Biopsy- and Biology-driven Optimization of Targeted Therapy in Subjects With Advanced Melanoma

Inclusion Criteria: 1. ≥ 18 years of age. 2. Signed written informed consent. 3. Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory. Subjects with ocular or mucosal melanoma are not eligible. 4. Assessable lesion for biopsy at week 2 not inferring with RECIST measurements (Biopsies for genetic/biomarker analyses must be taken from lesions not required for disease assessment) 5. Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1 for the definition of a measureable lesion. 6. For Cohort A: Must NOT have received prior treatment with BRAF or MEK inhibitor. If a prior systemic therapy (such as but not limited to chemotherapy, immunotherapy, biologic, vaccine and/or investigational treatment) in metastatic disease has been administered, four weeks or more since last systemic treatment must have passed. Must have recovered from any acute toxicity associated with prior therapy. 7. For Cohort B: Must have shown PR/CR during treatment with selective BRAF/MEK combination treatment that was discontinued due to tumor progression and received subsequent alternative treatment (such as but not limited to surgery, chemotherapy, immunotherapy, biologic, vaccine and/or investigational treatment), with a period of at least 3 months since last intake of BRAF/MEK inhibitor 8. All prior treatment-related toxicities (except alopecia) must be ≤ Grade 1 according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 9. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. 10\. Women of childbearing potential must have a negative urin pregnancy test within 7 days prior to registration and agree to use effective contraception, as defined in Section 9.8 throughout the treatment period, and for 4 months after the last dose of study treatment. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 9.8 throughout the treatment period, and for 4 months after the last dose of study treatment. 11. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 12. Adequate baseline organ function defined as Absolute Neutrophil Count ≥1.2 × 109/L Hemoglobin ≥ 9 g/dL Platelet count ≥ 100 x 109/L Prothrombinzeit (PT/INR) and Partial thromboplastin time ≤ 1.3 x upper laboratory norm (ULN) Albumin ≥ 2.5 g/dL Total bilirubin ≤ 1.5 x ULN Aspartate aminotransferase and Alanine Aminotransferase ≤ 2.5 x ULN Serum creatinine ≤ 1.5 mg/dL 13. A left ventricular ejection fraction (LVEF) ≥ the institutional lower limit of normal as measured by ECHO Exclusion Criteria: 1. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to registration and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to registration. 2. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to registration. 3. Current use of a prohibited medication 4. History of another malignancy. Exception: Subjects who have been disease-free for 3 years, subjects with a history of completely resected non-melanoma skin cancer, and/or subjects with successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled. 5. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures. 6. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), or active Hepatitis C Virus (HCV). Subjects with chronic or cleared HBV and/or HCV are eligible. 7. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency. 8. Subjects with brain metastases are excluded, unless: * All known lesions must be previously treated with surgery or stereotactic radiosurgery, and * Brain lesion(s), if present, must be confirmed stable (ie, no increase in lesion size) for 90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and * Asymptomatic with no corticosteroids requirement for 30 days prior to first dose of study drug(s), and * No enzyme-inducing anticonvulsants for 30 days prior to first dose of study drug(s). In addition, even in cases of no evidence of disease (NED), confirmation on two consecutive MRI or CT scans using contrast will be required. Enrollment of a subject with brain metastases who meet the above criteria requires approval of the sponsor 9. A history or evidence of cardiovascular risk including any of the following: 1. A QT interval corrected for heart rate using the Bazett's formula (QTcB; ³ 480 msec; 2. A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with controlled atrial fibrillation for \> 30 days prior to registration are eligible. 3. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to registration; or 4. A history or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines. 10. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including: 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); or Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: i. Evidence of new optic disc cupping; ii. Evidence of new visual field defects on automated perimetry; iii. Intraocular pressure \> 21 mmHg as measured by tonography. 11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO). 12. Interstitial lung disease or pneumonitis 13. Pregnant or breast-feeding females.