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

Study Overview
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Brief Summary
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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 .

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

Conditions
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Cancer

Intervention / Treatment
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* Drug: Trametinib (single tablet)
* Drug: Trametinib (Multiple tablet)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 1.1. 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trametinib (single tablet)<br>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. | Drug: Trametinib (single tablet)<br>* The drug substance is blended with inert<br>|
| Experimental: Trametinib PK study (multiple tablet)<br>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. | Drug: Trametinib (Multiple tablet)<br>* The drug substance is blended with inert<br>|
| Experimental: Trametinib PK study (single tablet)<br>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. | Drug: Trametinib (single tablet)<br>* The drug substance is blended with inert<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | Up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | 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 | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Up to Week 37 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, second line monotherapy, GSK1120212 (trametinib), MEK inhibitor, locally advanced or metastatic biliary tract cancers