Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Placebo-Controlled Phase III Trial of Yeast Derived GM-CSF Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With "No Evidence of Disease" After Complete Surgical Resection of "Locally Advanced" and/or Stage IV Melanoma
Brief Summary: This randomized phase III trial studies sargramostim or vaccine therapy alone to see how well they work compared to sargramostim and vaccine therapy together in preventing disease recurrence in patients with melanoma that has been removed by surgery. Sargramostim may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. It is not yet known whether yeast derived sargramostim and vaccine therapy are more effective alone or together in preventing recurrence of melanoma.


Options:
A: Inclusion Criteria:

* ≥18 years of age
* Written informed consent.
* Histologically confirmed, resectable American Joint Committee on Cancer (AJCC, 8th edition) stage IIIB, IIIC (Tx, T0, T1-4, N1b, N2b, N3b, M0) cutaneous melanoma or unknown primary melanoma with sufficient cutaneous and/or nodal disease to enable multiple excisional or core biopsies (at baseline, week 1 and week 2). 'Resectable' tumours are defined as having no significant vascular, central nervous system or bony involvement. Only cases where a complete surgical resection with tumour-free margins can safely be achieved are defined as resectable. Patients who may not have sufficient disease to enable multiple biopsies at weeks 1 and 2 will not be excluded, however the intention of the study is that at least one biopsy at these time points is required.
* Measurable disease according to RECIST version 1.1 criteria (≥ 10mm longest diameter for non-nodal lesions and / or ≥ 15mm in shortest diameter for lymph nodes) within 4 weeks of randomisation. 'Measurable' disease may be ascertained by CT or for cutaneous and superficial lesions, by caliper measurement with digital photography. CT preferred for all lesions where possible. PET imaging will be performed, but not used for the primary purpose of measuring response.
* BRAF V600 mutation positive on immunohistochemistry or a local molecular test (e.g. Oncofocus): a. A positive V600E immunohistochemistry stain at study entry should be formally quantified with a local molecular test following study entry (e.g. Oncofocus); b. Molecular BRAF mutation status should preferentially be confirmed using tissue taken from the presenting stage III / IV disease. Alternatively, archival primary tissue is also acceptable to confirm BRAF mutation status.
* Able to swallow and retain oral medication
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Demonstrated adequate organ function as defined:

  1. Absolute neutrophil count (ANC) ≥1.5 109/L
  2. Platelets ≥100 109/L
  3. Haemoglobin ≥90g/L
  4. Serum creatinine OR measured or calculated creatinine clearance (CrCl) (Glomerular filtration rate \[GFR\] can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for patient with creatinine levels \> 1.5 X institutional ULN.
  5. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN.
  6. Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases.
  7. Albumin \>25 g/L
  8. International Normalized Ratio (INR) or Prothrombin Time (PT)
  9. Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Anticipated life expectancy of \> 12 months.
* Women of childbearing potential: a negative serum pregnancy test within 72 hours of first dose of study treatment and effective contraception from 14 days prior to study treatment until 4 months after the last dose.
* Men with a female partner of childbearing potential to use effective contraception from 14 days prior to study treatment until 4 months after the last dose.

Exclusion Criteria:

* In transit disease
* Uveal or mucosal melanoma.
* Prior anti-cancer treatment for melanoma, except for the following:

  1. surgery for a primary melanoma or previous stage III melanoma,
  2. adjuvant radiotherapy to the primary melanoma resected site or to lymph nodes for previous Stage III disease,
  3. previous adjuvant interferon or ipilimumab for resected stage II or III melanoma, Previous adjuvant treatment with PD-1 inhibitors or BRAF/MEK inhibitors is not permitted.
* Received any investigational drug within 28 days or 5 half-lives of the planned first dose of this study treatment.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients and / or dimethyl sulfoxide (DMSO).
* Active infection requiring systemic therapy.
* Current use of any prohibited medication as described in protocol.
* Active autoimmune disease or a documented history of autoimmune disease or a syndrome requiring systemic steroids or immunosuppressive agents. Patients with the following are permitted to enrol:

  1. vitiligo,
  2. type I diabetes mellitus,
  3. residual hypothyroidism due to an autoimmune condition only requiring, and stable on hormone replacement,
  4. psoriasis not requiring systemic treatment,
  5. resolved childhood asthma or atopy,
  6. or conditions not expected to recur in the absence of an external trigger.
* A requirement for chronic systemic steroid therapy (\> 10mg/kg per day of prednisone or equivalent) within two weeks before the planned first dose of study treatment or any on any other form of immunosuppressive treatment. Patients who require inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose. Non-absorbed intra-articular steroid injections will also be permitted.
* A known history of another malignancy or concurrent malignancy unless the patient is disease-free for a minimum of 1 year, is completely treated and at low-risk of recurrence. The time requirement does not apply for patients with successful definitive resection or curative treatment of:

  1. Non-melanoma skin cancer (e.g. basal cell or squamous cell carcinoma of the skin),
  2. superficial bladder cancer,
  3. in situ carcinoma of the cervix,
  4. in situ breast cancer,
  5. atypical melanocytic hyperplasia or melanoma in situ
  6. other in situ carcinomas,
  7. multiple primary melanomas, or other treated low risk tumours.
* Known HIV, hepatitis B or C virus positive status or history of active tuberculosis (testing prior to randomisation is not required).
* Administration of a live vaccine with 30 days of planned first dose of study treatment. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed, however intranasal influenza vaccines (e.g., Fluad®) are live attenuated vaccines, and are not allowed. Any vaccine is cautionary within 30 days.
* Patients with a history or evidence of cardiovascular risk including any of the following:

  1. QT interval corrected for heart rate using the Bazett formula ≥480 msec, a diagnosis of long QT syndrome (Roman-Ward or Jervell Lange-Nielsen syndromes)
  2. Taking medications known to prolong the QT interval.
  3. Uncorrectable electrolyte abnormal abnormality (e.g. hypo- or hyperkalaemia, hypomagnesaemia, hypocalcaemia)
  4. Uncontrolled arrhythmias, with the exception of atrial fibrillation which is controlled for \> 30 days prior to randomisation.
  5. Patients with implanted cardioverter/defibrillators.
  6. Acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty or stenting within 6 months prior to randomisation.
  7. A history or current evidence of New York Heart Association (NYHA) ≥Grade 2 congestive heart failure
  8. A current left ventricular ejection fraction (LVEF) below than the lower limit of normal (LLN).
  9. Any abnormal cardiac valve morphology documented by echocardiogram which in the opinion of the investigator could interfere with the patient's safety.
  10. Treatment-refractory hypertension defined as a systolic blood pressure of \>140 mm Hg and/or a diastolic pressure of \>90 mm Hg, which cannot be controlled by anti-hypertensive treatment.
* Evidence or a risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR), including:

  1. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes).
  2. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR, such as evidence of new optic disc cupping.
  3. Intraocular pressure \> 21 mm Hg as measured by tonography.
  4. Evidence of new visual field defects on automated perimetry.
* History or evidence of interstitial lung disease or active non-infectious pneumonitis.
* Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient's safety, consent, or compliance.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another co-inhibitory T-cell receptor (i.e. OX-40, CTLA-4).
B: Inclusion Criteria:

* Histologically confirmed metastatic (Stage IV) melanoma of cutaneous origin
* ECOG performance status of \<=2
* Measurable disease according to modified RECIST
* Life expectancy of greater than 12 weeks
* LDH \<= 2.0 x ULN
* Clinical lab values within protocol parameters.
* At least 18 years old and able and willing to provide informed consent to participate

Exclusion Criteria:

* Previous cytotoxic chemotherapy treatment for melanoma
* Received more than one regimen of immunotherapy, kinase inhibitor, biologic therapy, vaccine or investigational non-chemotherapeutic treatment for melanoma.
* Presence of brain metastases
* Presence or history (\<= 5 years) of a second malignancy other than nonmelanoma skin cancer or cervical carcinoma in situ
* Female subjects who are pregnant or nursing
C: Inclusion Criteria:

* Adults at least 18 years of age
* World Health Organization (WHO) Performance Status 0 or 1
* Cytologically or histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months
* No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
* Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse
* No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
* No immunosuppressive medications within 6 months prior study inclusion
* 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 contra-ception. 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 (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception
* Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria:

* Distantly metastasized melanoma
* History of in-transit metastases within the last 6 months
* No measurable lesion according to RECIST 1.1
* 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
* Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) 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
D: Inclusion Criteria:

* Patients must have HLA-A2 status known prior to randomization; typing may be obtained through a local laboratory facility or through a reference lab utilized by the initiating institution; if typing is not available through these means, it may be obtained from the University of Pittsburgh
* All patients must have disease completely resected with one of the following in order to be eligible:

  * Completely resected disease
  * Any locoregional recurrence after prior adjuvant interferon or failure on S008
  * Any local recurrence of disease after adequate surgical excision of the original primary
  * Mucosal melanoma
  * Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary)
* The following groups of patients may be entered onto this trial only if they are ineligible for S0008 or are, in the opinion of the managing physician, medically unfit to receive standard high-dose interferon:

  * Any clinically evident satellite or in-transit disease
  * Stage II disease with gross extracapsular extension
  * Recurrence in a previously resected nodal basin
  * Four or more involved lymph nodes or matted lymph nodes
  * Ulcerated primary melanoma and any involved lymph nodes

    * NOTE: Patients who are eligible for S0008 will be strongly encouraged to participate in that study in preference to this one
* Patients must have been surgically rendered free of disease with negative margins on resected specimens; patients rendered free of disease by non-surgical means are not eligible
* Patients must be randomized within 112 days (16 weeks) of surgical resection; if more than one surgical procedure is required to render the patient disease-free, all required surgeries must be accomplished within this 16 week time period
* 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; one systemic treatment after a prior surgery is allowed, and must have been completed \>= 8 weeks prior to randomization; (when chemotherapy and biotherapy are given together as one planned treatment \[biochemotherapy\], this counts as one regimen); NOTE: Previous radiation therapy, including after the resection, is allowed as long as 30 days elapse between the radiation and initiation of therapy
* Prior treatment with GM-CSF or any peptides used in this protocol, is not allowed
* Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Patients must not have an active infection requiring treatment with parenteral antibiotics
* Patients must not have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that may interfere with compliance on any of the E4697 treatment regimens
* Patients must not have a diagnosis or evidence of organic brain syndrome or significant impairment of basal cognitive function or any psychiatric disorder that might preclude participation in the full protocol
* Patients must be able to self-administer or arrange for administration of subcutaneous injections
* Patients who have other current malignancies are not 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 who meet this criteria must be disease-free at time of randomization
* Patients with prior history of basal or squamous skin cancer are eligible; patients who meet this criteria must be disease-free at time of randomization
* Patients who have had multiple primary melanomas are eligible
* Patients with other malignancies are eligible if they have been continuously disease free for \> 5 years prior to the time of randomization
* Patients must not have autoimmune disorders, conditions of immunosuppression or treatment with systemic corticosteroids, including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or any steroid containing inhalers; 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, the patient is not likely to require these classes of drugs during the study
* Women of childbearing potential must not be pregnant (negative beta human chorionic gonadotropin \[bHCG\] within 2 weeks prior to randomization) or breast-feeding
* Women of childbearing potential and sexually active males must be counseled to use an accepted and effective method of contraception (including abstinence) while on treatment and for a period of 18 months after completing or discontinuing treatment
* All patients must have brain computed tomography (CT) or magnetic resonance imaging (MRI), chest CT or chest x-ray (CXR), and abdominal (liver) CT or MRI within 4 weeks prior to randomization; positron emission tomography (PET) scans are also acceptable in place of CT, CXR and/or abdominal MRI if obtained within 4 weeks prior to randomization; patients with lesions on the lower extremity must also have pelvic imaging within this time period; this is also strongly recommended for patients with lesions on the lower trunk; PET scans are acceptable
* Patients with resection of visceral disease must have imaging of the affected area/organ documenting disease-free status within 2 weeks prior to randomization
* White blood cells (WBC) \>= 3,000/mm?
* Platelet count \>= 100,000/mm?
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) =\< 2 x institutional upper limit (IUL) of normal
* Bilirubin =\< 2 x IUL of normal
* Serum creatinine =\< 1.8 mg/dl
* Alkaline phosphatase and lactate dehydrogenase (LDH) must be performed within 4 weeks prior to randomization; LDH must be normal; patients with abnormal alkaline phosphatase which is =\< 1.25 times the institutional upper limit of normal who have a negative CT or MRI of the liver and negative bone scan or a negative PET scan are eligible
* Patients with bone pain must have a bone scan within 4 weeks prior to randomization to document the absence of tumor

Answer: D