MEK162 in Combination With Capecitabine in Advanced Biliary Tract Cancer

Study Overview
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Brief Summary
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This study is to test the efficacy of MEK162 plus capecitabine in gemcitabine-pretreated advanced biliary tract cancer, and to explore the predictive biomarkers for future large-scale clinical trials using this combination.

Detailed Description
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Biliary tract cancer is one of rare cancers, which is relatively more frequent in east Asia. The frequency of KRAS mutation and/or BRAF mutation is reported at 40 to 60%. The prognosis is still very poor, with only limited treatment options. The most commonly used 1st-line chemotherapy is gemcitabine+cisplatin combination. In gemcitabine-pretreated advanced biliary tract cancer, fluoropyrimidine-based chemotherapy is used. However, the overall survival with these cytotoxic chemotherapies is still only about 8-10 months, calling for urgent development of efficient treatment options. Recently, mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibition was shown to have antitumor effects in KRAS mutated biliary tract cancers in preclinical model. In phase II study of MEK inhibitor (selumetinib) in metastatic biliary tract cancers, selumetinib displayed interesting activity and acceptable tolerability. MEK162 is an oral, highly selective MEK inhibitor. It was shown to promote apoptosis and in vivo antitumor activity against human biliary tract cancer cell lines. So far, there has been no study to test the MEK inhibitor mainly in gemcitabine-pretreated advanced biliary tract cancer, especially in combination of capecitabine chemotherapy. The aim of this study is to test the efficacy of MEK162 plus capecitabine in gemcitabine-pretreated advanced biliary tract cancer, and to explore the predictive biomarkers for future large-scale clinical trials using this combination.

Official Title
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Phase Ib Study of MEK162 in Combination With Capecitabine in Gemcitabine-pretreated Advanced Biliary Tract Cancer

Conditions
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Biliary Tract Cancer

Intervention / Treatment
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* Drug: MEK162+capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically / cytologically verified, non-resectable, recurrent, or metastatic biliary tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma Patients who have previously treated with gemcitabine-based chemotherapy (Prior treatment regimen up to 2 is allowed) Patients must have measurable or evaluable disease by RECIST 1.1 Eastern Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1 Age ≥ 20 years Adequate bone marrow function defined as: Hb ≥ 8 g/dl, absolute neutrophil count (ANC) ≥ 1500/microliter (mcL), Platelets ≥ 100 x10^3/mcL Adequate renal function defined as serum creatinine < 1.6 mg/dl and/or measured creatinine clearance from 24-hour urine collection of ≥ 60 ml/min Adequate hepatic function defined as total bilirubin ≤ 2 mg/dl, alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) Patients with biliary obstruction can join if bilirubin corrects to required limit after adequate biliary drainage Women of childbearing potential must have a negative pregnancy test within 7 days prior to study treatment Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Evidence of another active cancer that may influence patient outcome, except for nonmelanoma skin carcinoma, melanoma in-situ, in-situ carcinoma of the cervix curatively treated, treated superficial bladder cancer, and adenocarcinoma of the prostate that has been surgically treated with a post-treatment prostate surface antigen (PSA) that is non-detectable Known brain metastases or primary central nervous system tumors with seizures that are not well controlled with standard medical therapy Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements Known HIV positive patient Significant cardiovascular disease including congestive heart failure (New York Heart Association Class II or higher) or active angina pectoris Uncontrolled diabetes mellitus History of a myocardial infarction within 6 months History of a stroke or transient ischemic attack within 6 months Clinically significant peripheral vascular disease Major surgical procedure within 4 weeks Uncontrolled infection Known or suspected allergy to capecitabine Pregnant (positive pregnancy test) Breast-feeding should be discontinued if a nursing mother is to be treated on clinical trial Any condition that impairs patient's ability to swallow whole pills Malabsorption problem that may limit or inhibit the absorption of MEK162 History of any organ or bone marrow transplant

Ages Eligible for Study
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Minimum Age: 20 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 part<br>to assess the maximal tolerated dose (MTD) of MEK162+Capecitabine combination | Drug: MEK162+capecitabine<br>* In phase 1 part: capecitabine(mg/m2) will be given twice a day, 2 week on/1week off Q 3weeks + MEK162 twice a day, continuously, starting at 1000mg/m2 and 30mg/m2 respectively. Expansion part will be treated with the dose found at phase 1 part.<br>* Other names: MEK162, xeloda;|
| Experimental: Expansion part<br>to assess the efficacy (PFS) of MEK162+Capecitabine combination | Drug: MEK162+capecitabine<br>* In phase 1 part: capecitabine(mg/m2) will be given twice a day, 2 week on/1week off Q 3weeks + MEK162 twice a day, continuously, starting at 1000mg/m2 and 30mg/m2 respectively. Expansion part will be treated with the dose found at phase 1 part.<br>* Other names: MEK162, xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | MTD in all treated population (Phase 1 part) | 6 months | 
| Progression-free survival (PFS) | PFS in all treated population (Expansion part) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicity (DLT) | DLT in all treated population, according to NCI-CTCAE v 4.0 (Phase 1 part) | 6 months | 
| Recommended Phase 2 Dose (RP2D) | RP2D to be used at Expansion part (Phase 1 part) | 6 months | 
| Response rate | Response rate in all treated patients (Expansion part) | 6 months | 
| Overall survival (OS) | OS in all treated patients | 1 year |