Hepatic Impairment Study of Encorafenib in Combination With Binimetinib in BRAF Melanoma

Exclusion Criteria

• •1. A calculated Child-Pugh score that showed impairment for a reason other than liver dysfunction (e.g., cancer, cachexia);
• •2. History or symptoms of encephalopathy (Grade II or worse) within 4 weeks of Day -1 or subjetcs who were treated to control encephalopathy within 4 weeks of Day -1;
• •3. Clinical evidence of severe ascites (NCI-CTCAE grade 3 or 4);
• •4. History of surgical portosystemic shunt with complications (i.e., hepatic encephalopathy, heart failure). Trans jugular intrahepatic portosystemic shunt could have been allowed if not in use for ≥1 year;
• •5. Active bleeding during the last 28 days prior to dosing including variceal bleeding;
• •6. Anticoagulant therapy within 7 days prior to the first dose of study treatment (Day 1);
• •7. Any of the following:
• •1. Nitrosourea or mitomycin-C within 6 weeks prior to start of study treatment,
• •2. Other chemotherapy, radiation therapy that included \> 30% of the bone, marrow reserve, or biological therapy (e.g., antibodies) within 4 weeks prior to start of study treatment,
• •3. Continuous or intermittent small-molecule therapeutics or investigational agents within 5 half-lives of the agent or within 2 weeks prior to start of study treatment, whichever is the longest,
• •4. Residual Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 side effects of any such therapy (residual Grade 2 alopecia is permitted),
• •8. Discontinuation of prior BRAF and/or MEK inhibitor treatment due to severe, intolerable toxicity including left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion, CK elevation and rhabdomyolysis, uveitis;
• •9. Symptomatic brain metastasis; Note: Participants previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging \[MRI\] or computed tomography \[CT\] demonstrating no current evidence of progressive brain metastases at screening);
• •10. Leptomeningeal disease;
• •11. Use, within 2 weeks prior to the first dose of the study treatment (Day 1)any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5;
• •12. Human immunodeficiency virus (HIV) infection;
• •13. Active viral hepatitis (HBV-HCV) within 1 month before the first dose of study treatment (Day 1);
• •14. Known history of acute or chronic pancreatitis;
• •15. Concurrent neuromuscular disorder that is associated with the potential of elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy;
• •16. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
• •17. Clinically significant cardiac disease including any of the following:
• •1. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2),
• •2. Left ventricular ejection fraction (LVEF) \< 50% as determined by MUGA or ECHO,
• •3. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy,
• •4. History or presence of clinically significant ventricular arrhythmias or atrial fibrillation,
• •5. Clinically significant resting bradycardia,
• •6. Unstable angina pectoris ≤ 3 months prior to the start of study treatment,
• •7. Acute myocardial infarction ≤ 3 months prior to the start of study treatment,
• •8. Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value \>480 msec,
• •18. Impaired gastrointestinal function or disease which may significantly alter the absorption of study treatments (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, small bowel resection);
• •19. History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to to starting study treatment the first dose of study treatment (Day 1);
• •20. Thromboembolic event (e.g. including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli) except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment (Day 1); Note: Participants with catheter-related thromboembolic events are allowed;
• •21. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgement of the Investigator, would make the participant inappropriate for the study;
• •22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until termination of gestation, confirmed by a positive β- hCG laboratory test (\> 5 mIU/mL);
• •23. Known hypersensitivity or contraindication to any component of study treatment or their excipients;
• •24. Ongoing/active participation in another interventional clinical trial;
• •25. Has participated in another clinical trial with the administration of an investigational product within 4 weeks, or five times the half-life of the investigational product, whichever is longer, before the first dose of study treatment (Day 1);
• •26. Is a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study (secretary, nurse, technician…).