Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open Label, Single Centre, Phase II Pilot Study of Neoadjuvant Dabrafenib + Trametinib in Patients With Resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 Mutation Positive Melanoma
Brief Summary: This is an open label, single centre, phase II study of neoadjuvant drug treatment with dabrafenib + trametinib in patients with resectable American Joint Committee on Cancer (AJCC) Stage IIIB-C BRAF V600 mutation positive melanoma.

The main aim of this study is to find out if giving of a new combined drug treatment to patients with melanoma that has spread to the lymph nodes BEFORE they have surgery, will result in improved clinical and pathological response of the melanoma tissue after 12 weeks treatment.


Options:
A: 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
B: Inclusion Criteria:

1. Naïve to treatment for locally advanced unresectable disease (Stage IIIB and C). Prior adjuvant therapy (including immunotherapy, e.g., ipilimumab) is allowed if prior to nodal recurrence and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment.
2. Biopsy proven unresected melanoma patients with palpable regional lymph node metastases, presenting with AJCC stage IIIB-C or with recurrent regional lymphadenopathy that are not suitable or not preferred for surgical intervention.
3. BRAF V600 mutation positive.
4. Eastern Cooperative Oncology Group performance status of 0 or 1.
5. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
6. Adequate hematologic, renal and liver function within 7 days prior to the first dose of vemurafenib and cobimetinib.
7. Agree to always use an effective form(s) of contraception beginning from the informed consent signature date until at least 6 months after completion of study therapy.
8. Negative serum pregnancy test within 14 days prior to start of treatment in women of childbearing potential only.
9. Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Exclusion Criteria:

1. Cannot have received any prior therapy for the current recurrence or nodal disease. Previous adjuvant immunotherapy is allowed if prior to nodal recurrence and ≥ 3 months have elapsed from the last day of adjuvant therapy to start of study treatment.
2. History of prior RAF or MEK pathway inhibitor treatment.
3. Active malignancy (other than BRAF-mutated melanoma) or a previous malignancy within the past 3 years are excluded; except for patients with resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected melanoma in situ, resected carcinoma in-situ of the cervix, and resected carcinoma in-situ of the breast.
4. Evidence of distant metastatic disease.
5. History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or known infection with Human Immunodeficiency Virus (HIV), hepatitis B virus, or hepatitis C virus.
6. Active infection or chronic infection requiring chronic suppressive antibiotics.
7. Pregnant or breastfeeding at the time of enrollment.
8. Active autoimmune disease (e.g., systemic lupus erythematosus, autoimmune vasculitis, inflammatory bowel disease \[Crohn's disease and ulcerative colitis\]).
9. Acromegaly
10. History of malabsorption or other clinically significant metabolic dysfunction.
11. Any other serious concomitant medical condition that would compromise safety or compromise the ability to participate in the study.
12. Requires a concomitant medication or dietary supplement that is prohibited during the study.
13. Unwillingness or inability to comply with study and follow-up procedures.
14. Current, recent (within 28 days of enrolment) or planned use of any investigational product outside of this study.
15. The following foods or supplements are prohibited at least 7 days prior to initiation of and during study treatment:

    1. St. John's wort or hyperforin
    2. Grapefruit juice
16. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment / central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration.
17. Currently are known to have the following conditions:

    1. Uncontrolled glaucoma with intra-ocular pressures with \> 21 mmHg
    2. Retinal venous occlusion (RVO)
    3. Hypertensive retinopathy
18. Clinically significant cardiac dysfunction, including the following:

    1. Current unstable angina
    2. Current symptomatic congestive heart failure of New York Heart Association class 2 or higher
    3. History of congenital long QT syndrome or QTcF \> 450 msec at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus).
    4. Current uncontrolled hypertension ≥Grade 2 (patients with a history of hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).
    5. Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower.

17. Palliative radiotherapy or major surgery within 14 days prior to first dose of study treatment.
C: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com.

Inclusion Criteria:

* Age ≥ 18 years
* Complete and adequate resection of Stage III melanoma with histologically confirmed melanoma metastatic to lymph node
* Disease-free
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
* Randomization within 12 weeks of surgery

Exclusion Criteria:

* Prior therapy for melanoma except surgery
* Auto-immune disease
D: Inclusion Criteria:

* The subject must have clinical stage III resectable melanoma per investigator. Subjects may not have a diagnosis of uveal or mucosal melanoma.
* Either the subject or the subject's legally authorized representative must be willing and able to provide written informed consent before the performance of any protocol-related procedures.
* The subject must be ≥18 years of age on day of signing informed consent.
* The subject must have a performance status of 0 or 1 on the ECOG Performance Scale.
* The subject must demonstrate adequate organ function as defined in Table 1; all screening labs must be performed within 28 days of treatment initiation.

  * Hematologic System: Absolute neutrophil count (ANC) ≥1500/mcL; Platelets ≥100,000/mcL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
  * Renal System: Serum creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥50 mL/min for subject with creatinine levels \>1.5 X institutional ULN
  * Hepatic System: Serum total bilirubin ≤1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \>1.5 ULN; AST (SGOT) and ALT (SPGT) ≤2.5 X ULN OR ≤5 X ULN for subjects with liver metastases
* A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: A.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR B.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and is willing to use a highly effective method of contraception or abstain from heterosexual intercourse for at least 2 weeks prior to the time of first dose of study medication through 5 months after the last dose of study medication.
* Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
* Male subjects must agree to follow the contraceptive guidance in Appendix 3 starting with the first dose of study medication, while on study, through 7 months after the last dose of study medication.

Exclusion Criteria:

* Subject has unresectable disease; i.e. in the opinion of the surgical oncologist, all of the subject's melanoma cannot be completely removed with a clear margin.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), interferon, high dose IL-2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to the first dose of study drug. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy are an exception to this criterion.
* If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
* Subject has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks to the first dose of study drug.
* Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Has a known additional malignancy that is progressing or requires active treatment. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
* Has active autoimmune disease that has required systemic treatment in the past 3 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has evidence of active interstitial lung disease or a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
* Has an active infection requiring systemic therapy.
* Patients known to be positive for Human Immunodeficiency Virus (HIV) if they have a CD4 count of less than 350 mm3 and a serum HIV viral load \> 25,000 IU/mL
* Has active Hepatitis B infection or active Hepatitis C virus infection as determined by medical record review.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 5 months, if female, or 7 months, if male, after the last dose of investigational drug.
* Prisoners or subjects who are involuntarily incarcerated.
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

Answer: A