NCT04303403招募中1 期
Phase Ib Study Evaluating Safety and Tolerability of Combination Trametinib and Ruxolitinib in Patients With Advanced RAS Mutant Colorectal Cancer and Pancreatic Adenocarcinoma
National Cancer Centre, Singapore1 个研究点 分布在 1 个国家目标入组 48 人开始时间: 2018年7月31日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose
研究概览
简要总结
The purpose of this research study to find out if the drug trametinib in combination with ruxolitinib is safe, tolerable and has beneficial effects in people who has certain type of cancers including the type that you have. Patients with RAS mutant colorectal cancer and pancreatic adenocarcinoma are invited to participate in this study. This is the first time that both trametinib and ruxolitinib are studied in combination. Trametinib is marketed in several countries with the brand name Mekinist® for the treatment of melanoma (a type of skin cancer). Trametinib has been studied extensively in cancer and has been tested in many patients. Ruxolitinib is an oral inhibitor of JAK1 and JAK2 tyrosine kinases and is approved for treatment of adult polycythemia vera and myelofibrosis. Ruxolitinib has been studied extensively in many patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 21 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients (male or female) ≥
- •Patients with histological diagnosis of RAS mutant advanced colorectal and pancreatic adenocarcinoma having received at least 1 prior line of systemic therapy. Pancreatic cancer patients with KRAS mutation detected on plasma profiling having received at least 1 prior line of systemic therapy.
- •Patients must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.
- •Life expectancy of at least 3 months.
- •Written informed consent that is consistent with ICH-GCP guidelines.
- •Eastern Cooperative Oncology Group (ECOG) performance score ≤
- •Have adequate organ and hematologic function, as determined by:
- •Absolute neutrophil count (ANC) ≥ 1,500/μl.
- •Platelets ≥ 100,000/μl.
- •Haemoglobin ≥ 9g/dL.
- •Aspartate Amino Transferase (AST)/ Alanine Amino Transferase (ALT) ≤ 2.5 x upper limit of normal (ULN ≤ 5 x ULN is acceptable if liver metastases are present).
- •Total bilirubin ≤1.5 x ULN (< 3 ULN for patients with Gilbert syndrome).
- •Creatinine clearance ≥ 60ml/min.
- •Prothrombin time and activated partial thromboplastin time ≤ 1.5 x upper limit of normal (ULN) per institutional laboratory normal range.
- •Ejection fraction ≥ 50% with no symptoms attributable to heart failure.
- •Have normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QT interval corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.
- •For female patients of childbearing potential, a negative pregnancy test must be documented prior to enrolment.
- •Female and male patients who are fertile must agree to use a highly effective form of contraception with their sexual partners throughout study participation.
- •Have the willingness and ability to comply with scheduled visits and study procedures.
排除标准
- •Received cytotoxic chemotherapy, investigational agents, or radiation within 14 days of study drug commencement, or 5 half-lives, whichever is shorter, and with recovery of clinically significant toxicities from that therapy.
- •Received monoclonal antibodies or had surgery within 30 days of the first dose of study drug.
- •Have been diagnosed with another primary malignancy within the past 3 years of study drug commencement (except for adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer).
- •Have CNS metastases that are symptomatic, neurologically unstable, or requiring an increasing dose of corticosteroids.
- •Have meningeal involvement or spinal cord compression.
- •Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
- •Myocardial infarction (MI) within 6 months prior to the first dose.
- •Unstable angina within 6 months prior to first dose.
- •History of congestive heart failure (CHF).
- •History of clinically significant atrial arrhythmia.
- •Any history of ventricular arrhythmia.
- •Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.
- •Have history or the presence of pulmonary interstitial disease or drug related pneumonitis.
- •Have an ongoing or active infection.
- •Patients with active HBV and HCV are excluded unless they are undergoing treatment for HBV and HCV.
- •Have a history of or active significant gastrointestinal (GI) bleeding within 3 months of the first dose.
- •Patients who are on immunosuppressive therapy.
- •Patients who have retinal vein occlusion and retinal pigment epithelial detachment.
- •On medications which are potent and moderate inhibitor and inducers of CYP3A
- •Patients with moderate to severe hepatic impairment (Child Pugh B and C).
- •Patients with history of severe allergic skin reactions or current skin conditions.
研究组 & 干预措施
Dose Escalation and Expansion
Experimental
Dose Escalation:
Trametinib 2mg daily monotherapy for 14 days. Followed by combination oral trametinb (2mg starting dose) daily and oral ruxolitinib (5mg starting dose) twice daily at assigned doses.
Dose Expansion:
Combination oral trametinb daily and oral ruxolitinib twice daily at the maximum tolerated dose (MTD) established at the Dose Escalation phase.
A cycle of therapy will comprise of 28 days of combination trametinib and ruxolitinib treatment.
干预措施: Trametinib (Drug)
Dose Escalation and Expansion
Experimental
Dose Escalation:
Trametinib 2mg daily monotherapy for 14 days. Followed by combination oral trametinb (2mg starting dose) daily and oral ruxolitinib (5mg starting dose) twice daily at assigned doses.
Dose Expansion:
Combination oral trametinb daily and oral ruxolitinib twice daily at the maximum tolerated dose (MTD) established at the Dose Escalation phase.
A cycle of therapy will comprise of 28 days of combination trametinib and ruxolitinib treatment.
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Maximum Tolerated Dose
时间窗: 28 days (1 cycle)
Highest dose level at which less than one-third of the patients in the dose level experienced dose limiting toxicities (DLTs) during the first cycle of treatment
次要结局
- Frequency and severity of treatment-emergent Adverse Events and Serious Adverse Events(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline hematology laboratory parameters during treatment - Haemoglobin(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline hematology laboratory parameters during treatment - White blood count, Platelets, Absolute neutrophil count(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Urea, Sodium, Potassium, Chloride, Bicarbonate, Glucose, Magnesium, Calcium, Phosphate, Total cholesterol, High and low density lipoprotein, Triglycerides(From time of first study drug administration until 30 days after last dose of study drug)
- Tumour Markers: CEA and CA 19-9 in blood samples(From cycle 1 up to last cycle of treatment (each cycle is 28 days))
- Overall Response Rate(From time of first study drug administration until first occurrence of disease progression, up to 2 years)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Uric acid, Creatinine, Total bilirubin(From time of first study drug administration until 30 days after last dose of study drug)
- Overall Survival(From time of first study drug administration to death from any cause, up to 2 years)
- Changes between baseline and post-baseline hematology laboratory parameters during treatment - Neutrophils(From time of first study drug administration until 30 days after last dose of study drug)
- Disease Control Rate(From time of first study drug administration until best overall response, first occurence of disease progression, up to 2 years)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Total protein, Albumin(From time of first study drug administration until 30 days after last dose of study drug)
- Changes between baseline and post-baseline biochemistry laboratory parameters during treatment - Alkaline phosphatase, Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase, Beta-human chorionic gonadotrophin(From time of first study drug administration until 30 days after last dose of study drug)
- Frequency of dose interruptions(From time of first study drug administration until 30 days after last dose of study drug)
- Frequency of dose reductions(From time of first study drug administration until 30 days after last dose of study drug)
- Pharmacokinetics (PK): Trough concentrations of trametinb(From cycle 1-6 of study (each cycle is 28 days))
- Progression Free Survival(From time of first study drug administration until first occurence of disease progression, or death from any cause, up to 2 years)
研究者
研究点 (1)
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