Please select the eligibility criteria that correspond to the clinical trial below.
Title: Neoadjuvant Combination Biotherapy With Ipilimumab (3 mg/kg or 10 mg/kg) and High Dose IFN-Α2B in Patients With Locally/Regionally Advanced/Recurrent Melanoma: a Randomized Safety, Efficacy and Biomarker Study
Brief Summary: The purpose of this study is to evaluate the safety and potential effectiveness of a new treatment for advanced and recurrent melanoma involving the combination of Ipilimumab and IFN-α2b before surgery and to test for biomarker studies in blood and/or tumor to better understand this disease, how best to treat it and what patients should be treated with this combination.


Options:
A: Inclusion Criteria:

* Men and women, at least 18 years of age
* ECOG performance status 0 or 1
* Histologic diagnosis of melanoma staged:
* Tx or T1-4 and
* N1b, or N2b, or N2c, or N3
* M 0 that may present as any of the following groups:
* Primary melanoma with clinically apparent regional lymph node metastases, biopsy confirmed
* Clinically detected recurrence of melanoma at the proximal regional lymph node(s) basin, biopsy confirmed
* Clinically or histologically detected primary melanoma involving multiple regional nodal groups, biopsy confirmed
* Clinically detected single site of nodal metastatic melanoma arising from an unknown primary, biopsy confirmed
* Patients with intransit or satellite metastases with or without lymph node involvement are allowed if considered surgically resectable at baseline by the treating medical oncologist and surgical oncologist.

NOTE: All patients must be determined to be surgically resectable at baseline to be eligible for this neoadjuvant study.

* Patients must undergo biopsy (punch) or open biopsy (if done as part of a clinically indicated baseline diagnostic procedure) within 14 days of entry into the study. Lymphadenectomy/definitive surgery will be performed after at least 2 and generally not longer than 4 weeks of induction HDI-ipilimumab therapy. Additional delays for definitive lymphadenectomy/surgery are allowed if clinically indicated while awaiting the resolution of potential adverse events from HDI-ipilimumab therapy.
* 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 HDI-ipilimumab (at 6-8 weeks after the first dose of ipilimumab/HDI and prior to the definitive lymphadenectomy procedure).
* Required values for initial laboratory tests:
* WBC ≥ 3000/uL
* ANC ≥ 1500/uL
* Platelets ≥ 100 x 103/uL
* Hemoglobin ≥ 10 g/dL
* Creatinine ≤ 1.8 mg/dL
* AST/ALT ≤ 2.5 x ULN
* 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 HIV, Hepatitis B, or Hepatitis C

Exclusion Criteria:

* Clinical, radiological/laboratory, or pathological evidence of distant metastatic disease.
* Evidence of soft tissue involvement by gross extranodal extension of tumor manifest by fixation to the fascia, or matting of nodal tissue that would compromise surgical resection as determined by the surgical oncologist.
* 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 5 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.
* Autoimmune disease exclusions: a history of inflammatory bowel disease, a history of symptomatic 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).
* Any underlying medical or psychiatric condition, which in the opinion of the Investigator/Sub-Investigator will make the administration of ipilimumab or HDI hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
* Underlying heart conditions if deemed ineligible for surgery by cardiology consult.
* Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
* Prior treatment with ipilimumab or CD137 agonist or CTLA-4 inhibitor or agonist.
* 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 (who:
* Are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 26 weeks after cessation of study drug, or
* Have a positive pregnancy test at baseline, or
* Are pregnant or breastfeeding.
B: Inclusion Criteria:

* Age ≥18 years
* Histologically confirmed AJCC Stage IIIB or IIIC (Tx, T1-4, N1b, N2b, N2c, N3, Mo) cutaneous melanoma or unknown primary determined to be BRAF V600 mutation positive, with sufficient nodal or in-transit disease to enable biopsies prior to surgery.Patients must have disease that is measurable per RECIST version 1.1
* Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
* Adequate baseline organ function
* Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment
* Men with any female partner of childbearing potential must agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 4 months after the last dose of study treatment

Exclusion Criteria:

* Known mucosal or ocular melanoma or any unresectable in-transit metastases
* Evidence of distant metastatic disease on screening evaluation
* Prior anti-cancer treatment for melanoma (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, investigational treatment or radiotherapy). Prior surgery for melanoma is allowed.
* Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to commencing study treatment.
* Current or expected use of a prohibited medication(s)
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
* Known HIV
* A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
* History of another malignancy or a concurrent malignancy except:

  1. Patients who have been disease-free for 3 years and have a life expectancy of \> 5 years;
  2. Patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas.
* A history or evidence of cardiovascular risk including any of the following: a. QT interval corrected for heart rate using the Bazett's formula ≥480 msec or ≥ 450 msec for patients with bundle branch block; b. History or evidence of current clinically significant uncontrolled arrhythmias; c. History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to commencement of study treatment; d. History or evidence of current ≥ Class II congestive heart failure; e. Abnormal cardiac valve morphology documented by echocardiogram which in the opinion of the investigator could interfere with the patient's safety.

  f. Treatment refractory hypertension defined as a blood pressure of systolic \> 140 mm Hg and/or diastolic \> 90 mm Hg which cannot be controlled by anti-hypertensive therapy.
* A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
* Any serious or unstable pre-existing medical conditions (aside from the malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the treating clinician, could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures.
* Breastfeeding females
C: Key Inclusion Criteria:

* \>= 18 years of age
* Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma
* Measurable disease according to RECIST 1.1
* Women of childbearing potential with negative serum pregnancy test prior to randomisation
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Adequate baseline organ function

Key Exclusion Criteria:

* Any prior use of a BRAF or MEK inhibitor
* Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
* History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer)
* Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed)
* Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for \>= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for \>= 12 weeks, and are asymptomatic with no corticosteroid requirements for \>= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for \>= 4 weeks prior to randomisation
* History or evidence of cardiovascular risk (LVEF \< LLN; QTcB \>= 480 msec; blood pressure or systolic \>=140 mmHg or diastolic \>= 90 mmHg which cannot be controlled by anti-hypertensive therapy)
* History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
D: Inclusion criteria:

* Completely resected Stage III melanoma
* Tumor tissue available for evaluation of PD-L1 expression
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate organ function
* No prior therapy for melanoma except surgery for primary melanoma lesions (or previously treated with interferon for thick primary melanomas without evidence of lymph node involvement are eligible)
* Female participants of childbearing potential should be willing to use adequate methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication
* Male participants should agree to use an adequate method of birth control starting with the first dose of study therapy through 120 days after the last dose of study medication

Exclusion criteria:

* Mucosal or ocular melanoma
* History of (non-infectious) pneumonitis that required steroids or current pneumonitis
* History of or current interstitial lung disease
* History of hematologic or primary solid tumor malignancy, unless no evidence of that disease for 5 years
* Active autoimmune disease that has required systemic treatment in past 2 years
* Active infection requiring therapy
* Unstable hyperthyroidism or hypothyroidism
* Diagnosis of immunodeficiency
* Systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication
* Known history of human immunodeficiency virus (HIV), active Hepatitis B or C
* Treatment with live vaccine within 30 days prior to the first dose of study medication are not eligible
* Prior treatment with any anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibody or anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent, or prior participation in any Merck pembrolizumab clinical trial
* Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study medication
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study medication
* Participant is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial without prospective Institutional Review Board approval (by chair or designee) is given

Answer: A