NCT05510895已完成2 期
Neoadjuvant Encorafenib, Binimetinib and Cetuximab for Patients With BRAF V600E Mutated/pMMR Localized Colorectal Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Tumor regression grade (TRG)
研究概览
简要总结
AIO-KRK-0420 NeoBRAF is a single arm, multicenter, phase II trial with neoadjuvant encorafenib, binimetinib and cetuximab for patients with BRAF V600E mutated/pMMR localized colorectal cancer.
详细描述
This is a single arm, multicenter, phase II trial for patients with unresected BRAF V600E mutated/pMMR localized colorectal cancer (CRC). Patients enrolled will be treated with neoadjuvant encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly) for 8 weeks. Neoadjuvant treatment will be followed by surgery. First Endpoint is TRG (Tumor-Regression-Grade) which will be analyzed centrally. Patients with TRG>1 will receive adjuvant treatment with encorafenib (300mg QD), binimetinib (45mg BID) and cetuximab (500mg/m² biweekly) for up to 16 weeks. For patients with TRG<2 EOT will be reached 4-6 weeks after last dosage of encorafenib, binimetinib and cetuximab and further treatment is at investigator discretion (CAPOX recommended). All subjects will be followed every 3 months after surgery for up to 4 years after start of recruitment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Biopsy-confirmed adenocarcinoma of the colon or upper rectum if too high for radiotherapy.
- •Radiologically (CT/MRI) staged disease as: T3-4 (as invasion of surrounding tissue structures or organs) and/or nodal positive (N+ defined as regional lymph node(s) without fat hilus and short axis diameter of ≥1 cm), M
- •BRAF V600E mutation and pMMR or MSS (as determined by a validated test, preferably PCR or NGS).
- •ECOG performance status ≤
- •Age ≥ 18 years.
- •Adequate hematologic function at screening as follows:
- •ANC ≥ 1.5 x 109/L, platelets ≥ 100 x109/L, hemoglobin ≥ 9.0 g/dL.
- •Adequate liver function at screening as measured by serum transaminases (AST & ALT) ≤ 2.5 x ULN and total bilirubin ≤ 1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
- •Adequate renal function at screening: serum creatinine ≤ 1.5 x ULN.
- •Adequate serum electrolytes at screening defined as serum potassium and magnesium levels within institutional normal limits (Note: replacement treatment to achieve adequate electrolytes will be allowed.
- •Adequate cardiac function at screening characterized by left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO and QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤ 480 msec.
- •Negative serum pregnancy test at screening for women of childbearing potential.
- •Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drugs on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use highly effective contraception, defined as methods with a failure rate of less than 1 % per year, containing at least 1 form of non-hormonal contraception. Highly effective contraception is required at least 28 days prior, throughout and for at least 6 months after interventional study treatment (encorafenib, binimetinib and cetuximab).
- •Signed and dated written informed consent.
- •Ability to take oral medication.
- •Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations.
排除标准
- •Any prior systemic therapy, surgery or radiotherapy of the colorectal cancer disease.
- •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).
- •Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS >90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
- •Known severe hypersensitivity reactions to monoclonal antibodies or BRAF-/MEK-inhibitors (grade ≥ 3 NCI-CTCAE v 5), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
- •Pregnancy or lactation.
- •Known alcohol or drug abuse.
- •Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (≤ 6 months prior to enrolment); myocardial infarction (≤ 6 months prior to enrolment), acute coronary syndromes [including unstable angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting) ≤ 6 months prior to enrolment]; congestive heart failure (≥New York Heart Association Classification Class II); or history or current evidence of clinically significant arrhythmia and/or conduction abnormality (≤ 6 months prior to enrolment), except rate controlled atrial fibrillation and paroxysmal supraventricular tachycardia.
- •Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
- •Preexisting interstitial lung disease.
- •Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
- •History of thromboembolic or cerebrovascular events ≤ 6 months prior to enrolment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
- •Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
- •Known human immunodeficiency virus (HIV) infection or active hepatitis B or C infection.
- •All other significant diseases, which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment.
- •Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
- •Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, within 5 half-lives or 4 weeks (the longer period applies) prior to initiation of study treatment.
- •Current treatment with a non-topical medication or current intake of herbal preparations / supplements / foods known to be a strong inhibitor of CYP3A
- •However, patients who either discontinue such treatment/intake or switch to another medication at least 7 days prior to starting study treatment are eligible.
- •Concomitant use of St. John's Wort (hypericum perforatum).
研究组 & 干预措施
neoadjuvant and adjuvant triplet combination of encorafenib, binimetinib and cetuximab
Experimental
Neoadjuvant treatment with encorafenib, binimetinib and cetuximab for up to 8 weeks (4 biweekly cycles). In Week 10-12 surgery of the tumor followed by central determination of tumor regression grade (TRG).
TRG0-1: insufficient response to neoadjuvant triplet. Standard chemotherapy with fluoropyrimidines and oxaliplatin should be applied. TRG2-4: 4-8 weeks after surgery adjuvant treatment with encorafenib, binimetinib and cetuximab continues for up to 16 Weeks (8 biweekly cycles).
干预措施: Binimetinib (Drug)
结局指标
主要结局
Tumor regression grade (TRG)
时间窗: immediately after the surgery
Tumor regression will be centrally graded according to the grading system developed by Dworak et al (Dworak, Keilholz et al. 1997).
次要结局
- Overall survival (OS)(max 54 months)
- Translational research 1(max 54 months)
- Safety and tolerability (acc. to NCI CTC AE v5.0) incl. vital signs, clinical parameters and overall feasibility of the regimen(max 54 months)
- R0-resection rate(max 24 months)
- Overall Response Rate (ORR) according to RECIST v1.1(max 54 months)
- Disease free survival(max 54 months)
- Perioperative morbidity and mortality(max 24 months)
- Translational research 2(max 54 months)
- Translational research 3(max 54 months)
研究者
研究点 (1)
Loading locations...
相似试验
招募中
2 期
Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum CancerColorectal CancerBRAF V600E Mutation PositiveNCT05706779Federation Francophone de Cancerologie Digestive30
招募中
2 期
(Neo)Adjuvant BRAF/MEK Inhibition in pN1c MelanomaMelanoma Stage IIIIn-Transit Metastasis of Cutaneous MelanomaNCT05767879Leiden University Medical Center28
进行中（未招募）
1 期
Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal CancerBRAF NP_004324.2:p.V600EMetastatic Colon AdenocarcinomaMetastatic Microsatellite Stable Colorectal CarcinomaMetastatic Rectal AdenocarcinomaProgressive DiseaseRecurrent Colorectal CarcinomaStage III Colorectal Cancer AJCC v8Stage IIIA Colorectal Cancer AJCC v8Stage IIIB Colorectal Cancer AJCC v8Stage IIIC Colorectal Cancer AJCC v8Stage IV Colorectal Cancer AJCC v8Stage IVA Colorectal Cancer AJCC v8Stage IVB Colorectal Cancer AJCC v8Stage IVC Colorectal Cancer AJCC v8Unresectable Colon AdenocarcinomaUnresectable Rectal AdenocarcinomaNCT04017650M.D. Anderson Cancer Center38
终止
1 期
Encorafenib, Binimetinib, and Nivolumab in Treating Microsatellite Stable BRAF V600E Metastatic Colorectal CancerMetastatic Colon AdenocarcinomaMetastatic Colorectal AdenocarcinomaMetastatic Microsatellite Stable Colorectal CarcinomaMetastatic Rectal AdenocarcinomaStage III Colon CancerStage III Colorectal CancerStage III Rectal CancerStage IIIA Colon CancerStage IIIA Colorectal CancerStage IIIA Rectal CancerStage IIIB Colon CancerStage IIIB Colorectal CancerStage IIIB Rectal CancerStage IIIC Colon CancerStage IIIC Colorectal CancerStage IIIC Rectal CancerStage IV Colon CancerStage IV Colorectal CancerStage IV Rectal CancerStage IVA Colon CancerStage IVA Colorectal CancerStage IVA Rectal CancerStage IVB Colon CancerStage IVB Colorectal CancerStage IVB Rectal CancerStage IVC Colon CancerStage IVC Colorectal CancerStage IVC Rectal CancerNCT04044430University of California, San Francisco2
终止
2 期
Testing Treatment With Encorafenib and Binimetinib Before Surgery for Melanoma With Lymph Node InvolvementMelanoma of Unknown PrimaryMetastatic Malignant Neoplasm in Lymph NodePathologic Stage IIIB Cutaneous Melanoma AJCC v8Pathologic Stage IIIC Cutaneous Melanoma AJCC v8Pathologic Stage IIID Cutaneous Melanoma AJCC v8Recurrent Cutaneous MelanomaNCT04221438ECOG-ACRIN Cancer Research Group3