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 .
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
The drug substance is blended with inert
The drug substance is blended with inert
GSK Investigational Site
Chiba, Japan
GSK Investigational Site
Osaka, Japan
GSK Investigational Site
Shizuoka, Japan
GSK Investigational Site
Tokyo, Japan
GSK Investigational Site
Tokyo, Japan
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
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.
Time frame: Up to Week 12
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
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).
Time frame: Up to Week 12
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or Protocol-Specific SAEs
Time frame: until 26-Feb-2016
Expression of Interstitial Lung Disease Marker KL-6
Interstitial lung disease markers KL-6 assessments were carried out at Baseline (Day 1), Week 12, Week 20, Week 24, Week 28, Week 32, and Week 36
Time frame: From Baseline up to Week 36
Expression of Interstitial Lung Disease Marker Surfactant Protein D
Interstitial lung disease marker Surfactant Protein D assessments were carried out at Baseline (Day 1), Week 12, and Week 28
Time frame: Baseline, Week 12, and Week 28
Number of Participants With the Indicated Worst-case On-therapy Clinical Chemistry Grade Shifts From Baseline
Shift from baseline was calculated as the post baseline value minus the baseline value for albumin, alkalaine phosphatase (AP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatine kinase (CK), creatinine, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, and phosphate. A Worst Post Baseline (WPB) grade shift is defined as the worst change that occurred at any measured timepoint during the treatment period. Grading was determined by the NCI Common Terminology Criteria for Adverse Events Version 3.0 (NCI-CTCAE). Participants with missing baseline grade were designated a baseline grade of 0.
Time frame: From Baseline up to Week 36
Number of Participants With the Indicated Worst-case On-therapy Coagulation Grade Shifts From Baseline
Shift from baseline was calculated as the post baseline value minus the baseline value for activated partial thromboplastin time (APTT) and prothrombin time (PT). A Worst Post Baseline (WPB) grade shift is defined as the worst change that occurred at any measured timepoint during the treatment period. Grading was determined by the NCI Common Terminology Criteria for Adverse Events Version 3.0 (NCI-CTCAE). Participants with missing baseline grade were designated a baseline grade of 0.
Time frame: From Baseline up to Week 36
Number of Participants With the Indicated Worst-case On-therapy Hematology Grade Shifts From Baseline
Shift from baseline was calculated as the post baseline value minus the baseline value for hemoglobin, lymphocytes, neutrophils, platelets, and leukocytes. A Worst Post Baseline (WPB) grade shift is defined as the worst change that occurred at any measured timepoint during the treatment period. Grading was determined by the NCI Common Terminology Criteria for Adverse Events Version 3.0 (NCI-CTCAE). Participants with missing baseline grade were designated a baseline grade of 0.
Time frame: 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
Change from baseline was calculated as the post baseline value minus the baseline value for cancer antigen 19-9 (CA 19-9), chloride, lactate dehydrogenase (LDH), and urea. A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Measurements were designated as either Decreased to Low (DTL) or Increased to High (ITH) or Change to Normal/No Change (CN/NC). Participants with missing baseline measurements or visit measurements were considered to be missing. Participants were counted twice if the participant Decreased to Low and Increased to High.
Time frame: 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
Change from baseline was calculated as the post baseline value minus the baseline value for prothrombin time (PT). A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Measurements were designated as either Decreased to Low (DTL) or Increased to High (ITH) or Change to Normal/No Change (CN/NC). Participants with missing baseline measurements or visit measurements were considered to be missing. Participants were counted twice if the participant Decreased to Low and Increased to High.
Time frame: 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
Change from baseline was calculated as the post baseline value minus the baseline value for basophils, eosinophils, and monocytes. A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Measurements were designated as either Decreased to Low (DTL) or Increased to High (ITH) or Change to Normal/No Change (CN/NC). Participants with missing baseline measurements or visit measurements were considered to be missing. Participants were counted twice if the participant Decreased to Low and Increased to High.
Time frame: 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
Change from baseline was calculated as the post baseline value minus the baseline value for carcinoembryonic antigen (CEA). A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Measurements were designated as either Decreased to Low (DTL) or Increased to High (ITH) or Change to Normal/No Change (CN/NC). Participants with missing baseline measurements or visit measurements were considered to be missing. Participants were counted twice if the participant Decreased to Low and Increased to High.
Time frame: From Baseline up to Week 36
Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Body Temperature
Body temperature was categorized as Decrease to \<=35; Change to Normal or No Change and Increase to \>=38. Change from baseline was calculated as the post baseline value minus the baseline value. A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Participants with missing baseline measurements or visit measurements were considered to be missing.
Time frame: From Baseline up to Week 36
Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Blood Pressure
Systolic and diastolic blood pressure was measured after sitting for at least 5 minutes. Systolic blood pressure (SBP) was categorized as: Grade 0 (\<120), Grade 1 (\>=120-\<140), Grade 2 (\>=140-\<160) and Grade 3 (\>=160). Diastolic blood pressure (DBP) was categorized as Grade 0 (\<80), Grade 1 (\>=80-\<90), Grade 2 (\>=90-\<100), and Grade 3 (\>=100). Change from baseline was calculated as the post baseline value minus the baseline value. A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Participants with missing baseline measurements or visit measurements were considered to be missing.
Time frame: From Baseline up to Week 36
Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Pulse Rate
Pulse rate was categorized as Decrease to \<60, Change to Normal or No Change, and Increase to \>100. Change from baseline was calculated as the post baseline value minus the baseline value. A Worst Post Baseline (WPB) change is defined as the worst change that occurred at any measured timepoint during the treatment period. Participants with missing baseline measurements or visit measurements were considered to be missing.
Time frame: From Baseline up to Week 36
Change From Baseline in Oxygen Saturation (SpO2)
Oxygen Saturation was measured at Baseline (Day 1), Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32 and Week 36. For records occurring after baseline, change from baseline was calculated as the post baseline value minus the baseline value. When either the baseline or visit value was missing, the change from baseline was considered to be missing.
Time frame: From Baseline up to Week 36
Number of Participants With Progression-Free Survival as Assessed by Investigator
Progression-Free Survival (PFS) is defined as the interval of time (in weeks) between the date of randomization and the earlier of the date of disease progression and the date of death due to any cause. Disease progression was based on the assessments by the Investigator. If a participant received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS in the participant was censored at the last adequate assessment prior the initiation of the new anti-cancer therapy. Otherwise, if a participant did not have a documented date of progression or death, PFS in the participant was censored at the last adequate assessment.
Time frame: Up to Week 37
Number of Participants With Progression-Free Survival as Assessed by Independent Radiologist
Progression-Free Survival (PFS) is defined as the interval of time (in weeks) between the date of randomization and the earlier of the date of disease progression and the date of death due to any cause. Disease progression was based on the assessments by the independent radiologist. If a participant received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS in the participant was censored at the last adequate assessment prior the initiation of the new anti-cancer therapy. Otherwise, if a participant did not have a documented date of progression or death, PFS in the participant was censored at the last adequate assessment.
Time frame: Up to Week 37
Number of Participants With Overall Survival
Overall Survival (OS) is defined as the interval of time (in weeks) between the date of randomization and the date of death due to any cause. For participants that did not die, time of death was censored at the date of last contact. The date of death was taken from that recorded on the Record of Death page. Death on study due to any cause was included. One year OS was calculated from Kaplan-Meier estimates.
Time frame: Up to Week 39
Number of Participants With Overall Response Rate as Assessed by Investigator Per RECIST 1.1 Criteria
Overall Response Rate (ORR) is defined as the number of participants achieving a confirmed CR or PR per RECIST 1.1 criteria from the start of treatment until disease progression or the start of new anti-cancer therapy. ORR was based on responses from the Investigator assessment of best overall response, the best overall response is the best response recorded from the start of the treatment until disease progression/recurrence. ORR is calculated as CR + PR.
Time frame: Up to Week 37
Number of Participants With Overall Response Rate as Assessed by Independent Radiologist Per RECIST 1.1 Criteria
Overall Response Rate (ORR) is defined as the number of participants achieving a confirmed CR or PR per RECIST 1.1 criteria from the start of treatment until disease progression or the start of new anti-cancer therapy. ORR was based on responses from the Independent Radiologist assessment of best overall response, the best overall response is the best response recorded from the start of the treatment until disease progression/recurrence. ORR is calculated as CR + PR.
Time frame: Up to Week 37
Number of Participants With Investigator-Assessed Time to Response
Time to response (TTR) event was defined as achievement of a confirmed CR or PR, as the time from date of randomization until date of first documented evidence of CR or PR (whichever status is recorded first). If a participant received subsequent anti-cancer therapy prior to the date of documented progression or death, progression free survival (PFS) in the participant was censored at the last adequate assessment prior the initiation of the new anti-cancer therapy. Otherwise, if a participant did not have a documented date of progression or death, PFS in the participant was censored at the last adequate assessment.
Time frame: Up to Week 37
Number of Weeks Until Time to Response Assessed With Independent Radiologist
Time to response (TTR) event was defined as achievement of a confirmed CR or PR, as the time from date of randomization until date of first documented evidence of CR or PR (whichever status is recorded first). If a participant received subsequent anti-cancer therapy prior to the date of documented progression or death, progression free survival (PFS) in the participant was censored at the last adequate assessment prior the initiation of the new anti-cancer therapy. Otherwise, if a participant did not have a documented date of progression or death, PFS in the participant was censored at the last adequate assessment. Only 1 participant reached PR therefore estimated time to response cannot be presented. The time to response for this patient is presented as the actual number of weeks to PR.
Time frame: Up to Week 37
Number of Participants With Investigator-Assessed Duration of Response
Duration of response was summarized for participants with a confirmed CR or PR and is defined as the time (in weeks) from the initial response (CR/PR) to first documented disease progression or death due to any cause. If a participant received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS in the participant was censored at the last adequate assessment prior the initiation of the new anti-cancer therapy. Otherwise, if a participant did not have a documented date of progression or death, PFS in the participant was censored at the last adequate assessment.
Time frame: Up to Week 37
Number of Participants With Independent Radiologist Assessed Duration of Response
Duration of response was summarized for participants with a confirmed CR or PR and is defined as the time (in weeks) from the initial response (CR/PR) to first documented disease progression or death due to any cause. If a participant received subsequent anti-cancer therapy prior to the date of documented progression or death, PFS in the participant was censored at the last adequate assessment prior the initiation of the new anti-cancer therapy. Otherwise, if a participant did not have a documented date of progression or death, PFS in the participant was censored at the last adequate assessment.
Time frame: Up to Week 37
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