A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the efficacy and safety of ramucirumab or merestinib or placebo plus cisplatin and gemcitabine in participants with advanced or metastatic biliary tract cancer.

Official Title
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Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo Plus Cisplatin and Gemcitabine as First-Line Treatment in Patients With Advanced or Metastatic Biliary Tract Cancer

Conditions
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Biliary Tract Cancer, Metastatic Cancer, Advanced Cancer

Intervention / Treatment
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* Drug: Ramucirumab
* Drug: Merestinib
* Drug: Cisplatin
* Drug: Gemcitabine
* Drug: Placebo Oral
* Drug: Placebo IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have an Eastern Cooperative Oncology Group performance status of 0 or 1. Have a histologically or cytologically confirmed diagnosis of non-resectable, recurrent, or metastatic biliary tract adenocarcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or Ampulla of Vater) . Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST). Have adequate biliary drainage. Have adequate organ function. Males and females are sterile, postmenopausal, or compliant with a highly effective contraceptive method. Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose. Are willing to provide blood/serum/plasma and tumor tissue samples for research purposes. Submission of blood/serum/plasma and tumor tissue samples is mandatory for participation in this study, unless restricted per local regulations. Exclusion Criteria: Previous systemic therapy for locally advanced or metastatic disease is not allowed. Have a history of or have current hepatic encephalopathy of any grade, or ascites of Grade >1, or cirrhosis with Child-Pugh Stage B or higher. Have ongoing or recent (≤6 months) hepatorenal syndrome. Have had a major surgical procedure or significant traumatic injury including nonhealing wound, peptic ulcer, or bone fracture ≤28 days prior to randomization. Anticipate having a major surgical procedure during the course of the study. Has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression. Within 6 months prior to randomization, have had any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack. Have an uncontrolled arterial hypertension with systolic blood pressure ≥150 or diastolic blood pressure ≥90 millimeters of mercury (mm Hg) despite standard medical management. Have a previous malignancy within 5 years of study entry or a concurrent malignancy. Have a history of gastrointestinal perforation and/or fistulae within 6 months prior to randomization. Have a known allergy or hypersensitivity reaction to any of the treatment components. Have a history of uncontrolled hereditary or acquired thrombotic disorder. Have uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain. Have mixed hepatocellular biliary tract cancer histology. Have a corrected QT interval >470 milliseconds as calculated by the Fridericia equation.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine<br>Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;Drug: Cisplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;|
| Placebo Comparator: Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine<br>Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). | Drug: Cisplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;Drug: Placebo IV<br>* Administered IV<br>|
| Experimental: 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine<br>Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). | Drug: Merestinib<br>* Administered orally<br>* Other names: LY2801653;Drug: Cisplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;|
| Placebo Comparator: Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine<br>Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). | Drug: Cisplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;Drug: Placebo Oral<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS time was measured from the date of randomization until the first radiographic documentation of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. | Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS defined as the time from from randomization to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive. | Randomization to Date of Death from Any Cause (Up To 48 Months) | 
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | ORR was the number of participants who achieve a best overall response of CR or PR divided by the total number of participants randomized to the corresponding treatment arm as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Randomization to Disease Progression (Up To 30 Months) | 
| Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | Disease Control Rate (DCR) was the number of participants who achieve a best overall response of CR, PR, or SD divided by the total number of participants randomized to the corresponding treatment arm as per RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. | Randomization to Disease Progression (Up To 30 Months) | 
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D). | C1 D8, C2 D1, C3 D1, C4 D1,C5 D1,C7 D1, C9 D1 and C13 D1: Within 3 days Prior to Infusion(PTI) | 
| PK: Plasma Concentration of Merestinib | PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced. | C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning | 
| Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group. | Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months) | 
| Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180.Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as Improved if they had positive change from baseline, Worsened if they had negative change from baseline, and Stable otherwise. | Baseline, Follow Up (Up To 48 Months) | 
| Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | EQ-5D-5L is a 2-part questionnaire that assesses general health status for 'today'. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using country-specific algorithms, with scores ranging from less than 0 (where zero is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). Index values were calculated using the US algorithm (-0.109 to 1). A higher score indicates better health state. | Baseline, Follow Up (Up To 48 Months) | 
| Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score | EQ-5D-5L is a 2-part questionnaire that assesses general health status 'today'. The second part is assessed using a VAS on which the patient rates their perceived health state, ranging from 0 millimeter (the worst health you can imagine) to 100 millimeter (the best health you can imagine). | Baseline, Follow Up (Up To 48 Months) |