Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy

Prior treatment

• Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs)
• Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics
• Current use of a prohibited medication as described in Section 8.9
• Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (see section 7.5)

Other illness

• BRAF wild-type malignant melanoma
• Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib
• History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study
• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
• Child Pugh B or C liver disease
• Coronary syndromes (including myocardial infarction within 6 months or unstable angina)
• Treatment refractory hypertension defined as a blood pressure of systolic \>150 mmHg and/or diastolic \>95 mm Hg on \>3 occasions which cannot be controlled by anti-hypertensive therapy
• 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)
• Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness

Lab values

• Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
• A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of \<50% (see appendix C)
• Uncorrectable electrolyte abnormalities \> CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥ 480msec) or taking medicinal products known to prolong the QT interval

Other

• Metastasis to the brain or leptomeninges
• Prisoners or patients who are involuntarily incarcerated

• At Screening
• Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study
• Histological confirmation of cutaneous melanoma
• ≥ 18 years of age
• Stage III un-resectable/ IV disease
• Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1)
• BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known)
• ECOG performance status 0/1/2
• Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs
• Adequate organ function as defined below:
  • Haemoglobin ≥ 9 g/dL ii. White blood count ≥ 2 x109/L iii. ANCa ≥ 1.2 x109/L iv. Platelet count ≥ 75 x109/L v. Albumin ≥ 2.5 g/dL vi. Total bilirubinb ≤ 1.5 x ULNa vii. ASTa or ALTa ≤ 3 x ULNa viii. Calculated creatinine clearance ≥ 30ml/min
• Women of childbearing potential participating in the study (WOCBP see Appendix B for definition) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug.
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 28 days following last dose of drug (either encorafenib or binimetinib), (see Appendix B).
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib), (see Appendix B).
  • At randomisation:
• Left Ventricular Ejection fraction (LVEF) ≥ 50% or ≥LLNa by ECHO
• BRAF ctDNA TAB level of ≥15 copies/ml of plasma