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Biliary Tract Diseases

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Biliary Tract Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

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.

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.

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.

Trametinib (single tablet)

Trametinib (Multiple tablet)

GSK Clinical Trials

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 .

A Phase IIa Study of the MEK Inhibitor Trametinib Monotherapy in the Treatment of Biliary Tract Cancers

A Phase IIa Study of the MEK Inhibitor GSK1120212 Monotherapy in the Treatment of Gemcitabine Refractory Locally Advanced, Recurrent or Metastatic Biliary Tract Cancers

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.

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).

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

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

Interstitial lung disease marker Surfactant Protein D assessments were carried out at Baseline (Day 1), Week 12, and Week 28

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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 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.

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.

GlaxoSmithKline

SAEs and non-serious AEs are reported for members of the Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.

Participants received GSK1120212 at 2 milligram (mg), either as four tablets of 0.5 mg or one tablet of 2 mg at Day 1. At Day 2 and for the remaining study period, participants received continuous daily dosing of one tablet of 2 mg GSK1120212 once-daily until disease progression or death or until study treatment stopping criteria was met.

GSK1120212 2 mg

Age, Continuous

Sex: Female, Male

Asian - Japanese Heritage

Race/Ethnicity, Customized

GSK Response Center

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Non-CR/Non-PD

Progressive Disease (PD)

Not Evaluable (NE)

Progressive Disease before week 12

Censored before week 12

CR+PR+SD+Non-CR/Non-PD

Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.

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

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

Any AE

Any SAE

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Baseline, n=20

Week 12, n=3

Week 20, n=1

Week 24, n=1

Week 28, n=2

Week 32, n=1

Week 36, n=1

Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. Only those participants with analyzable data at the indicated time point were assessed.

Expression of Interstitial Lung Disease Marker KL-6

Baseline, n=17

Week 12, n=2

Week 28, n=1

Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period. Only those participants with analyzable data at the indicated time point were assessed (represented by n=x).

Expression of Interstitial Lung Disease Marker Surfactant Protein D

Albumin, WPB, Any grade increase, n=20

Albumin, WPB, Increase to grade 3, n=20

Albumin, WPB, Increase to grade 4, n=20

AP, WPB, Any grade increase, n=20

AP, WPB, Increase to grade 3, n=20

AP, WPB, Increase to grade 4, n=20

ALT, WPB, Any grade increase, n=20

ALT, WPB, Increase to grade 3, n=20

ALT, WPB, Increase to grade 4, n=20

AST, WPB, Any grade increase, n=20

AST, WPB, Increase to grade 3, n=20

AST, WPB, Increase to grade 4, n=20

Bilirubin, WPB, Any grade increase, n=20

Bilirubin, WPB, Increase to grade 3, n=20

Bilirubin, WPB, Increase to grade 4, n=20

CK, WPB, Any grade increase, n=2

CK, WPB, Increase to grade 3, n=2

CK, WPB, Increase to grade 4, n=2

Creatinine, WPB, Any grade increase, n=20

Creatinine, WPB, Increase to grade 3, n=20

Creatinine, WPB, Increase to grade 4, n=20

Hypercalcemia, WPB, Any grade increase, n=20

Hypercalcemia, WPB, Increase to grade 3, n=20

Hypercalcemia, WPB, Increase to grade 4, n=20

Hyperglycemia, WPB, Any grade increase, n=20

Hyperglycemia, WPB, Increase to grade 3, n=20

Hyperglycemia, WPB, Increase to grade 4, n=20

Hyperkalemia, WPB, Any grade increase, n=20

Hyperkalemia, WPB, Increase to grade 3, n=20

Hyperkalemia, WPB, Increase to grade 4, n=20

Hypermagnesemia, WPB, Any grade increase, n=20

Hypermagnesemia, WPB, Increase to grade 3, n=20

Hypermagnesemia, WPB, Increase to grade 4, n=20

Hypernatremia, WPB, Any grade increase, n=20

Hypernatremia, WPB, Increase to grade 3, n=20

Hypernatremia, WPB, Increase to grade 4, n=20

Hypocalcemia, WPB, Any grade increase, n=20

Hypocalcemia, WPB, Increase to grade 3, n=20

Hypocalcemia, WPB, Increase to grade 4, n=20

Hypoglycemia, WPB, Any grade increase, n=20

Hypoglycemia, WPB, Increase to grade 3, n=20

Hypoglycemia, WPB, Increase to grade 4, n=20

Hypokalemia, WPB, Any grade increase, n=20

Hypokalemia, WPB, Increase to grade 3, n=20

Hypokalemia, WPB, Increase to grade 4, n=20

Hypomagnesemia, WPB, Any grade increase, n=20

Hypomagnesemia, WPB, Increase to grade 3, n=20

Hypomagnesemia, WPB, Increase to grade 4, n=20

Hyponatremia, WPB, Any grade increase, n=20

Hyponatremia, WPB, Increase to grade 3, n=20

Hyponatremia, WPB, Increase to grade 4, n=20

Phosphate, WPB, Any grade increase, n=20

Phosphate, WPB, Increase to grade 3, n=20

Phosphate, WPB, Increase to grade 4, n=20

Number of Participants With the Indicated Worst-case On-therapy Clinical Chemistry Grade Shifts From Baseline

APTT, WPB, Any grade increase, n=18

APTT, WPB, Increase to grade 3, n=18

APTT, WPB, Increase to grade 4, n=18

PT, WPB, Any grade increase, n=18

PT, WPB, Increase to grade 3, n=18

PT, WPB, Increase to grade 4, n=18

Number of Participants With the Indicated Worst-case On-therapy Coagulation Grade Shifts From Baseline

Hemoglobin, WPB, Any grade increase, n=20

Hemoglobin, WPB, Increase to grade 3, n=20

Hemoglobin, WPB, Increase to grade 4, n=20

Lymphocytes, WPB, Any grade increase, n=20

Lymphocytes, WPB, Increase to grade 3, n=20

Lymphocytes, WPB, Increase to grade 4, n=20

Neutrophils, WPB, Any grade increase, n=20

Neutrophils, WPB, Increase to grade 3, n=20

Neutrophils, WPB, Increase to grade 4, n=20

Platelets, WPB, Any grade increase, n=20

Platelets, WPB, Increase to grade 3, n=20

Platelets, WPB, Increase to grade 4, n=20

Leukocytes, WPB, Any grade increase, n=20

Leukocytes, WPB, Increase to grade 3, n=20

Leukocytes, WPB, Increase to grade 4, n=20

Number of Participants With the Indicated Worst-case On-therapy Hematology Grade Shifts From Baseline

CA 19-9,WPB,DTL,n=20

CA 19-9,WPB,CN/NC,n=20

CA 19-9,WPB,ITH,n=20

Chloride,WPB,DTL,n=20

Chloride,WPB,CN/NC,n=20

Chloride,WPB,ITH,n=20

LDH,WPB,DTL,n=20

LDH,WPB,CN/NC,n=20

LDH,WPB,ITH,n=20

Urea,WPB,DTL,n=20

Urea,WPB,CN/NC,n=20

Urea,WPB,ITH,n=20

Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Clinical Chemistry Measurements With Respect to the Normal Range

PT,WPB,DTL,n=11

PT,WPB,CN/NC,n=11

PT,WPB,ITH,n=11

Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Prothrombin Time Measurements With Respect to the Normal Range

Basophils,WPB,DTL,n=20

Basophils,WPB,CN/NC,n=20

Basophils,WPB,ITH,n=20

Eosinophils,WPB,DTL,n=20

Eosinophils,WPB,CN/NC,n=20

Eosinophils,WPB,ITH,n=20

Monocytes,WPB,DTL,n=20

Monocytes,WPB,CN/NC,n=20

Monocytes,WPB,ITH,n=20

Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Hematology Measurements With Respect to the Normal Range

CEA,WPB,DTL,n=19

CEA,WPB,CN/NC,n=19

CEA,WPB,ITH,n=19

Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Carcinoembryonic Antigen Measurements With Respect to the Normal Range

WPB, Decrease to <=35, n=20

WPB, Change to normal or no change , n=20

WPB, Increase to >=38, n=20

Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Body Temperature

Spots Global Cancer Trial Database for trametinib (multiple tablet)