DYNAMIC

DyNAMIc is designed as a randomised, parallel arm proof-of-concept study to:

1. Test our hypothesis that tumours respond (measured by ctDNA mutant BRAF TAB level) to reintroduction of targeted therapy (following drug holiday).

2. Test the thresholds we have simulated based on our pre-clinical data are correct or whether they

need refining based on response in patients examined prospectively.

Patients with stage III un-resectable or stage IV BRAF mutant metastatic melanoma eligible for the study will

be randomised 1:3 (continuous:adaptive). All patients will commence encorafenib (E) 450mg once daily plus

binimetinib (B) 45mg twice daily continuous dosing for 4 weeks. A baseline blood sample will be taken within

24 hours prior to commencing E+B to test for the level of ctDNA (Baseline TAB). At week 2 and week 4,

further blood for ctDNA will be taken. Patients who meet the inclusion criteria will be randomised by week 2

of treatment. Patients will be stratified by ctDNA level at baseline. Patients will be treated until disease

progression (RECIST v1.1) on CT scan whilst taking E+B, or stop due to patient choice/toxicity. 

Patients eligible for the trial must comply with all of the following at randomisation:

1. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study.

2. Histological confirmation of cutaneous melanoma.

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, and CT or MRI (brain) scan (RECIST v1.1).

6. BRAF p.V600E/K/R mutation confirmed (exact point mutation must be known).

7. BRAF ctDNA TAB level of ≥15 copies/ml of plasma.

8. ECOG performance status 0/1/2.

9. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drug.

10. Adequate organ function as defined by:

Haemoglobin >9 g/dL

White blood count >=2x10 9/L

ANC >=1.2x10 9/L

Platelet count >=75x10 9/L

Albumin >=2.5 g/dL

Total bilirubin <=1.5 x ULN

AST or ALT <=3 x ULN

Calculated creatinine clearance >=30ml/min

Left ventricular Ejection fraction (LVEF) >=50% or >=LLN by ECHO

11. Women of childbearing potential (WOCBP) participating in the study must have a negative serum or urine pregnancy test within 72 hours prior to the start of study drug.

12. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 1 month following last dose of drug (either encorafenib or binimetinib).

13. 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).

14. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements.

However, WOCBP participating in the study who are continuously not heterosexually active must still undergo pregnancy testing. 

Any patient meeting any of the criteria listed below at baseline will be excluded from study participation:

1. Prior systemic targeted BRAF/MEKi targeted therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS >=6 months following discontinuation of drugs.

2. BRAF wild-type malignant melanoma.

3. Metastasis to the brain or leptomeninges

4. Any contraindication to treatment with Encorafenib or Binimetinib as per the local Summary of Product Characteristics

5. Hypersensitivity to the active substanceor 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 (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. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

11. Child Pugh B or C liver disease.

12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina).

13. A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50%.

14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mmHg on >3 occasions which cannot be controlled by anti-hypertensive therapy.

15. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline QTC interval ≥480msec) or taking medicinal products known to prolong the QT interval.

16. 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).

17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to the first dose of study drugs.

18. Prisoners or patients who are involuntarily incarcerated.

19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness. 

Research Nurse: Sirjana Devkota (x3921) Carolyn.Hatch@lthtr.nhs.uk

Administrator: Bethany Webster (x8475)