COLUMBUS-AD

Molecular pre-screening

1. Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations.

2. Male or female ≥ 18 years of age.

3. Surgically resected, with tumor free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT3b-pT4bN0) cutaneous melanoma per AJCC 8th edition.

4. Sentinel node (SN) staged node negative (pN0).

5. Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma.

6. Available tumor sample for central determination of the BRAFV600E/K mutation. FFPE tumor tissue block or a minimum of 10 slides, optimally up to 20 slides.

Screening

1. Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations.

2. Melanoma confirmed centrally to be BRAF V600E/K mutation-positive.

3. Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed respectively within 6 weeks and 2 weeks before the randomization (Day 1).

4. Randomization within 12 weeks from full surgical resection including sentinel lymph node biopsy (SLNB).

5. Recovered from definitive surgery (e.g. complete wound healing, no uncontrolled wound infections or indwelling drains).

6. ECOG performance status of 0 or 1.

7. Adequate haematological function:

i. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

ii. Platelets ≥ 100 x 109/L

iii. Hemoglobin ≥ 9.0 g/dL.

8. Adequate renal function:

Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min by Cockcroft Gault formula.

9. Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits.

10. Adequate hepatic function:

i. Serum total bilirubin ≤ 1.5 x ULN and < 2 mg/dL

ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN.

11. Adequate cardiac function:

i. Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram

ii. Mean triplicate QT interval corrected for heart rate according to Fridericia’s formula (QTcF) value ≤ 480 msec and no history of QT syndrome.

12. Adequate coagulation function, defined as INR ≤1.5 × ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range.

13. Negative serum β-HCG test (female patient of childbearing potential only) performed within 3 days prior to Day 1.

14. Participants of childbearing / reproductive potential should use adequate birth control measures. 

Molecular pre-screening

1. Unknown ulceration status.

2. Uveal and mucosal melanoma.

3. Clinically apparent metastases (N+/M1).

4. Microsatellites, satellites and/or in-transit metastases.

5. Local (scar) recurrences.

Screening

1. Breast feeding women.

2. Pregnancy.

3. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

4. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization:

i. Note 1: Thromboembolic or cerebrovascular events include stroke, transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive) deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis;

ii. Note 2: Participants with thromboembolic events related to indwelling catheters or other procedures may be enrolled.

5. Previous or concurrent malignancy for the past 3 years (must be free from disease for at least 3 years). Except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and any in situ cancer.

6. Any condition with a life expectancy of less than 5 years.

7. Participants with a prior cancer associated with RAS mutation.

8. Previous treatment for melanoma beyond complete surgical resection (any prior systemic anticancer therapy; prior radiotherapy).

9. Hypersensitivity to the study drugs or to any of the excipients.

10. Participants with severe lactose intolerance (e.g. Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption).

11. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:

i. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to randomization;

ii. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);

iii. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite optimal therapy;

iv. Presence of clinically significant cardiac arrhythmias including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia (stable controlled atrial fibrillation or paroxysmal supraventricular tachycardia is accepted).

12. Neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).

13. Non-infectious pneumonitis and Interstitial Lung Disease.

14. Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at screening or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending.

15. Participants with active bacterial, fungal, or viral infection, including, but not limited to:

HBV, HCV, and known HIV or AIDS-related illness, or an infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.

Note: Participants receiving prophylactic antibiotics (eg, for prevention of a urinary tract infection) are exceptions and may participate.

Note: Participants with a positive HBsAg (i.e., either acute or chronic active hepatitis) are excluded. Those with positive anti-HBcAb but negative HBsAg and anti-HBsAb profile may be eligible upon review and approval by the sponsor or designee.

Note: Participants with positive HCV antibody but undetectable HCV viral load may be eligible upon review and approval by the sponsor or designee.

Note: Participants with confirmed stable HIV disease may be eligible if they have viral load < 50 copies/mL and CD4 count > 200 cells/mm3, and on stable antiretroviral therapy for at least 6 months, provided that they meet all other study eligibility criteria. Testing for HIV is not mandated for study entry; however, testing must be performed at sites where mandated locally following local clinical practice.

16. Unable to ingest or digest tablets and capsules. This can be caused by any impaired gastrointestinal function or disease, such as for example: ulcerative diseases, malabsorption syndrome, small bowel resection, ileus, etc. Or any condition causing

uncontrolled nausea, vomiting or diarrhoea.

17. Presence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule according to Investigator’s judgement; those conditions should be assessed with the patient before randomization in the trial.

18. Participant is a family member of the investigator or any associate, colleague and employee assisting in the study conduct (secretary, nurse, technician) or is otherwise in a position likely to represent a conflict of interest, the participant is only eligible if the informed consent has been sought by an appropriately qualified individual who is completely independent of this relationship.

19. Participation in a clinical study with administration of an investigational product within 4 weeks or five times the half-life of the investigational product, whichever is longer, before the first dose of study treatment.

20. Participants who has forfeited his / her freedom by administrative or legal award or is under guardianship. 

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

Administrator: Rob Speirs (x8475)