Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.

Adjuvant Encorafenib & Binimetinib vs. Placebo in Fully Resected Stage IIB/C BRAF V600E/K Mutated Melanoma: a Randomized Triple-blind Phase III Study in Collaboration With the EORTC Melanoma Group

The purpose of the Columbus-AD study is to evaluate the efficacy and safety of 12 months of encorafenib in combination with binimetinib in adjuvant setting of BRAF V600E/K mutant stage IIB/C melanoma versus the current standard of care (surveillance).

This is a randomized triple-blind placebo-controlled international multicenter phase III superiority clinical trial.

Participants with completely resected cutaneous melanoma and documented BRAF V600E/K status by central assay will be randomized 1 to 1 to receive either treatment with encorafenib and binimetinib or their two placebos for 12 months. Patients will be stratified according to the stage of the disease according to AJCC version 8 between:

• stage IIB (i.e., pT3b or pT4a)
• stage IIC (i.e., pT4b).

The long-term evaluation of all endpoints (including information about the occurrence of new treatment-related adverse events, if any) will take place 10 years from the randomization of the last patient.

Inclusion Criteria:

Pre-Screening

• Male or female ≥ 18 years of age;
• Surgically resected, with tumour free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT3b-pT4bN0) cutaneous melanomaa;
• Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma.
• Sentinel node (SN) staged node negative (pN0);
• Available tumour sample for central determination of the BRAF V600E/K mutation.

Screening

• Melanoma confirmed centrally to be BRAF V600E/K mutation-positive;

• 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 randomization (Day 1);

• No more than 12 weeks elapsed between full surgical resection (including SLNB) and randomization;

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

• ECOG performance status of 0 or 1;

• Adequate haematological function as defined as Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L and Hemoglobin

  ≥ 9.0 g/dL;

• Adequate renal function as defined as Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min;

• Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits;

• Adequate hepatic function as defined as Serum total bilirubin ≤ 1.5 x ULN and < 2 mg/dL, Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN;

• Adequate cardiac function as defined as LVEF ≥ 50% as determined by MUGA scan or echocardiogram and Mean triplicate QTcF value ≤ 480 msec and no history of QT syndrome;

• 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;

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

• Female patients of child-bearing potential and male patients must agree to follow the protocol's contraception guidance during the treatment period and for ≥30 days after last administration.

Exclusion Criteria:

Pre-screening

• Unknown ulceration status;
• Uveal and mucosal melanoma;
• Clinically apparent metastases (N+/M1);
• Microsatellites, satellites and/or in-transit metastases,
• Local (scar) recurrences.

Screening

• Breast feeding women;
• Pregnant women;
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO;
• History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization;
• History of previous or concurrent malignancy within preceding 3 years or any condition with a life expectancy of less than 5 years;
• Participants with a prior cancer associated with RAS mutation;
• Prior systemic anticancer therapy for melanoma or radiotherapy for melanoma;
• Hypersensitivity to the study drugs or to any of the excipients;
• Participants with severe lactose intolerance (e.g., Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption);
• Impaired cardiovascular function or clinically significant cardiovascular diseases;
• Neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
• Non-infectious pneumonitis and Interstitial Lung Disease;
• 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;
• 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.