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

• ClinicalTrials.gov Identifier: NCT02711553
• Recruitment Status: Active, not recruiting
• First Posted: March 17, 2016
• Results First Posted: February 26, 2021
• Last Update Posted: October 20, 2022
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: March 14, 2016
• First Posted Date: March 17, 2016
• Results First Submitted Date: February 8, 2021
• Results First Posted Date: February 26, 2021
• Last Update Posted Date: October 20, 2022
• Actual Study Start Date: May 19, 2016
• Actual Primary Completion Date: February 16, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2021)

Progression Free Survival (PFS) [ Time Frame: Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months) ]

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.

• Original Primary Outcome Measures (submitted: March 14, 2016): Progression Free Survival (PFS) [ Time Frame: Baseline to Progressive Disease or Death from Any Cause (Approximately 30 Months) ]

Current Secondary Outcome Measures (submitted: October 18, 2022)

• Overall Survival (OS) [ Time Frame: Randomization to Date of Death from Any Cause (Up To 48 Months) ]
  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.
• Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Randomization to Disease Progression (Up To 30 Months) ]
  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.
• Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [ Time Frame: Randomization to Disease Progression (Up To 30 Months) ]
  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.
• Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: 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 was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).
• PK: Plasma Concentration of Merestinib [ Time Frame: C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning ]
  PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.
• Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies [ Time Frame: Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months) ]
  Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group.
• Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) [ Time Frame: Baseline, Follow Up (Up To 48 Months) ]
  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.
• Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score [ Time Frame: Baseline, Follow Up (Up To 48 Months) ]
  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.
• Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score [ Time Frame: Baseline, Follow Up (Up To 48 Months) ]
  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).

Original Secondary Outcome Measures (submitted: March 14, 2016)

• Overall Survival (OS) [ Time Frame: Baseline to Date of Death from Any Cause (Approximately 48 Months) ]
• Proportion of Participants with a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) [ Time Frame: Baseline to Disease Progression (Approximately 30 Months) ]
• Proportion of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) [ Time Frame: Baseline to Disease Progression (Approximately 30 Months) ]
• Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Predose Cycle 1 Day 8 through Cycle 8 Day 8 (21 Day Cycles) ]
• PK: Plasma Concentration of Merestinib [ Time Frame: Cycle 1 through Cycle 8 (21 Day Cycles) ]
• Number of Participants with Treatment-Emergent Anti-Ramucirumab Antibodies [ Time Frame: Predose Cycle 1 Day 1 through Follow Up (Approximately 48 Months) ]
• Change from Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) [ Time Frame: Baseline, Follow Up (Approximately 48 Months) ]
• Change from Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) [ Time Frame: Baseline, Follow Up (Approximately 48 Months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Biliary Tract Cancer
• Metastatic Cancer
• Advanced Cancer

Intervention

• Drug: Ramucirumab
  Administered IV
  Other Name: LY3009806
• Drug: Merestinib
  Administered orally
  Other Name: LY2801653
• Drug: Cisplatin
  Administered IV
• Drug: Gemcitabine
  Administered IV
  Other Name: LY188011
• Drug: Placebo Oral
  Administered orally
• Drug: Placebo IV
  Administered IV

Study Arms

• Experimental: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
  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).
  Interventions:

  • Drug: Ramucirumab
  • Drug: Cisplatin
  • Drug: Gemcitabine
• Placebo Comparator: Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
  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).
  Interventions:

  • Drug: Cisplatin
  • Drug: Gemcitabine
  • Drug: Placebo IV
• Experimental: 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
  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).
  Interventions:

  • Drug: Merestinib
  • Drug: Cisplatin
  • Drug: Gemcitabine
• Placebo Comparator: Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine
  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).
  Interventions:

  • Drug: Cisplatin
  • Drug: Gemcitabine
  • Drug: Placebo Oral

• Publications *: Valle JW, Vogel A, Denlinger CS, He AR, Bai LY, Orlova R, Van Cutsem E, Adeva J, Chen LT, Obermannova R, Ettrich TJ, Chen JS, Wasan H, Girvan AC, Zhang W, Liu J, Tang C, Ebert PJ, Aggarwal A, McNeely SC, Moser BA, Oliveira JM, Carlesi R, Walgren RA, Oh DY. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1468-1482. doi: 10.1016/S1470-2045(21)00409-5. Erratum In: Lancet Oncol. 2021 Nov;22(11):e472.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 8, 2021): 309
• Original Estimated Enrollment (submitted: March 14, 2016): 300
• Estimated Study Completion Date: December 31, 2023
• Actual Primary Completion Date: February 16, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Czechia, Denmark, France, Germany, Hungary, Japan, Korea, Republic of, Mexico, Russian Federation, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic, Italy

Administrative Information

• NCT Number: NCT02711553
• Other Study ID Numbers: 16329; I3O-MC-JSBF ( Other Identifier: Eli Lilly and Company ); 2015-004699-31 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and european union (EU), whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: October 15, 2022