A Safety and Efficacy Study of XERMELO® + First-line Chemotherapy in Patients With Advanced Biliary Tract Cancer

Study Overview
=================
Brief Summary
-----------------
A Phase 2, multicenter, open-label, 2-stage study to assess the safety, tolerability, and efficacy of XERMELO in combination with first-line (1L) therapy (cisplatin [cis] plus gemcitabine [gem])

Detailed Description
-----------------
A Phase 2, multicenter, open-label, 2-stage study to assess the safety, tolerability, and efficacy of XERMELO in combination with first-line (1L) therapy cis plus gem in patients with unresectable, locally advanced, recurrent or metastatic biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer), who are naïve to tumor-directed therapy in the locally advanced or metastatic setting, and for which treatment with 1L therapy (defined as a combination of cis plus gem) is planned.

Official Title
-----------------
A Phase 2, Multicenter, Open-label, Safety and Efficacy Study of XERMELO® (Telotristat Ethyl) Plus First-line Chemotherapy in Patients With Locally Advanced, Unresectable, Recurrent or Metastatic Biliary Tract Cancer (BTC)

Conditions
-----------------
Biliary Tract Cancer (BTC)

Intervention / Treatment
-----------------
* Drug: telotristat ethyl


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female adults, ≥18 years of age. Patients of childbearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose of XERMELO Histopathologically or cytologically-confirmed, unresectable, locally advanced, recurrent, or metastatic biliary tract cancer (BTC) Naïve to tumor-directed therapy in locally advanced, unresectable, or metastatic setting Measurable disease Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Plans to initiate treatment with 1L therapy (cisplatin plus gemcitabine) Ability to provide written informed consent prior to participation in any study-related procedure Exclusion Criteria: Prior exposure to XERMELO, telotristat ethyl, telotristat etiprate, LX1032, or LX1606 Primary tumor site in the ampulla of Vater Treatment with photodynamic therapy for localized disease or to relieve biliary obstruction in the presence of metastatic disease within the past 30 days Hematology laboratory values of: a. Absolute neutrophil count (ANC) ≤1,500 cells/mm^3; or b. Platelets ≤100,000 cells/mm^3; or c. Hemoglobin (Hgb) ≤9 g/dL; or d. White blood count (WBC) ≤3,000 cells/mm^3 Hepatic laboratory values of aspartate aminotransferase (AST) or alanine aminotransferase (ALT): a. >5 x upper limit of normal (ULN) if patient has documented history of hepatic metastases; or b. >2.5 x ULN if no liver metastases are present Serum albumin <2.8 g/dL Total bilirubin >1.5 x ULN or >1.5 mg/dL Prothrombin time (PT) or international normalized ratio (INR) >1.5 x ULN Serum creatinine or serum urea >1.5 x ULN Estimated glomerular filtration rate (eGFR) <50 mL/min Positive pregnancy test, pregnant, or breastfeeding Any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study Any clinically significant and/or uncontrolled cardiac-related abnormality that would compromise patient safety or the outcome of the study Myocardial infarction within the past 6 months Active bleeding diathesis Life expectancy ≤3 months Current complaints of persistent constipation or history of chronic constipation, bowel obstruction or fecaloma within the past 6 months Receiving chronic treatment with corticosteroids ≥5 mg of prednisone per day (or equivalent) or other immunosuppressive agent(s) History and/or uncontrolled hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV Ab), or human immunodeficiency virus (HIV)-1 or HIV-2 History of substance or alcohol abuse within the past 2 years History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption History of malignancy or active treatment for malignancy within 5 years Receipt of live, attenuated vaccine or close contact with someone who has received a live, attenuated vaccine within the past 1 month Receipt of any investigational agent or study treatment (ie, any treatment or therapy not approved by the FDA for the treatment of BTC) within the past 30 days Receipt of any protein or antibody-based therapeutic agents within the past 3 months Treatment with any tumor-directed therapy within the past 6 months with curative intent Existence of any surgical or medical condition that, in the judgment of the Investigator, might compromise patient safety or the outcome of the study Presence of any clinically significant findings (relative to the patient population) during review of medical history or upon physical exam that, in the Investigator's or Medical Monitor's opinion, would compromise patient safety or the outcome of the study Evidence of brain metastases Unable or unwilling to communicate or cooperate with the Investigator for any reason Employee of Sponsor or clinical site, or relative of any member of a clinical site's staff

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Xermelo 250mg plus first line therapy for a week, then Xermelo 500mg<br>Xermelo 250 milligram (mg) plus first line therapy for a week, then Xermelo 500mg plus first line therapy for the duration of the study | Drug: telotristat ethyl<br>* XERMELO (telotristat ethyl) tablets administered as 250 mg (1 x 250-mg tablet) three times a day plus first line therapy for 7 days, then XERMELO (telotristat ethyl) tablets administered as 500 mg (2 x 250-mg tablets) three times a day plus first line therapy for the duration of the study<br>* Other names: telotristat ethyl + (cisplatin [cis] plus gemcitabine [gem]);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression-free Survival (PFS) as Evaluated by Central Radiologist's Assessment | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, or similar definition as accurate and appropriate. | Month 6 | 
| Project Overall Survival Rate at Month 6 | Overall Survival (OS) was defined as the time from the frist dose of study treatment until the date of death due to any cause. Duration of Overall Survival (OS) in days is defined as (Date of event/censoring- date of First dose +1). Use Kaplan Meier method to project survival rate at month 6. | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) was defined as the time from first dose of study treatment until the date of death due to any cause. | First dose of study treatment until the date of death due to any cause, whichever came first, a median of approximately 17.67 months | 
| Project Overall Survival Rate at Month 12 | Overall Survival (OS) was defined as the time from the first dose of study treatment until the date of death due to any cause. Duration of Overall Survival (OS) in days is defined as (Date of event/censoring - date of first dose +1). Use Kaplan Meier method to project survival rate at month 12. | 12 Months | 
| Median Progression Free Survival | Scheduled disease assessment at Cycle 19 Day 1 was used to determine PFS response rate at Month 12. | Month 12 | 
| Disease Control Rate (DCR), Central Radiologist's Assessment | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.. | Month 6 | 
| Disease Control Rate (DCR), Central Radiologist's Assessment | Disease control rate (DCR) was defined as the proportion of patients with best overall response of SD longer than 6 weeks from first dosing, confirmed PR, or confirmed CR. | Month 12 | 
| Disease Control Rate (DCR), Central Radiologist's Assessment | Disease control rate (DCR) was defined as the proportion of patients with best overall response of SD longer than 6 weeks from first dosing, confirmed PR, or confirmed CR. | End of Study up to 24 months | 
| Overall (Objective) Response Rate (ORR), Central Radiologist's Assessment | Overall response rate (ORR) was defined as the proportion of patients with best overall response of confirmed PR or confirmed CR. The best overall response was the best overall response recorded from the start of study treatment until the EOS considering any requirement for confirmation. (CR) + partial response (PR) at Months 6 | Month 6 | 
| Overall (Objective) Response Rate (ORR), Central Radiologist's Assessment | Overall response rate (ORR) was defined as the proportion of patients (Number of Responders) with best overall response of confirmed PR or confirmed CR. The best overall response was the best overall response recorded from the start of study treatment until Month 12. | Month 12 | 
| Overall (Objective) Response Rate, Central Radiologist's Assessment | Overall response rate (ORR) was defined as the proportion of patients with best overall response of confirmed PR or confirmed CR. The best overall response was the best overall response recorded from the start of study treatment until the EOS considering any requirement for confirmation. | End of Study as defined up to 24 months | 
| Summary of Duration of Progression Free Survival, Local Radiologist's Assessment | Summary of Duration of Median Progression Free Survival, Local Radiologist's Assessment. Patient progression was defined from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 7 months. | up to 7 months | 
| Progression Free Survival, Local Radiologist's Assessment | Summary of Median Progression Free Survival, Local Radiologist's Assessment. Defined as the time from first dose of study treatment until the first date of either disease progression or death due to any cause. Scheduled disease assessment at Cycle 19 Day 1 was used to determine PFS response rate at Month 12. | Month 12 | 
| Progression Free Survival, Local Radiologist's Assessment | Summary of Median Progression Free Survival, Local Radiologist's Assessment, End of Study | End of Study as defined up to 24 months | 
| Overall (Objective) Response Rate, Local Read | Overall response rate (ORR) was defined as the proportion of patients with best overall response of confirmed PR or confirmed CR. The best overall response was the best overall response recorded from the start of study treatment at Month 6. | 6 Months | 
| Overall (Objective) Response Rate, Local Reader's Assessment | Overall response rate (ORR) was defined as the proportion of patients with best overall response of confirmed PR or confirmed CR. The best overall response was the best overall response recorded from the start of study treatment at Month 12. | 12 Months | 
| Overall (Objective) Response Rate (ORR), Local Reader's Assessment | Overall response rate (ORR) was defined as the proportion of patients with best overall response of confirmed PR or confirmed CR. The best overall response was the best overall response recorded from the start of study treatment until the EOS considering any requirement for confirmation. | End of Study as defined up to 24 months | 
| Disease Control Rate (DCR), Local Reviewer | Disease control rate (DCR) was defined as the proportion of patients with best overall response of SD longer than 6 weeks from first dosing, confirmed PR, or confirmed CR. | Month 12 as defined by 1 year | 
| Disease Control Rate (DCR), Local Reviewer | Disease control rate (DCR), Local Reviewer, 6 Months | Month 6 | 
| Disease Control Rate End of Study, Local Reviewer | Disease control rate (DCR) was defined as the proportion of patients with best overall response of SD longer than 6 weeks from first dosing, confirmed PR, or confirmed CR. | End of Study as defined up to 24 months | 
| Mean Change From Baseline in Plasma 5-hydroxyindoleacetic Acid (5-HIAA) | Mean change from Baseline to Month 6 plasma level 5-hydroxyindoleacetic acid (5-HIAA) | Month 6 | 
| Mean Change From Baseline in Plasma 5-hydroxyindoleacetic Acid (5-HIAA) | Mean change from Baseline to Month 12 in plasma level 5-hydroxyindoleacetic Acid (5-HIAA) | Month 12 | 
| Mean Change From Baseline in Plasma 5-hydroxyindoleacetic Acid (5-HIAA) | Mean change from Baseline to End of Study in plasma 5-hydroxyindoleacetic acid (5-HIAA) | End of Study as defined up to 24 months | 
| Change From Baseline in Carbohydrate Antigen 19-9 (CA 19-9) | Mean change from Baseline to month 6 in plasma carbohydrate antigen 19-9 (CA 19-9) | Month 6 | 
| Change From Baseline in Carbohydrate Antigen 19-9 (CA 19-9) | Mean change from Baseline to Month 12 in plasma carbohydrate antigen 19-9 (CA 19-9) | Month 12 | 
| Change From Baseline in Plasma Carbohydrate Antigen 19-9 (CA 19-9) | Mean change from Baseline to End of Study in plasma carbohydrate antigen 19-9 (CA 19-9) | End of Study as defined up to 24 months | 
| Weight Change From Baseline | Mean change in weight at Month 6 from baseline measurement | Month 6 | 
| Weight Change From Baseline | Mean change in weight at Month 12 from baseline measurement | Month 12 | 
| Weight Change From Baseline | Mean change in weight from baseline to End of Study | End of Study as defined up to 24 months | 
| Change From Baseline in Serum Albumin | Mean change from Baseline to Month 6 serum albumin levels | Month 6 | 
| Change From Baseline in Serum Albumin | Mean change from Baseline to Month 12 serum albumin levels | Month 12 | 
| Change From Baseline in Serum Albumin | Mean change from Baseline to End of Study serum albumin levels | End of Study as defined up to 24 months |