Melanoma Cancer Melanoma and other malignant neoplasms of skin
Conditions
Interventions
Current interventions as of 16/05/2025:
Target population:
The target population will be male and female participants aged 18 and over with stage III (B/C/D), or extracranial oligometastatic stage I
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 16/05/2025: 1. Written informed consent to participate 2. Aged =18 years old 3. AJCC 8th edition stage III (B/C/D), or extracranial oligometastatic stage IV BRAFV600 mutant melanoma, based on histological/cytological and radiological assessments for which surgery is planned, and resection is expected to remove all known tumour(s) with R0 resection margins. ‘Oligometastatic stage IV’ is defined for the purpose of this trial as M stage disease confined to a single body organ excluding the brain that can be readily removed surgically with anticipated clear margins 4. For stage III patients, confirmation of no evidence of distant metastatic disease using preferred imaging modalities including CT body or PET/CT and CT or MRI head 5. For stage IV patients, confirmation of no evidence of unresectable metastatic disease, or metastatic disease in more than 1 body organ, using preferred imaging modalities including CT body or PET/CT and CT or MRI head. The site of metastasis should not be in bone, or CNS, or in any other body site where complete resection is not feasible 6. The planned resectable disease must be radiologically measurable using standard imaging modalities 7. Baseline tumour assessments must be done within 28 days prior to registration 8. BRAF V600 mutation confirmed by PCR or NGS 9. Received no prior BRAF or MEK inhibitors 10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix 3 – Karnofsky and ECOG Performance Status Scale) 11. Predicted life expectancy >12 months 12. Normal QTc interval (<480 msec) on ECG and left ventricular ejection fraction within normal limits, assessed by echocardiogram or MUGA 13. Adequate bone marrow function defined as: 13.1. Absolute neutrophil count (ANC) =1.5 x 10e9/l 13.2. Haemoglobin (Hb) =90 g/l 13.3. Platelets =100 x 10e9 /l 14. Adequate liver function defined as: 14.1. Aspartate aminotransferase (AST) and/or alanine transaminase (ALT) =2.5 x upper limit of normal range (ULN) 14.2. Total bilirubin <1.5 x ULN (except if the patient has Gilbert Syndrome or liver metastases, in which case the bilirubin must be <3 x ULN) 15. Adequate renal function defined as: 15.1. Serum creatinine =1.5 x ULN or 15.2. Calculated creatinine clearance by Cockcroft-Gault of =40 ml/min 16. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, completion of QoL and PROM questionnaires and other procedures described in the protocol 17. Women of child-bearing potential (WCBP) and all sexually active male patients must agree to use effective contraception methods throughout treatment as per section 11.10 of this protocol 18. Ability to swallow the trial medication 19. Confirmation of adequate diagnostic tumour tissue available for research studies (see laboratory manual to confirm minimum tissue requirements) _____ Previous inclusion criteria: 1. Written informed consent to participate 2. Aged =18 years old 3. AJCC 8th edition stage III (B/C/D), or extracranial oligometastatic stage IV BRAFV600 mutant melanoma, based on histological/cytological and radiological assessments for which surgery is planned, and resection is expected to remove all known tumour(s) with R0 resection margins. ‘Oligometastatic stage IV’ is defined for the purpose of this trial as M stage disease confined to a single body organ excluding the brain that can be readily removed surgically with anticipated clear margins 4. For stage III patients, confir
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 16/05/2025: 1. Prior adjuvant therapy for resected primary or locoregional melanoma 2. Other invasive malignancies diagnosed within the last 2 years which are not in complete remission, or for which additional therapy is required 3. Brain or bone metastases 4. Non-cutaneous primary site of melanoma 5. Prior radiotherapy to the site planned for surgery 6. History or current evidence of retinal vein occlusion (RVO) or risk factors for RVO (uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes) 7. Left ventricular function 480 msec on electrocardiogram (ECG) 8.5. Left ventricular ejection fraction below the lower limit of normal 8.6. Presence of active infection 8.7. Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C 9. Known allergy or hypersensitivity to Encorafenib or Binimetinib, or their excipients. Binimetinib contains lactose, so patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption will be excluded 10. Women who are pregnant, plan to become pregnant or are lactating during the trial period 11. Use of other investigational anti-cancer drugs (a washout period of 28 days would be required) 12. Use of strong inducers and inhibitors of CYP3A4 (Appendix 5 – Prohibited Medication) 13. Known HIV or active Hep B or Hep C infection 14. Patients who have neuromuscular disorders associated with elevated creatine phosphokinase (CK, e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) 15. Autoimmune conditions requiring regular or intermittent use of any systemic steroid or immunosuppressive drugs, with the exception of steroid inhalers 16. Any immunotherapy in the last 3 months 17. Prior radiotherapy to the site of disease planned for resection 18. Concurrent participation in an interventional clinical trial (observational studies are allowed) _____ Previous exclusion criteria: 1. Prior adjuvant therapy for resected primary or locoregional melanoma 2. Other invasive malignancies diagnosed within the last 2 years which are not in complete remission, or for which additional therapy is required 3. Brain or bone metastases 4. Non-cutaneous primary site of melanoma 5. Prior radiotherapy to the site planned for surgery 6. History or current evidence of retinal vein occlusion (RVO) or risk factors for RVO (uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes) 7. Left ventricular function < 50% 8. Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the inv
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Current primary outcome measure as of 16/05/2025: The primary outcome measure is pathological complete response, in patients who complete 8 weeks of pre-operative EncoBini and undergo complete surgical resection. _____ Previous primary outcome measure as of 14/06/2022: Pathological complete response of the resected tumour (defined as an absence of residual viable malignant cells on H&E staining), in patients randomised to the EncoBini arm, who complete 8 weeks of pre-operative EncoBini and undergo complete surgical resection (R0). Previous primary outcome measure: Pathological complete response, measured by the absence of residual viable malignant cells on Haemotoxylin and Eosin (H&E) staining of tumour removed at surgery, in patients randomised to the EncoBini arm, who complete 8 weeks of pre-operative EncoBini and undergo complete surgical resection; Timepoint(s): Week 8 | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 16/05/2025: 1. Treatment compliance will be defined as the percentage of total planned doses of encorafenib and binimetinib received before and after surgery. 2. Pre-operative radiological response will be assessed on imaging undertaken at 8 weeks, according to Response Evaluation Criteria In Solid Tumours (RECIST v1.1, Appendix 1) 3. Pathological overall (complete, near-complete, partial and non-response) response will be assessed by pathological assessment of resected tumour specimens 4. Adverse drug reactions will be assessed using the standard cancer National Cancer Institute (NCI) CTCAE v5.0 criteria 5. Surgical adverse events will be captured up until 30 days after surgery 6. Lymphoedema events: lymphoedema affecting upper or lower limbs will be assessed in patients undergoing either axillary/supraclavicular lymphadenectomy, or inguinal/pelvic lymphadenectomy. Lymphoedema events will be determined by comparing serial limb circumference measurements (as a surrogate marker for post-operative lymphoedema) pre- and post-surgery. Lymphoedema is defined as >16% increase in the circumference of the limb associated with the nodal field that underwent lymphadenectomy at 6 and 12 months after the date of surgery compared with pre-surgery measurement. 7. EFS: Event-free survival is defined as the time from trial enrolment to disease progression or recurrence (local or distant disease development, or death), whichever occurs first, assessed by the treating investigators. Patients who remained alive without disease progression/recurrence at the time of data analyses are censored at their last date of clinical follow-up for progression/recurrence. 8. RFS: Relapse-free survival is defined as the time from surgery to disease recurrence (local or distant disease development, or death), whichever occurs first, assessed by the treating investigators. Patients who remained alive without disease recurrence at the time of data analyses are | — |
Countries
England, Northern Ireland, Scotland, United Kingdom, Wales
Outcome results
None listed