FOLFOX in Combination With Binimetinib as 2nd Line Therapy for Patients With Advanced Biliary Tract Cancers With MAPK Pathway Alterations: A ComboMATCH Treatment Trial
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 66
- 试验地点
- 395
- 主要终点
- Overall survival (OS)
研究概览
简要总结
This phase II ComboMATCH treatment trial compares the usual treatment of modified leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) chemotherapy to using binimetinib plus mFOLFOX6 chemotherapy to shrink tumors in patients with biliary tract cancers that have spread to other places in the body (advanced) and had progression of cancer after previous treatments (2nd line setting). Fluorouracil is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in the body. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It works by killing tumor cells. Leucovorin may help the other drugs in the mFOLFOX6 chemotherapy regimen work better by making tumor cells more sensitive to the drugs. Binimetinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals tumor cells to multiply. This helps to stop or slow the spread of tumor cells. Giving binimetinib in combination with mFOLFOX6 chemotherapy may be effective in shrinking or stabilizing advanced biliary tract cancers in the 2nd line setting.
详细描述
PRIMARY OBJECTIVE:
I. To determine whether binimetinib and mFOLFOX6 combination therapy improves overall survival (OS) compared to mFOLFOX6 alone in patients with advanced/recurrent biliary tract cancer (BTC) and with alterations in RAS/RAF/MEK/ERK pathway, who have progressed on one prior line of therapy.
SECONDARY OBJECTIVES:
I. To determine whether binimetinib and mFOLFOX6 combination therapy improves objective response rate (ORR) compared to FOLFOX alone.
II. To determine if clinical outcomes including progression free survival (PFS), duration of response (DOR), and disease control rate (DCR) are improved with combination treatment of binimetinib and mFOLFOX6 compared to FOLFOX alone in patients with advanced/recurrent BTC and with alterations in RAS/RAF/MEK/ERK pathway who have progression on one prior line of therapy.
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
- •Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-A6 based on the presence of an actionable mutation as defined in EAY191
- •GENERAL COMBOMATCH EAY191:
- •Patients must be registered to the ComboMATCH Registration Protocol (EAY191)
- •Patients must have RAS/RAF/MEK/ERK mutations as determined by the ComboMATCH screening assessment
- •Patients must not have BRAF V600E as determined by the ComboMATCH screening assessment
- •Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have archival tissue available from within 12 months prior to registration on the ComboMATCH Registration Trial (EAY191).
- •Please note the current actionable marker of interest (aMOI)/actionable alteration list for this treatment trial can be found on the Cancer Trials Support Unit (CTSU) website
- •Please note novel/Dynamic aMOI can be submitted for review per the process described in the ComboMATCH Registration Protocol
- •EAY191-A6 REGISTRATION:
- •Participants must have histologically confirmed BTC (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma [EHC] or gallbladder cancer [GBC]) that is unresectable or recurrent with a confirmed RAS/RAF/MEK/ERK pathway mutation via any Clinical Laboratory Improvement Act (CLIA)-certified method. BRAFV600E mutations are not eligible due to other ongoing/upcoming studies in this disease cohort
- •Tumor tissue must be available:
- •Adequate archival tumor specimen (obtained within 12 months of EAY191 registration which has not had a Response Evaluation Criteria in Solid Tumors (RECIST) response, complete response (CR) or partial response (PR), to any intervening therapy after collection of the tissue) must be available with formalin-fixed paraffin-embedded tumor tissue (blocks or slides) OR
- •Consent to a new tumor tissue biopsy which is not a representative target lesion. This lesion must be amenable to a minimal risk image-guided or direct vision biopsy
- •A new biopsy is preferred but is not required for enrollment in EAY191-A6 if sufficient archival tissue is available as described above.
- •Measurable disease per RECIST 1.1 Of note, in the case when a baseline biopsy is done after scans are obtained, a lesion separate from one that is biopsied needs to be measurable per RECIST 1.
- •All radiologic studies must be performed within 28 days prior to registration
- •Progression of disease on gemcitabine based first-line regimen (i.e. only one prior line of therapy is permitted)
- •No systemic anti-cancer therapy within 4 weeks of registration to EAY191-A6
- •No prior MEK inhibitor therapy
- •No prior history of treatment with a direct and specific inhibitor of KRAS
- •Patients who only received radio-sensitizing chemotherapy with fluorouracil (5-FU) or capecitabine are eligible, but need to have received and failed first-line systemic chemotherapy upon recurrence. Peri-operative systemic 5-FU/capecitabine and/or oxaliplatin, is allowed if it's been more than 12 months of registration to EAY191-A6
- •No major surgery within 4 weeks (excluding placement of vascular access) of registration to EAY191-A6
- •No minor surgery within 2 weeks of registration to EAY191-A6
- •No palliative radiotherapy within 1 week of registration to EAY191-A6
- •Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
- •Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required
- •Adequate contraception is needed for at least 30 days after the last dose of binimetinib and breastfeeding should be discontinued for at least 3 days after the last dose of binimetinib. For FOLFOX regimen, 9 months is recommended for contraception after last dose of oxaliplatin for females of childbearing potential and 6 months for males
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- •Absolute neutrophil count (ANC) >= 1,000/mm^3, no growth factor within 14 days of 1st dose
- •Platelet count >= 75,000/mm^3
- •Creatinine < 1.6 x upper limit of normal (ULN) OR
- •Calculated (Calc.) creatinine clearance >= 50 mL/min, as calculated by the Cockcroft-Gault formula
- •Total bilirubin =< 2.0 x upper limit of normal (ULN); Patients with Gilbert syndrome may enroll if < 3.0 x ULN
- •Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) =< 5.0 x upper limit of normal (ULN)
- •Hemoglobin >= 8 g/dL, no transfusion within 7 days of 1st dose
- •Creatine phosphokinase =< 2.5 x ULN
- •High blood pressure more than 160/90 despite treatment are ineligible
- •No history of interstitial lung disease. No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- •Patients should not have history of bowel perforation or intestinal fistulas in the last 6 months
- •Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease are ineligible
- •Must have adequate cardiac function with left ventricular ejection fraction >= 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan. Patients with congenital long QT syndrome are not permitted
- •No history of prolonged QTc or at risk for prolonged QTc due to any reason (for example, concomitant medications during or before chemotherapy that may increase the risk of prolonged QTc), uncontrolled congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease
- •No active skin disorder that has required systemic therapy within the past 1 year
- •No history of rhabdomyolysis
- •No concurrent ocular disorders, including:
- •Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including but not limited to uncontrolled hypertension, uncontrolled diabetes
- •Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO
- •Patients with a history of corneal erosion (instability of corneal epithelium), corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions
- •Patients with known or at risk for retinopathies, uveitis or retinal vein occlusion
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排除标准
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研究组 & 干预措施
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Oxaliplatin (Drug)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Biopsy Procedure (Procedure)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Biospecimen Collection (Procedure)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Leucovorin Calcium (Drug)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Binimetinib (Drug)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Computed Tomography (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Fluorouracil (Drug)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Fluorouracil (Drug)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Oxaliplatin (Drug)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Leucovorin Calcium (Drug)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Bone Scan (Procedure)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Computed Tomography (Procedure)
Arm 1 (mFOLFOX6)
Patients receive leucovorin IV over 2 hours and oxaliplatin IV over 2 hours on day 1, and fluorouracil IV over 46-48 hours on days 1-2. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Biopsy Procedure (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Biospecimen Collection (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Bone Scan (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Echocardiography Test (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm 2 (binimetinib, mFOLFOX6)
Patients receive binimetinib PO on days 1-14, and leucovorin IV, oxaliplatin IV, and fluorouracil IV as in Arm 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA and collection of blood during screening and on study, and undergo CT with contrast, MRI, or FDG-PET throughout the trial as clinically indicated. Patients may also undergo bone scans on study and may undergo biopsies throughout the study as clinically indicated.
干预措施: Multigated Acquisition Scan (Procedure)
结局指标
主要结局
Overall survival (OS)
时间窗: From randomization to the time of death due to any cause, assessed up to 30 months
The primary efficacy analysis will be to compare the OS distributions between those treated with modified leucovorin, fluorouracil and oxaliplatin (mFOLFOX6) and binimetinib versus (vs.) mFOLFOX6. Despite being a randomized phase II trial, we will utilize an intent to treat approach such that patients will be analyzed based on the treatment arm to which they were randomized. As defined above, OS will be compared between the two treatment arms using Kaplan-Meier methods. The hazard ratio, median OS, and estimated OS rates at 6, 12, 18, 24, and 30 months will be estimated along with corresponding 95% confidence intervals. Anticipating that the treatment arms will be balanced in terms of the potential confounders reflect in the stratification factors, a log-rank test will be used to compare the OS distributions between the two treatment arms in this cohort.
次要结局
- Objective response(Up to 5 years)
- Progression free survival (PFS)(From study entry to the first of either disease progression or death from any cause, assessed up to 5 years)
- Clinical benefit(Up to 5 years)
- Incidence of adverse events(Up to 5 years)
- Duration of response (DoR)(Up to 5 years)