NCT05270044进行中（未招募）3 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 815
- 试验地点
- 155
- 主要终点
- Recurrence-free survival (RFS)
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- •Pre-screening
- •Unknown ulceration status;
- •Uveal and mucosal melanoma;
- •Clinically apparent metastases (N+/M1);
- •Microsatellites, satellites and/or in-transit metastases,
- •Local (scar) recurrences.
- •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.
研究组 & 干预措施
Arm A
Experimental
Encorafenib and Binimetinib
干预措施: Encorafenib and Binimetinib (Drug)
Arm B
Placebo Comparator
Placebo to match Encorafenib Placebo to match Binimetinib
干预措施: Placebo to match Encorafenib ; Placebo to match Binimetinib (Drug)
结局指标
主要结局
Recurrence-free survival (RFS)
时间窗: Approximately 4.4 years from the accrual of the first patient.
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.
次要结局
- Distant metastasis-free survival (DMFS)(Approximately 6.0 years from first patient in)
- Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in ophtalmic examination(From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months)
- Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)-Cmax(From randomization up to 11 months)
- Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_AUC(From randomization up to 11 months)
- Overall survival (OS)(Approximately 10 years from first Patient In.)
- Safety -Incidence of Serious adverse events (SAEs)(From the signing of the ICF to study completion- approximately 10 years from last patient in)
- Safety and tolerability-Treatment emergent adverse events (TEAEs) leading to dose interruption, reduction and discontinuation.(On treatment period - 12 months from randomization.)
- Performance status using the Eastern Co-operative Oncology Group (ECOG) performance status scale.(From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months)
- Safety -Incidence, nature and severity of cutaneous malignancies by dermatological examination(From the signing of 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(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(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.(From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months)
- Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_Cmin(From randomization up to 11 months)
- Safety - Incidence, nature, severity and seriousness of treatment emergent adverse events (TEAEs)(From the signing of the ICF up to 30 days after end of treatment- approximately 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)(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) .(From the signing of the ICF up to 30 months.)
- Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmax(From randomization up to 11 months)
- Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-AUC(From randomization up to 11 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.(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 Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30)(From the signing of the ICF up to 30 months.)
- Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmin(From randomization up to 11 months)
研究者
研究点 (155)
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