Randomized Trial of Consolidation Targeted Adjuvant Therapy With Encorafenib and Cetuximab Versus Usual Care for Patients With Stage II/III BRAF V600E Colon Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 1
- 试验地点
- 202
- 主要终点
- Circulating tumor deoxyribonucleic acid (ctDNA) clearance rate (Phase II; ctDNA positive cohort)
研究概览
简要总结
This phase II/III trial compares the effect of the combination of encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab combination after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.
详细描述
The primary and secondary objectives of the study:
PRIMARY OBJECTIVES:
I. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)
SECONDARY OBJECTIVES:
I. To evaluate and compare overall survival (OS) between the two treatment arms.
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
- 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
- •PRE-REGISTRATION (STEP 0) ELIGIBILITY CRITERIA:
- •Pre-registration for central tumor testing will occur after colon resection. Pre-registration can occur at any time after surgery through a twelve week period after completion of standard adjuvant therapy
- •BRAF V600 mutational status may be determined either locally or by central testing. This testing is mandatory prior to registration to determine eligibility. Tissue submission should be initiated as soon after surgery as possible. For tumors evaluated at local laboratories, formalin-fixed paraffin-embedded (FFPE) tumor tissue must still be submitted for central confirmation of BRAF status
- •REGISTRATION (STEP 1) ELIGIBILITY CRITERIA:
- •Histologically-proven stage III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk (pT4) stage II colon adenocarcinoma. Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve) and must have been completely resected
- •BRAF V600E mutation
- •MMR proficient (pMMR) or microsatellite stable (MSS) tumor
- •Histologic documentation: adenocarcinoma
- •Stage: III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk II (pT4)
- •Tumor site: colon
- •Patients must have received at least 3 months of adjuvant chemotherapy with either leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) (minimum of 5 cycles) or capecitabine and oxaliplatin (CAPOX) (minimum of 3 cycles)
- •Adjuvant therapy must be completed at most 8 weeks prior to registration
- •No other prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy) or radiation therapy for the current colon cancer is permitted
- •Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
- •Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- •Platelet count >= 75 x 10^9/L
- •Hemoglobin > 9.0 g/dL
- •Total bilirubin =< 1.5 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN
- •Corrected QT (QTc) Interval =< 480 msec
- •Creatinine = calculated (calc.) creatinine clearance >= 40 mL/min
- •No evidence of active and uncontrolled bacterial or viral infection (including active hepatitis B or hepatitis C infection) within 2 weeks prior to start of study intervention; exceptions include:
- •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- •* Participants who are hepatitis B surface antigen (HBsAg) negative (-), hepatitis B core antibody (HBcAb) positive (+) are eligible and should be monitored/treated as per local standard of care
- •No medical condition such as uncontrolled infection, uncontrolled diabetes mellitus, or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
- •Patients with known history or current symptoms of cardiac disease or history of treatment with cardiotoxic agents in the last 12 months, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- •No uncontrolled or poorly-controlled hypertension (> 180 mmHg systolic or > 130 mmHg diastolic)
- •No history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximab
- •No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 years
- •Patients are not considered to have a "currently active" malignancy if they had a gastric or bowel carcinoid < 1 cm, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) of the breast without invasive cancer, or endometrial dysplasia/carcinoma in situ
- •Patients are not considered to have a "currently active" malignancy if they had a sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasive
- •No known medical condition causing an inability to swallow oral formulations of agents
- •No residual Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade >= 2 toxicity from prior chemotherapy, with the exception of grade 2 alopecia or neuropathy
- •Drugs that prolong the QTc interval should be avoided if possible, as encorafenib can prolong the QTc interval. Drugs that are generally accepted to have a risk of causing Torsades de Pointes should be discontinued or replaced with drugs that do not carry this risk if at all possible. Patients who receive potential QTc-prolonging medications should be monitored closely
- •Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed during treatment on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study
- •Chronic concomitant treatment with strong CYP3A4 inducers is not allowed during treatment on this study. Patients must discontinue the drug 14 days prior to registration on the study
排除标准
- 未提供
研究组 & 干预措施
Arm II (patient observation)
Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Patient Observation (Other)
Arm I (encorafenib, cetuximab)
Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for a total of 6 cycles in the absence of disease recurrence or unacceptable toxicity. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Encorafenib (Drug)
Arm I (encorafenib, cetuximab)
Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for a total of 6 cycles in the absence of disease recurrence or unacceptable toxicity. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Biospecimen Collection (Procedure)
Arm II (patient observation)
Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Biospecimen Collection (Procedure)
Arm II (patient observation)
Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Computed Tomography (Procedure)
Arm II (patient observation)
Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (encorafenib, cetuximab)
Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for a total of 6 cycles in the absence of disease recurrence or unacceptable toxicity. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Computed Tomography (Procedure)
Arm I (encorafenib, cetuximab)
Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for a total of 6 cycles in the absence of disease recurrence or unacceptable toxicity. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (encorafenib, cetuximab)
Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for a total of 6 cycles in the absence of disease recurrence or unacceptable toxicity. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.
干预措施: Cetuximab (Biological)
结局指标
主要结局
Circulating tumor deoxyribonucleic acid (ctDNA) clearance rate (Phase II; ctDNA positive cohort)
时间窗: At 6 months after randomization
defined as the proportion of patients with undetectable ctDNA status at 6 months after randomization among patients with detectable ctDNA status at randomization. The ctDNA clearance rate at 6 months after randomization in experimental arm will be compared to control arm by Chi-squared test. The one-sided p-value will be reported. Due to small sample size, Cochran and Mantel-Haenszel test, stratified by stratification factors will be performed as sensitivity analysis.
Disease free survival (DFS) (Phase III)
时间窗: Assessed up to 6 years after randomization
Defined as the time from the date of randomization to the date of first documented recurrence or death due to all cause, whichever occurs first. Patients without events observed at the end of the study will be censored at the date of last disease evaluation which shows no evidence of disease. At each analysis (Interim #1, Interim #2, and Final), stratified Cox model will be conducted to compare DFS in the experimental arm to DFS in the control arm with stratification factors as stratum, based on all data collected at the analysis time point.
tDNA recurrence-free survival rate (ctDNA-RFS) (Phase II; ctDNA negative cohort)
时间窗: at 6 months after randomization
Defined as the proportion of patients who remained undetectable ctDNA status, recurrence-free, and alive at 6 months after randomization among patients with undetectable ctDNA status at randomization. The ctDNA-RFS in experimental arm will be compared to control arm by Cochran and Mantel-Haenszel test, stratified by stratification factors. The one-sided p-value will be reported.
次要结局
- Alternative disease free survival(assessed up to 6 years)
- Overall Survival(Assessed up to 6 years)
- Incidence of adverse events after randomization(up to 6 years)