Phase II Study of Cobimetinib in Combination With Vemurafenib in Active Melanoma Brain Metastases
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 5
- 试验地点
- 6
- 主要终点
- Objective Intracranial Response (OIRR)
研究概览
简要总结
The purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.
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
- •Signed informed consent
- •Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600-mutation
- •Melanoma must be documented to contain a BRAFV600 mutation by a CLIA approved laboratory
- •At least one measurable intracranial target lesion for which all of the following criteria are met:
- •previously untreated or progressive according to RECIST 1.1 (equal to or greater than 20% increase in longest diameter on baseline scan) after previous local therapy (SRS and/or craniotomy)
- •immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (SRS and/or craniotomy)
- •largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced MRI
- •Prior therapies for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy will be allowed but prior BRAF or MEK not allowed
- •ECOG PS 0-2
- •Life expectancy >12 weeks
- •Age 18 years or older
- •Adequate bone marrow function as indicated by the following:
- •ANC > 1500/µL
- •Platelets ≥ 100,000/µL
- •Hemoglobin > 9 g/dL
- •Adequate renal function, as indicated by creatinine =/< 1.5 x the upper limit of normal (ULN)
- •Adequate liver function, as indicated by bilirubin =/< 1.5 x ULN
- •AST or ALT < 3 x ULN (patients with documented liver metastases: AST and/or ALT =/< 5 x ULN)
- •Able to swallow pills
- •Negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year
- •Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the Investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
排除标准
- •Active infection
- •Prior therapy with BRAFi and/or MEKi
- •Leptomeningeal disease
- •Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS
- •Increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. Symptomatic patients that have stable or decreasing corticosteroid use in the past 7 days will be allowed
- •Current use of therapeutic warfarin
- •Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia
- •Conditions that will interfere significantly with the absorption of drugs
- •Inability to undergo MRI secondary to metal, claustrophobia, Gadolinium Contrast allergy
- •Pregnant, lactating, or breast feeding women
- •Prior radiation therapy within the last 14 days
- •Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- •Unwillingness or inability to comply with study and follow-up procedures
- •The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
- •St. John's wort or hyperforin
- •Grapefruit juice
- •History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, Retinal Vein Occlusion (RVO), or neovascular macular degeneration
- •Uncontrolled glaucoma with intra-ocular pressures > 21mmHg
- •Serum cholesterol ≥ Grade 2
- •Hypertriglyceridemia ≥ Grade 2
- •Hyperglycemia (fasting) ≥ Grade 2
- •History of clinically significant cardiac dysfunction, including the following:
- •Current unstable angina
- •Current symptomatic congestive heart failure of NYHA class 2 or higher
- •History of congenital long QT syndrome or mean QTcF > 450 msec at baseline or uncorrectable electrolyte abnormalities
- •Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible)
- •Left ventricular ejection fraction (LVEF) below 50%
- •Uncontrolled Arrhythmias
- •Myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months
研究组 & 干预措施
Cobimetinib in Combination with Vemurafenib
Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water.
Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water.
干预措施: Cobimetinib (Drug)
Cobimetinib in Combination with Vemurafenib
Vemurafenib (960 mg twice a day) will be taken on Days 1 - 28 of each 28-day treatment cycle. The first dose of vemurafenib should be taken in the morning, and the second dose should be taken in the evening. Vemurafenib can be taken with or without a meal and should be taken with a glass of water.
Cobimetinib (60 mg once a day) will be taken on Days 1 - 21 of each 28-day treatment cycle. The cobimetinib tablet should be taken at approximately the same time each day in the morning with the vemurafenib dose, but no later than 4 hours after the scheduled time. Cobimetinib can be taken with or without a meal and should never be chewed, cut, or crushed and should be taken with a glass of water.
干预措施: Vemurafenib (Drug)
结局指标
主要结局
Objective Intracranial Response (OIRR)
时间窗: Until disease progression, less than or equal to 5 years.
Change in overall size of the sum of diameters from baseline of up to 5 intracranial target lesions in response to study treatment, achieved by individual patients.
次要结局
- Overall Response(Until disease progression, less than or equal to 5 years.)
- Progression-free Survival (PFS)(Up to 5 years)
- Overall Survival (OS)(Up to 5 years)
- Duration of Response(Until disease progression, less than or equal to 5 years.)
- Immune Modulation in Peripheral Blood(Up to 5 years)
- Early Markers of Progression in Peripheral Blood(Up to 5 years)
- Health-related Quality of Life as Measured by The Functional Assessment of Cancer Therapy (FACT) - Brain (FACT-Br)(Up to 5 years)
研究者
Melissa Burgess, MD
Assistant Professor
University of Pittsburgh