Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Phase II Study to Evaluate the Effect of Bosentan in Patients With Stage IV Metastatic Melanoma Treated With Dacarbazine
Brief Summary: The study is designed as a multicenter, double blind, parallel-group, placebo-controlled, randomized, event driven Phase II study of DTIC with or without bosentan as first-line treatment in patients with stage IV melanoma.


Options:
A: Inclusion Criteria:

1. mPAP 21-24 mmHg, TPG \> 11mmHg, PAWP \<15 mmHg and/or
2. Exercise induced elevated mPAP-values \>30 mmHg, PAWP \<18 mmHg; TPG \>15 mmHg, as defined in Saggar et al. (2012) without left heart or severe lung disease or systemic arterial hypertension
3. Adult patients having completed his/her 18th birthday
4. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association
5. SSc-disease duration \>3 years
6. Able to understand and willing to sign the Informed Consent Form
7. Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.

Exclusion Criteria:

1. Any connective tissue diseases (CTD) other than SSc
2. Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest
3. Patients presenting normal mPAP values, that is mPAP\<21 mmHg at rest, ≤30 mmHg during exercise, PAWP \>=15 mmHg at rest or \<=18 mmHg during exercise
4. Ongoing or a history of \>2 weeks of continued use of therapies that are considered definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
5. Except for diuretics and corticosteroids medical treatment should not be expected to change 4 weeks prior inclusion into the study and during the entire 12-week study period.
6. Known intolerance to ambrisentan or one of its excipients
7. Clinically significant anemia (hemoglobin concentration of less than 75% of the lower limit of normal, LLN)
8. Forced vital capacity (FVC) \<60%, forced expiratory volume in first second (FEV1) \<65%
9. Severe interstitial lung disease, idiopathic pulmonary fibrosis
10. Renal insufficiency (glomerular filtration rate \[GFR\] \<60 mL/min/1.73m2 for at least 3 months)
11. Baseline values of hepatic aminotransferases (ALT and/or AST) \>3 x upper limit of normal (ULN)
12. Systolic blood pressure \<85 mmHg;
13. evidence of inadequately treated blood pressure \>160/90 mmHg and/or blood pressure during exercise \>220/120 mmHg
14. Patients referred with clinically significant overt heart failure
15. Clinically significant fluid retention
16. Previous evidence or diagnosis of clinically relevant left heart disease, i.e. at least one of the following: Previous echocardiography with estimated left ventricular (LV) ejection fraction \<50%, previous history of cardiogenic pulmonary edema, increased size of left atrium (\>50 mm)
17. Known significant diastolic dysfunction associated with clinical heart failure
18. Known coronary disease or significant valvular heart disease
19. Known congenital heart defects such as single ventricle, transposition, Eisenmenger
20. Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) \>1.2 cm)
21. Participation in any clinical drug trial within 4 weeks prior to screening of this study and/or who is scheduled to receive another investigational medicinal product (IMP) during the course of this study
22. Pregnancy or lactation
B: Inclusion Criteria:

1. Male or female patients 18 years of age or older
2. Histologically proven malignant melanoma (Balch et al., J. Clin Oncol. 19(16): 3635-48, 2001) with stage IV measurable disease as defined by RECIST criteria (Therasse et al., J Natl Cancer Inst, 92(3): 205-16, 2000).
3. Patients with prior radiation therapy (\> 30 days prior to study drug initiation) will be allowed provided the indicator lesion(s) used for this study was (were) outside the field of radiation or represent new lesions not previously irradiated.
4. Patients who had no prior therapy with DTIC.
5. Patients with cutaneous melanoma lesions must consent to having a biopsy obtained during the screening period and at the end of treatment for exploratory analysis of endothelin receptor expression. Biopsies obtained prior to the study that have been frozen in accordance with procedures specified for this protocol may be used.
6. ECOG performance status (≤ 2)
7. Life expectancy \> 12 weeks
8. Female patients must be non-pregnant, non-breast feeding, and either post menopausal, surgically sterile, or practicing a reliable method of contraception (hormonal methods alone are not sufficient)
9. Provide written informed consent
10. Willing to return to study center for follow up

Exclusion Criteria:

1. ALT and/or AST \> 3 × the upper limit of normal (ULN) at screening OR ALT and /or AST \> 2 x ULN and total bilirubin \> 2.0 mg/dl at screening
2. Lactate dehydrogenase \> 1.5 x ULN
3. Hemoglobin \>30% below the lower limit of normal
4. Systolic blood pressure \< 85 mmHg
5. NYHA class III/IV congestive heart failure
6. Any prior chemotherapy, biological therapy or immunotherapy for stage IV metastatic disease.
7. Received immunotherapy \< 30 days before treatment start (completed adjuvant immunotherapy for previous resected metastatic disease is allowed)
8. Concurrent use of calcineurin inhibitors (cyclosporine A, tacrolimus), sirolimus, fluconazole or glibenclamide (glyburide) or expected to receive any of these drugs during the study at inclusion and during the study.
9. History of other malignancy in the last 5 years, with the exception of squamous cell carcinoma of the skin treated with local resection and basal cell carcinoma
10. CNS metastases or carcinomatous meningitis
11. Ocular melanoma
12. Known hypersensitivity to any excipients of Tracleer™
13. Prior therapy with bosentan
14. Use of therapy with another investigational drug within 4 weeks of the start of dosing with bosentan or plan to receive such treatment during the study
15. Known drug or alcohol dependence or any other factor that will interfere with the conduct of the study
16. Any standard contraindications for the use of DTIC as per Australian package insert
C: Inclusion Criteria:

* Patients with known sarcoidosis 21.
* Age 18 or greater
* Patients with documented pulmonary hypertension with a PA mean \> 25 mm Hg as measured by cardiac catheterization within six months of entry into the study. Pulmonary artery occluding pressure and or left ventricular end diastolic pressure must be less than 15 mm Hg.
* Patients with WHO class II or III
* Six minute walk distance of between 100 to 500 meters
* Patients on stable immunotherapy for their sarcoidosis, including prednisone, methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, thalidomide, and/or infliximab
* Patients able to provide written consent

Exclusion Criteria:

* Patients on pulmonary vasodilator drugs (flolan, remodulin, bosentan, sildenafil) n the prior 28 days. Patients on stable dose of calcium channel blocker for more than 1 month prior to right heart catheterization can be continued on the calcium channel blocker.
* Patients with severe airway obstruction as defined by FEV1/FVC of less than 35%
* Patients with World Health Organization (WHO) class IV status.
* Patients who are pregnant or breast feeding
* Patients with significant left ventricular dysfunction with a left ventricular ejection fraction of less than 35%
* Cardiac index \< 2.0 liters and/or right atrial pressure \>15 mm Hg
* Significant liver dysfunction not due to sarcoidosis.
* Patients with severe other organ disease felt by investigators to impact on survival during the course of the study.
* Patients unable to perform the 6 minute walk study
D: Inclusion Criteria:

* Symptomatic pulmonary hypertension in modified NYHA functional class II to IV due to CTEPH as demonstrated by ventilation/perfusion lung scanning and pulmonary angiography.
* CTEPH judged inoperable because of peripheral localization of thrombotic material or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) with no evidence of recurrent thromboembolism and not amenable to repeated surgery.
* 6-minute walk test (6MWT) distance \< 450 m.
* Hemodynamic evaluation showing: Mean pulmonary arterial pressure (mPAP) \>= 25 mmHg; Pulmonary capillary wedge pressure (PCWP) \< 15 mmHg; Pulmonary vascular resistance (PVR) at rest \>= 300 dyn×sec/cm5
* For patients who underwent PEA, hemodynamic evaluation must have been performed more than 6 months after PEA.
* For all patients, hemodynamic evaluation must have been performed with the 3 months immediately preceding inclusion.
* Men or women \>= 18 and =\< 80 years of age (Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception).
* Anticoagulants at efficacious dose for at least 3 months prior to randomization.
* Signed informed consent prior to initiation of any study-mandated procedure.

Exclusion Criteria:

* Other forms of pulmonary hypertension including pulmonary hypertension related to sickle cell disease.
* Obstructive lung disease: FEV1/FVC \< 0.5 after bronchodilator.
* Severe restrictive lung disease: Total Lung Capacity \< 60% of predicted value.
* Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g., angina pectoris, intermittent claudication.
* Symptomatic pulmonary embolism within 6 months prior to randomization.
* Pulmonary endarterectomy within 6 months prior to randomization.
* Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
* Illness with a life expectancy of less than 6 months.
* Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
* AST and/or ALT \> 3 times the upper limit of normal ranges.· Hemoglobin concentration \< 75% the lower limit of normal ranges.
* Pregnancy or breast-feeding.
* Systolic blood pressure (BP) \< 85 mmHg.
* Treatment or planned treatment with another investigational drug and/or pulmonary angioplasty within 3 months prior to randomization.
* Treatment with an endothelin receptor antagonist, a phosphodiesterase inhibitor, L-arginine or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months prior to randomization.
* Treatment for pulmonary hypertension within 1 month prior to randomization, excluding calcium channel blockers if present for at least 1 month before randomization.
* Treatment with calcineurin-inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus, fluconazole, glibenclamide (glyburide) within 1 week prior to randomization.
* Known hypersensitivity to bosentan or any of the excipients.

Answer: B