gault glomerular filtration rate estimation:
   * CrCL= ((140-age) x (weight in kg) x (72 x (serum creatinine in mg/dL)-1) (x 0.85 if female)
   * For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 × ULN within 28 days prior to initiation of study treatment
   * For patients receiving therapeutic anticoagulation: stable anticoagulant regi-men and stable INR during the 28 days immediately preceding initiation of study treatment
9. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

   1. With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 6 months after the last dose of study treatment. Men must refrain from donating sperm during this same period.
   2. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study treatment to avoid exposing the embryo.
   3. The reliability of sexual abstinence should be evaluated in relation to the dura-tion of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception
10. For WOCBP: agreement to remain abstinent (refrain from heterosexual inter-course) or use a contraceptive method with a failure rate of \<1% per year during the treatment period and for 6 months after the last dose of study treatment

    1. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state, and has not undergone surgical sterilization
    2. Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUD), and copper IUDs.
    3. Hormonal contraceptive methods must be supplemented by a barrier method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception.
11. Female subjects who are lactating have to discontinue nursing prior to the first dose of study drug and must refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

Exclusion Criteria:

1. Candidates for direct surgery: patients with single site easily resectable metasta-sis
2. Major surgical procedure or significant traumatic injury within 2 weeks prior to first dose of study drug treatment
3. Palliative radiotherapy within 14 days prior to initiation of study treatment
4. Active malignancy (other than BRAFV600 mutation-positive melanoma) or malig-nancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected BCC, resected cuSCC, resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the patient has been disease-free for at least 3 years

   a. Patients with a history of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer are eligible for the study.
5. A history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, CSCR, RVO, or ne-ovascular macular degeneration

   a. Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO: i. History of serous retinopathy ii. History of RVO iii. Evidence of ongoing serous retinopathy or RVO at baseline
6. History of clinically significant cardiac dysfunction, including the following:

   1. Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99mmHg despite opti-mal medical management
   2. Unstable angina, or new-onset angina within 3 months prior to initiation of study treatment
   3. Symptomatic congestive heart failure, defined as NYHA Class II or higher
   4. Myocardial infarction within 3 months prior to initiation of study treatment
   5. Unstable arrhythmia
   6. History of congenital long QT syndrome
   7. QTcF ≥480 ms at screening, or uncorrectable abnormalities in serum electro-lytes
   8. LVEF below the institutional lower limit of normal or below 50%, whichever is lower
7. Untreated or actively progressing CNS lesions (carcinomatous meningitis)
8. Patients with a history of CNS lesions are eligible, provided that all of the following criteria are met:

   1. Measurable disease, per RECIST v1.1, must be present outside the CNS
   2. All known CNS lesions have been treated with radiotherapy or surgery
   3. CNS lesions have not been treated with whole-brain radiotherapy, except in patients who underwent definitive resection of or stereotactic therapy for all radiologically detectable parenchymal brain lesions
   4. Absence of interim progression must be confirmed by radiographic study within 4 weeks prior to initiation of study treatment. If new CNS metastases are suspected during the screening period, a confirmatory radiographic study is required prior to initiation of study treatment
   5. Any radiotherapy or surgery must be completed ≥ 4 weeks prior to initiation of study treatment
   6. There is no ongoing requirement for corticosteroids, and any prior corticosteroid treatment must be discontinued ≥ 2 weeks prior to initiation of study treatment. Treatment with an anticonvulsant at a stable dose is allowed
   7. No history of intracranial hemorrhage from CNS lesions
9. History of metastases to brain stem, midbrain, pons, or medulla, or within 10 mm of the optic apparatus
10. History of leptomeningeal metastatic disease
11. Anticipated use of any concomitant medication during or within 7 days prior to initiation of study treatment that is known to cause QT prolongation. Patients with regular amiodaron intake in the last 365 days cannot be included.
12. Uncontrolled diabetes or symptomatic hyperglycemia
13. History of malabsorption or other clinically significant metabolic dysfunction that may interfere with absorption of oral study treatment
14. Pregnancy or lactation period or intention to become pregnant during the study.

    a. WOCBP must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment
15. Prior allogeneic stem cell or solid organ transplantation
16. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

    a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
17. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus ery-thematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

    a. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for the study after discussion with and approval by the Medical Monitor b. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for the study after discussion with and approval by the Medical Monitor c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with der-matologic manifestations only are eligible for the study provided all of following conditions are met: i. Rash must cover \< 10% of body surface area ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroids iii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral cor-ticosteroids within the previous 12 months
18. Known clinically significant liver disease, including alcoholism, cirrhosis, fatty liver, and other inherited liver disease as well as active viral disease including:

    1. Positive HIV test at screening
    2. Active HBV infection, defined as having a positive HBsAg test at screening Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total HBcAb test at screening, are eligible for the study
    3. Active HCV infection, defined as having a positive HCV antibody test and a positive HCV RNA test at screening
19. Active tuberculosis
20. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
21. Any Grade ≥ 3 hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment
22. History of stroke, reversible ischemic neurological defect, or transient ischemic at-tack within 6 months prior to initiation of study treatment
23. Current severe, uncontrolled systemic disease or any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or could jeopardize the safety of the patient and their compliance in the study
24. Signs or symptoms of clinically relevant infection and/or treatment with therapeutic systemic antibiotics within 2 weeks prior to initiation of study treatment

    a. Patients receiving prophylactic antibiotics are eligible for the study
25. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
26. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the study

    1. Patients who have received acute, low-dose systemic immunosuppressant medication ≥ 4 weeks prior to ini-tiation of study treatment or a one-time pulse dose of systemic immunosup-pressant medication are eligible for the study.
    2. The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids , or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
27. Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells
28. Known hypersensitivity to any component of the atezo, cobi, or vem formulations
29. History of severe allergic, anaphylactic or other hypersensitivity reactions to chi-meric or humanized antibodies or fusion proteins
30. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 4 weeks of the start of study treatment.
31. Inability or unwillingness to swallow pills
32. Any psychological, familial, sociological, or geographical conditions that may hamper compliance with the protocol and follow-up after treatment discontinuation
33. Requirement for concomitant therapy or food that is prohibited during the study, as described in Sections 10.10 and 10.11.
34. Patient is unable to comply with the study protocol for any other reason
C: Inclusion Criteria:

* Men and women at least 18 years of age
* Willing and able to give written informed consent
* Performance status Eastern Cooperative Oncology Group (ECOG) zero or 1
* Histologic diagnosis of melanoma belonging to the following AJCC Tumor Node and Metastasis (TNM) stages: Tx or T1-4 and N1b or N2 or N2c or N3 and/or M0 or M1 (if considered surgically operable)
* Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or distant metastasis, or at the time of clinically detected nodal and/or in-transit recurrence and/or distant metastasis and may belong to any of the following groups: Primary melanoma with clinically apparent (overt) regional lymph node metastases.
* Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin.
* Clinically detected primary melanoma involving multiple regional nodal groups.
* Clinically detected site of nodal metastatic melanoma arising from an unknown primary.
* Patients with intransit or satellite metastases with or without lymph node involvement are allowed if they are considered surgically resectable at baseline.
* Patients with distant metastases with or without intransit or lymph node involvement are allowed if they are considered potentially surgically resectable at baseline. NOTE: All patients must be determined to be surgically resectable at baseline to be eligible for this neoadjuvant study.
* Have measurable disease based on RECIST 1.1.
* Have provided tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy. Patients must undergo biopsy (core, punch) or open incisional/excisional biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 4 weeks of registration on the study.
* Patients must have been evaluated by standard-of-care full body imaging studies (CT, PET/CT or MRI) as part of the initial clinical work-up at baseline (no more than 4 weeks prior to study enrollment) and after completion of induction nivolumab-ipilimumab or nivolumab alone (at 6-8 weeks after the first dose of induction and prior to the definitive surgery procedure).
* Required values for initial laboratory tests:

  * White blood cell (WBC) 3000/uL
  * Absolute neutrophil count (ANC) 1500/uL
  * Platelets 100 x 103/uL
  * Hemoglobin 10 g/dL
  * Aspartate transaminase/alanine transaminase (AST/ALT) 2.5 x unique learner number (ULN)
  * Bilirubin 1.5 ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  * Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C

Exclusion Criteria:

* Subject will be excluded from participating in the trial if they meet any of the following criteria:
* Patients are excluded if they have a history of central nervous system (CNS)metastases.
* Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
* Any other malignancy from which the patient has been disease-free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
* Patients will be excluded if they have an active, known or suspected autoimmune disease. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g., Wegener's Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome).
* Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
* Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
* Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
* Has an active infection requiring systemic therapy.
* Has received a live vaccine within 30 days prior to the first dose of trial treatment.
* Any underlying medical or psychiatric condition, which in the opinion of the Investigator/Sub-Investigator will make the administration of ipilimumab or nivolumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
* Patients with underlying heart conditions who are deemed ineligible for surgery by cardiology consult.
* A history of prior treatment with ipilimumab, nivolumab or other cytotoxic T-lymphocyte-associated protein (CTLA-4), progressive disease (PD1) or PD-L1 inhibitor.
* Prior treatment with interferon alfa is allowed.
* A history of prior radiotherapy, chemotherapy, including infusion or perfusion therapy for current disease or any immunotherapy including tumor vaccines, interferon-alfa, interleukins, levamisole or other biologic response modifiers within the past 4 weeks.
* Concomitant therapy with any of the following: IL 2 or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; unless discontinued ≥ 4 weeks. A history of occasional use of steroid inhalers is allowed.
* Women of childbearing potential (WOCBP), defined above in Section 3.3, who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 23 weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding.
* Melanoma of Uveal Origin
D: Inclusion criteria

1. Subjects must have recurrent stage III (i.e., recurrent regional metastasis), or stage IV (i.e., any distant metastasis) melanoma for which surgical resection would be clinically recommended, with biopsy proven (current or previous) Stage III or Stage IV disease. Any biopsies obtained to demonstrate recurrent regional metastasis or distant metastasis must be considered clinically appropriate for clinical management and must not be performed solely for meeting eligibility criteria. In addition, subjects must have disease that has not yet been completely excised.
2. Patients must have disease which involves 3 or fewer sites. A nodal basin recurrence will be scored as one site, even if multiple nodes are positive. "Clustered" subcutaneous and/or cutaneous lesions that can be removed in a single surgical excision will be scored as one site, even if multiple subcutaneous and/or cutaneous lesions are present.
3. The subjects' disease is determined to be completely resectable with uninvolved margins using standard surgical guidelines based on physical exam and radiographic imaging (MRI or CT of the head, and CT or MRI of the chest, abdomen and pelvis).
4. Subjects must have one of the following: a) Stage III melanoma with recurrence after prior surgery, with or without subsequent adjuvant systemic (standard or experimental) and/or radiotherapy management Or b) Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary)
5. Subjects must be 18 years old or older OR if they are 15 years old or greater, considered to be mature minors, able to give adult informed consent (with parental co-signature), meet all other eligibility criteria, and also weigh at least 45 kg.. Subjects must weigh at least 45 kg in order to safely provide sufficient blood for monitoring studies (see section 7.7 for details).
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Subjects must have adequate bone marrow, liver, and renal function.
8. Subjects with one or more of the following cardiac risk factors must complete a stress radionuclide scan with no evidence of myocardial ischemia or heart failure: (a) a history of cardiac disease, (b) age greater than 65 years old, (c) any clinically significant abnormality found on ECG (required at baseline), or (d) significant risk factors for coronary artery disease (history of significant dyslipidemia; any treatment for dyslipidemia; or two first degree relatives with a documented myocardial infarction prior to age 55).
9. Subjects with significant history of pulmonary disease, shortness of breath at rest, or known Chronic Obstructive Pulmonary Disease (COPD) must have pulmonary function tests within 35% of normal age-predicted values.
10. Subjects must be willing and able to provide informed written consent prior to any study-related procedures.
11. Subjects must have no immediate requirements for palliative chemotherapy, palliative radiotherapy, or palliative hormonal therapy.
12. Subjects must be willing and able to discontinue antihypertensive medications if advised to do so for days of hu14.18-IL2 infusion.
13. Subjects must have slides available from stage III or stage IV melanoma. Paraffin blocks are preferable, but at a minimum, slides documenting melanoma by biopsy (including fine needle cytology) must be available for pathology review, and potential restaining/staining (see Section 7.4, Surgical Pathology Guidelines). Prior histologic demonstration of metastatic melanoma (either stage III or Stage IV) may be utilized if a repeat biopsy is not clinically needed to to establish eligibility.

Exclusion criteria

1. Subjects are ineligible if they have received monoclonal antibodies (mAb) during biologic therapy, tumor imaging, purging of autologous marrow/stem cells for re-infusion or for any other reason unless serological testing is performed. If the absence of detectable antibody (over background) to hu14.18 is documented, the subject is eligible for the study.
2. Subjects treated with IL2 in the past that developed intolerable (Grade 4) IL2-related side effects are not eligible.
3. Subjects who have received any (standard or experimental) systemic therapy for stage IV disease are not eligible.
4. Women of childbearing potential will be excluded if they are pregnant, nursing, or not using effective contraception during the treatment period.
5. Subjects with symptoms of ischemic cardiac disease, congestive heart failure, myocardial infarct within the immediate preceding 6 months and/or uncontrolled cardiac rhythm disturbance are ineligible.
6. Subjects with significant psychiatric disabilities or seizure disorders are ineligible.
7. Subjects who have had major surgery within the past 3 weeks are ineligible.
8. Subjects with clinically detectable pleural effusions or ascites are ineligible.
9. Subjects with organ allografts are ineligible.
10. Subjects who require or are likely to require corticosteroid or other immunosuppressive drugs or have used them within 2 weeks of registration are ineligible.
11. Subjects with significant intercurrent illnesses are ineligible.
12. Subjects with active infections or active peptic ulcer unless these conditions are corrected or controlled are ineligible.
13. Subjects with brain metastases, whether active or inactive, are ineligible. A head MRI or head CT scan will be required at baseline to rule out silent metastases.
14. Subjects with active second malignancy other than non-melanoma skin cancer are ineligible. Patients will be considered eligible if they have been continuously disease free for \> 5 years prior to the time of enrollment.
15. Subjects who are infected with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBs Ag) carrier state or with clinical evidence of hepatitis are ineligible. Treatment may be initiated before laboratory confirmation of HIV and HBs Ag negativity, but will be stopped if results are positive.
16. Subjects with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade \> 2) are ineligible.
17. Subjects with a known hypersensitivity to the study drug, Tween-80® or to human immunoglobulin are ineligible.
18. Patients with a known history of diabetes mellitus that has required systemic therapy within the past 3 months (either oral hypoglycemic agents or insulin) will be excluded, as treatment with hu14.18-IL2 may alter blood glucose levels.
19. Subjects with a legal incapacity or limited legal capacity are ineligible.
20. Subjects with bone metastases are ineligible.

Answer: C