Circulating tumour DNA guided Adaptive BRAF and MEK Inhibitor therapy
Cutaneous melanoma
Current interventions as of 01/10/2025: Randomisations are processed using an online system. Both arms use encorafenib (450 mg once daily) plus binimetinib (45 mg twice daily) which are both administered orally. Arm A is standard of care (SOC) for the condition and, in line with the licence, both drugs are given continuously until progression occurs or when there is no longer clinical benefit from taking the treatment, or when the treatment ends. Arm B is adaptive treatment. This means the treatment is stopped and re-started as guided by the amount of circulating tumour DNA (ctDNA) in a patient’s bloodstream; treatment on this arm will also cease upon progression or when there is no longer clinical benefit from taking the treatment, or when the treatment ends. When ‘on-treatment’, patients on arm B will receive the SOC dose of both drugs. All participants on arm B will commence with one SOC cycle of both drugs before switching to being ‘off-treatment’. The levels of ctDNA is known as the Tumour Activity Burden (TAB). The ctDNA TAB provides guidance on the resistance levels of the tumour. Pre-defined ctDNA TAB threshold levels are used to indicate when treatment should stop/re-start. These levels will be assessed and reviewed during the trial. All participants, regardless of treatment arm, will provide blood samples for ctDNA TAB analysis every 2 weeks up to progression. Once progression occurs, all participants will be followed up every 3 months until the end of the study, withdrawal or death. Previous interventions: Randomisations are processed using an online system. Both arms use encorafenib (450 mg once daily) plus binimetinib (45 mg twice daily) which are both administered orally. Arm A is standard of care (SOC) for the condition and, in line with the licence, both drugs are given continuously until relapse occurs. Arm B is adaptive treatment. This means the treatment is stopped and re-started as guided by the amount of circulating tumour DNA (ctDNA) in a p
Current key inclusion criteria as of 09/06/2026: At screening: 1. Written and informed consent obtained from the participant and agreement of the participant to comply with the requirements of the study 2. Histological confirmation of cutaneous melanoma, including acral 3. ≥18 years of age 4. Stage III un-resectable/ IV disease 5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, or clinically accurately measurable (RECIST v1.1) 6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known) 7. ECOG performance status 0/1/2 8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs 9. Adequate organ function enabling safe administration of the study treatment 10. Women of childbearing potential participating in the study (WOCBP) 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 11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month 28 days following last dose of drug (either encorafenib or binimetinib) 12. 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) Prior to randomisation: 13. BRAF ctDNA level of ≥7 copies/ml of plasma. (If there is a discrepancy between the screening and baseline 1 ctDNA TAB levels this should be discussed via the DyNAMIc trial team at the LCTC.) 14. Left Ventricular Ejection fraction (LVEF) ≥50% of ≥LLN by ECHO _____ Previous key inclusion criteria as of 01/10/2025: At screening: 1. Written and informed consent obtained from the participant and agreement of the participant to comply with the requirements of the study 2. Histological confirmation o
Current key exclusion criteria as of 09/06/2026: 1. 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) 2. BRAF wild-type malignant melanoma 3. Current evidence of active metastasis to the brain or leptomeninges (the designation of “active metastasis” should be determined by the local clinical care team in discussion with the DyNAMIc study team at LCTC if needed and informed by recent imaging.) 4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics 5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib 6. Current use of a prohibited medication as described in the protocol 7. 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. Discussion via the DyNAMIc trial team at LCTC as to whether they can be included in the study is allowed and the outcome of the discussion will determine entry. 8. 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 9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 10. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (as described in the protocol) 11. Prisoners or patients who