A Phase IIa Study of the MEK Inhibitor GSK1120212 Monotherapy in the Treatment of Gemcitabine Refractory Locally Advanced, Recurrent or Metastatic Biliary Tract Cancers
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Number of Participants With Indicated Non-progressive Disease as Assessed by Investigator Per Response Evaluation Criteria In Solid Tumor Version 1.1 (RECIST 1.1) at Week 12
研究概览
简要总结
This is a Phase IIa, open-label, single-arm, multi-center study to evaluate the efficacy and safety of orally administered MEK inhibitor trametinib as the second line in subjects with advanced or metastatic biliary tract cancers (BTC) in Japanese population. The primary endpoint of this study is 12 week non-progressive disease (PD) rate defined as the percentage of subjects without progression at Week 12. As a sub-study, pharmacokinetics (PK) of four tablets of 0.5 milligram (mg) tablet, or one tablet of 2 mg tablet to achieve 2 mg daily regimen will be assessed to evaluate the pharmacokinetics of trametinib in Japanese population.
Eligible subjects will be randomized to receive trametinib at the recommended Phase II dose of 2 mg every day as one 2 mg tablet or four 0.5 mg tablets on Day 1. From Day 2 until disease progression or withdrawal from the study treatment, all subjects will receive one tablet of 2 mg trametinib . Disease assessment will be performed every 8 week. Translational research is also planned to evaluate the potential blood or tumor tissue-derived biomarkers for biological activity, and sensitivity or resistance to treatment with trametinib .
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female of age 20 years or older inclusive, at the time of signing the informed consent.
- •Japanese patients with histologically or cytologically confirmed cholangiocarcinoma (intra- or extrahepatic) or gallbladder cancer or ampulla of Vater cancer are eligible for which all of the following criteria have to be met: Nonresectable, recurrent, and/or metastatic disease.
- •Disease progression after up to two lines of systemic chemotherapies including no more than one line of gemcitabine-based chemotherapy. Note: Systemic therapy in adjuvant setting is not allowed as prior therapy.
- •More than 21 days have elapsed since any prior anti-tumor therapy.
- •At least one of the tumor samples for archived tissue at initial diagnosis or archived tissue at recent progression or fresh biopsy at recent progression (collect within 21 days from randomization if none of the archived tissues are available) is available prior to randomization to provide for translational research.
- •Measurable disease, i.e. presenting with at least one measurable lesion per the RESIST 1.
- •Performance status score of ≤1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
- •Estimated life expectancy of at least 12 weeks.
- •All prior treatment- related toxicities must be common terminology criteria for adverse events (CTCAE) (Version 4.0) ≤ Grade 1 (except alopecia) at the time of randomization.
- •Negative for hepatitis C virus (HCV) test, hepatitis B surface (HBs) antigen, hepatitis virus Bc (HBc) antibody, and HBs antibody. HBs antigen-negative subjects who test positive for both HBc antibody and HBs antibody or either of them may be eligible when their HBV DNA quantification result is negative.
- •Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
- •Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and agree to use effective contraception throughout the treatment period, and for 4 months after the last dose of study treatment.
- •Adequate baseline organ function for haematological, hepatic, renal, cardiac systems.
排除标准
- •History of another malignancy.
- •Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
- •Radiotherapy completed within 2 weeks prior to randomization.
- •History of interstitial lung disease or pneumonitis.
- •Having a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).
- •Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to randomization and/or chemotherapy without the potential for delayed toxicity within 21days prior to randomization.
- •Any prior use of any MEK inhibitors (including but not limited to trametinib, AZD6244 (selumetinib), RDEA119).
- •Current use of a prohibited medication.
- •History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
- •Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
- •Known Human Immunodeficiency Virus (HIV) infection. History or evidence of cardiovascular risk including a QT interval corrected for heart rate using the Bazett's formula (QTcB) interval >480 msec, history or evidence of current clinically significant uncontrolled arrhythmias, history of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization, history or evidence of current > or = Class II congestive heart failure as defined by New York Heart Association, treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy, subjects with intra-cardiac defibrillators or permanent pacemakers.
- •Known cardiac metastases.
研究组 & 干预措施
Trametinib (single tablet)
Subjects will receive, trametinib once daily as a single tablet of 2 mg administered orally with eight ounces of water under fasting conditions either one hour before or 2 hours after a meal.
干预措施: Trametinib (single tablet) (Drug)
Trametinib PK study (multiple tablet)
Subjects will receive on Day 1, trametinib as four tablets of 0.5 mg administered orally with eight ounces of water under fasting conditions either one hour before or 2 hours after a meal.
干预措施: Trametinib (Multiple tablet) (Drug)
Trametinib PK study (single tablet)
Subjects will receive Day 2 onwards, trametinib once daily as a single tablet of 2 mg administered orally with eight ounces of water under fasting conditions either one hour before or 2 hours after a meal.
干预措施: Trametinib (single tablet) (Drug)
结局指标
主要结局
Number of Participants With Indicated Non-progressive Disease as Assessed by Investigator Per Response Evaluation Criteria In Solid Tumor Version 1.1 (RECIST 1.1) at Week 12
时间窗: Up to Week 12
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the diameters of target lesions; Stable Disease(SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Progressive Disease(PD), At least a 20% increase in the sum of the diameters of target lesions. Non-PD = CR + PR + SD.
Number of Participants With Indicated Non-progressive Disease as Assessed by Independent Radiologist Per Response Evaluation Criteria In Solid Tumor Version 1.1 (RECIST 1.1) at Week 12
时间窗: Up to Week 12
Twelve week non-progressive disease (PD) at Week 12 was evaluated by computed tomography. Non- PD was calculated as the sum of complete response (CR), partial response (PR), and stable disease (SD).
次要结局
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)(until 26-Feb-2016)
- Expression of Interstitial Lung Disease Marker KL-6(From Baseline up to Week 36)
- Expression of Interstitial Lung Disease Marker Surfactant Protein D(Baseline, Week 12, and Week 28)
- Number of Participants With the Indicated Worst-case On-therapy Clinical Chemistry Grade Shifts From Baseline(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Coagulation Grade Shifts From Baseline(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Hematology Grade Shifts From Baseline(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Clinical Chemistry Measurements With Respect to the Normal Range(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Prothrombin Time Measurements With Respect to the Normal Range(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Hematology Measurements With Respect to the Normal Range(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Carcinoembryonic Antigen Measurements With Respect to the Normal Range(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Body Temperature(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Blood Pressure(From Baseline up to Week 36)
- Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Pulse Rate(From Baseline up to Week 36)
- Change From Baseline in Oxygen Saturation (SpO2)(From Baseline up to Week 36)
- Number of Participants With Progression-Free Survival as Assessed by Investigator(Up to Week 37)
- Number of Participants With Progression-Free Survival as Assessed by Independent Radiologist(Up to Week 37)
- Number of Participants With Overall Survival(Up to Week 39)
- Number of Participants With Overall Response Rate as Assessed by Investigator Per RECIST 1.1 Criteria(Up to Week 37)
- Number of Participants With Overall Response Rate as Assessed by Independent Radiologist Per RECIST 1.1 Criteria(Up to Week 37)
- Number of Participants With Investigator-Assessed Time to Response(Up to Week 37)
- Number of Weeks Until Time to Response Assessed With Independent Radiologist(Up to Week 37)
- Number of Participants With Investigator-Assessed Duration of Response(Up to Week 37)
- Number of Participants With Independent Radiologist Assessed Duration of Response(Up to Week 37)