Cutaneous melanoma Cancer Malignant melanoma of skin, unspecified
Conditions
Interventions
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 administe
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 re
Sponsors
The Christie NHS Foundation Trust
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
Inclusion criteria: 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 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 (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 as defined below: 9.1. Haemoglobin =9 g/dL 9.2. White blood count =2 x 10^(9)/L 9.3. ANC =1.2 x 10(9)/L 9.4. Platelet count =75 x 10^(9)/L 9.5. Albumin =2.5 g/dL 9.6. Total bilirubinb =1.5 x ULN 9.7. AST or ALT =3 x ULN 9.8. Calculated creatinine clearance =30 ml/min 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) At randomisation: 13. BRAF ctDNA level of =7 copies/ml of plasma 14. Left Ventricular
Exclusion criteria
Exclusion criteria: 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 are involuntarily incarcerated 12. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness _____ Previous key exclusion criteria as of 15/10/2025: 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 (patients with prior definitive treatment with immune therapy/radiotherapy (including SRS) or surgery), with no evidence of progression in the last 3 months, can be included 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 8. Any serious or unstable pre-existing medical conditions (as
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximal reduction in percentage mutant copies/ml (ctDNA mutant BRAF copies/ml of plasma) from baseline 2 TAB level upon restart of drugs following first drug off period. Measured longitudinally throughout the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Current key secondary outcome(s) as of 09/06/2026: 1. ctDNA mutant BRAF copies/ml of plasma. Measured longitudinally throughout the study. 2. Maximal response (complete response (CR)/partial response (PR)/stable disease (SD)/progressive disease (PD)) using RECIST v1.1 criteria. Measured from Baseline 1 until RECIST progression/clinical deterioration. 3. Percentage of participants who have experienced disease progression or death. Progression Free Survival, defined as time from randomisation to progression (RECIST v1.1 and in Arm B defined as progression whilst on targeted therapy unless stopped due to toxicity/choice). Measured continuously throughout the study. 4. Time to clinical deterioration. Defined as either the point of progression (defined as per RECIST v1.1) or in participants treated beyond progression, at the time of clinically determined deterioration, defined at the discretion of the treating clinician, specifically due to progression of the underlying cancer. Measured continuously throughout the study. 5. Overall survival, defined as time from randomisation until death from any cause. Measured continuously throughout the study. 6. Overall survival, defined as time from randomisation until death from melanoma. Measured continuously throughout the study. 7. Number of adaptive therapy cycles completed. Measured longitudinally throughout the study. 8. Median duration of adaptive therapy cycles. Measured longitudinally throughout the study. 9. Percentage of ctDNA results reported within 5 days from sample receipt into the laboratory. Measured longitudinally throughout the study. 10. EORTC QLQ-C30 and PRO-CTCAE. Measured longitudinally throughout the study. 11. Adverse Events and Serious Adverse Events defined by CTCAE version 5. Measured continuously throughout the study. 12. Number and location of sites of progression. At disease progression on imaging _____ Previous secondary outcome measures as of 01/10/2025: 1. ctDNA mutant BRAF copies/ml of plasm | — |
Countries
England, Scotland, United Kingdom, Wales
Contacts
Public ContactDyNAMIc Trial Manager
Outcome results
None listed