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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Encorafenib and Binimetinib
* Drug: Placebo to match Encorafenib ; Placebo to match Binimetinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Encorafenib and Binimetinib | Drug: Encorafenib and Binimetinib<br>* Encorafenib 450 mg (6 × 75 mg capsules) once daily (QD) and binimetinib 45 mg (3 x 15 mg tablets) twice daily (BID) orally for a maximum of 12 months.<br>* Other names: Encorafenib: Braftovi / Binimetinib: Mektovi;|
| Placebo Comparator: Arm B<br>Placebo to match Encorafenib Placebo to match Binimetinib | Drug: Placebo to match Encorafenib ; Placebo to match Binimetinib<br>* Encorafenib (6 × 75 mg placebo capsules) QD and binimetinib (3 × 15 mg placebo tablets) BID placebos orally for a maximum of 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) | RFS is defined as the time between the date of randomization and the date of 1) first recurrence (local, regional, or a distant metastasis), 2) new melanoma that is known to be either ulcerated, thick (Breslow thickness>1 mm) or requiring a treatment other than surgery or 3) death (whatever the cause), whichever occurs first. | Approximately 4.4 years from the accrual of the first patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant metastasis-free survival (DMFS) | DMFS is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. | Approximately 6.0 years from first patient in | 
| Overall survival (OS) | OS is defined as time from randomization to the date of death whatever the cause. | Approximately 10 years from first Patient In. | 
| Safety - Incidence, nature, severity and seriousness of treatment emergent adverse events (TEAEs) | Incidence nature and severity of adverse events and SAEs graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | From the signing of the ICF up to 30 days after end of treatment- approximately 14.5 months | 
| Safety -Incidence, nature and severity of cutaneous malignancies by dermatological examination | This is to monitor for the possible development of keratoacanthoma and/or squamous cell carcinoma and new primary melanoma, as these have been reported to occur with selective BRAF inhibitor treatment. Incidence, nature and severity of new cutaneous malignancies (kerantoacanthoma, squamous cell carcinoma and new primary melanoma) will be recorded and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | From the signing of ICF to study completion- approximately 10 years from last patient in | 
| Safety -Incidence of Serious adverse events (SAEs) | Incidence nature and severity of serious adverse events will be recorded and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | From the signing of the ICF to study completion- approximately 10 years from last patient in | 
| Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in physical examination | Standard physical examinations on cardiovascular, respiratory, gastrointestinal, dermatological, ophthalmological and neurological systems will be performed and will be evaluated based on normal/abnormal and clinical significance observations. Number of participants with TEAEs related to abnormal or clinical significance observations to the physical examinations after the start of study drug will be reported. | From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months | 
| Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in vital signs | Clinically notable elevated values: Systolic blood pressure (BP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic BP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; Heart rate: ≥ 100 beats/min (bpm) with increase from baseline of ≥ 15 bpm; Body temperature [°C] ≥ 38°C). Clinically notable low values: Systolic BP: <120 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic BP: < 80 mmHg with decrease from baseline of ≥ 15 mmHg; Heart rate: <50 bpm with decrease from baseline of ≥ 15 bpm; Body temperature [°C]: ≤ 35 °C | From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months | 
| Safety and tolerability : Incidence of TEAEs related to notable changes in clinical safety laboratory parameters from baseline. | incidence of treatment-emergent adverse events (TEAEs) related to notable changes in clinical safety laboratory parameters from baseline. Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 5.0 will be graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift is defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. | From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months | 
| Safety and tolerability -Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of 12-lead electrocardiograms (ECGs) | 12-lead ECGs will be obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT [millisecond (ms)] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline > 60 ms, new > 450 ms, new > 480 ms, new > 500 ms. | From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months | 
| Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of echocardiogram or multigated acquisition (ECHO/MUGA) scans. | ECHO/MUGA scan assess Left Ventricular Ejection Fraction (LVEF). Changes from baseline of LVEF measurements over time will be reported | From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months | 
| Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in ophtalmic examination | Changes from baseline and worse value on ophthalmic examination over time will be reported. a full ophthalmic examination by an ophthalmologist will be performed (at baseline an end of treatment) including best corrected visual acuity (BCVA), slit lamp examination, intraocular pressure (IOP), dilatedfundoscopy and optical coherence tomography (OCT). Retinal examination is required to identify findings associated with retinal pigment epithelial detachments (RPED), serous detachment of the retina and RVO (OCT and angiography). the investigator will also monthly monitor visual assesment (general inspection of the eyes, examination of motility and alignment, visual disturbance including diminished central vision, blurred vision or loss of vision). | From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months | 
| Safety and tolerability-Treatment emergent adverse events (TEAEs) leading to dose interruption, reduction and discontinuation. | Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy | On treatment period - 12 months from randomization. | 
| Performance status using the Eastern Co-operative Oncology Group (ECOG) performance status scale. | Changes from baseline and worse value on Eastern Cooperative Oncology Group (ECOG) Scale with a range from 0 to 5 with lower score mean a lower functional impairment, 5 corresponding to death . | From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months | 
| Patient-reported health-related (HRQoL)-European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) . | To determine if there is any change from baseline during the treatment and every 6 months thereafter up to 30 months in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire scores. EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The descriptive system has five dimension (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each is rated according to a five-point verbal rating scale (VRS): 1. no problems, 2. slight problems, 3. moderate problems, 4. severe problems and 5. extreme problems) and translated into a five-digit number that describes the participant's health state | From the signing of the ICF up to 30 months. | 
| Patient-reported health-related (HRQoL)_European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30) | To determine if there is any change from baseline during the treatment and every 6 months thereafter up to 30 months in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30) questionnaire scores EORTC QLQ-C30 consists of fifteen multi-item scales: five functional scales (physical, role, cognitive, emotional and social); nine symptom/items scales (fatigue, pain, nausea, vomiting, dyspnea, insomnia, apetite loss, constipation, diarrhae and financial difficulties) and a global health and Quality of Life (QoL) scale. Each scale in the questionnaire will be scored (0 to 100). High scores represents a high health/quality of life | From the signing of the ICF up to 30 months. | 
| Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_Cmin | Minimum serum concentration (Cmin) will be calculated and reported. | From randomization up to 11 months | 
| Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)-Cmax | Maximum serum concentration (Cmax) will be calculated and reported. | From randomization up to 11 months | 
| Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_AUC | Area under the curve (AUC) will be calculated and reported. | From randomization up to 11 months | 
| Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmin | Minimum serum concentration (Cmin) will be calculated and reported | From randomization up to 11 months | 
| Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmax | Maximum serum concentration (Cmax) will be calculated and reported. | From randomization up to 11 months | 
| Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-AUC | Area under the curve (AUC) will be calculated and reported. | From randomization up to 11 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adjuvant, Melanoma, Stage II, BRAFV600E/K