adjuvant encorafenib and binimetinib in high-risk stage ii melanoma with a braf mutation.

Conditions: Melanoma

Summary: 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.

Eligibility criteria:
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.

Keywords: melanoma stage ii brafv600e/k adjuvant