A study of encorafenib and binimetinib given before and after surgery, compared with standard treatment after surgery, in patients with BRAF-mutant melanoma
- Conditions
- MelanomaCancerMelanoma and other malignant neoplasms of skin
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 45
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 randomisation
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 2 – 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 11.9 of this protocol
18. Be able to swallow the trial medication
19. Confirmation of adequate diagnostic tumour tissue available for research studies (see laboratory manual to confirm minimum tissue requirements)
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 investigator would place the patient at undue risk or interfere with the trial. Examples include, but are not limited to:
8.1. Patients with uncontrolled ischaemic heart or other cardiovascular event (myocardial infarction (MI), new angina, stroke transient ischaemic attack (TIA), or new congestive cardiac failure (CCF)) within the last 6 months
8.2. Uncontrolled hypertension
8.3. Patients with stable but significant cardiovascular disease defined by heart failure (New York Heart Association Functional Classification (NYHF) III or IV, see Appendix 3) or frequent angina
8.4. Patients with baseline QTC interval > 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 4 – 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 allowed)
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method