Biliary Tract Cancer, Metastatic Cancer, Advanced Cancer
Conditions
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.
Interventions
DRUGRamucirumab
Administered IV
DRUGMerestinib
Administered orally
DRUGCisplatin
Administered IV
DRUGGemcitabine
Administered IV
DRUGPlacebo Oral
Administered orally
DRUGPlacebo IV
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 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) | 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 | 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 | 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. |
| Overall Survival (OS) | 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. |
| Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | 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 | 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 | 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). |
| Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | 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. |
Countries
Argentina, Australia, Austria, Belgium, Czechia, Denmark, France, Germany, Hungary, Mexico, Russia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
In the Participant Flow, participants who completed were those who died due to any cause or were alive and on study at conclusion but off treatment.
Participants by arm
| Arm | Count |
|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received 8 mg/kg 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 ramucirumab therapy). | 106 |
| 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). | 52 |
| 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). | 102 |
| 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). | 49 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 3 | 6 | 3 |
| Overall Study | On Study Treatment at Study Conclusion | 1 | 1 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Total |
|---|---|---|---|---|---|
| Age, Continuous | 63.49 years STANDARD_DEVIATION 9.76 | 57.06 years STANDARD_DEVIATION 11.67 | 60.95 years STANDARD_DEVIATION 9.14 | 62.00 years STANDARD_DEVIATION 9.14 | 61.33 years STANDARD_DEVIATION 10.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 106 Participants | 52 Participants | 102 Participants | 49 Participants | 309 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 11 Participants | 26 Participants | 9 Participants | 66 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 5 Participants | 4 Participants | 1 Participants | 17 Participants |
| Race (NIH/OMB) White | 78 Participants | 35 Participants | 70 Participants | 38 Participants | 221 Participants |
| Region of Enrollment Argentina | 11 Participants | 3 Participants | 8 Participants | 3 Participants | 25 Participants |
| Region of Enrollment Australia | 6 Participants | 2 Participants | 2 Participants | 4 Participants | 14 Participants |
| Region of Enrollment Austria | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 6 Participants |
| Region of Enrollment Belgium | 6 Participants | 1 Participants | 3 Participants | 4 Participants | 14 Participants |
| Region of Enrollment Czechia | 2 Participants | 2 Participants | 5 Participants | 2 Participants | 11 Participants |
| Region of Enrollment Denmark | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 6 Participants |
| Region of Enrollment France | 8 Participants | 5 Participants | 5 Participants | 2 Participants | 20 Participants |
| Region of Enrollment Germany | 3 Participants | 1 Participants | 8 Participants | 5 Participants | 17 Participants |
| Region of Enrollment Hungary | 5 Participants | 7 Participants | 4 Participants | 1 Participants | 17 Participants |
| Region of Enrollment Mexico | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 7 Participants |
| Region of Enrollment Russia | 9 Participants | 2 Participants | 4 Participants | 6 Participants | 21 Participants |
| Region of Enrollment South Korea | 8 Participants | 6 Participants | 12 Participants | 4 Participants | 30 Participants |
| Region of Enrollment Spain | 8 Participants | 3 Participants | 10 Participants | 1 Participants | 22 Participants |
| Region of Enrollment Sweden | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Taiwan | 9 Participants | 5 Participants | 13 Participants | 4 Participants | 31 Participants |
| Region of Enrollment Turkey | 6 Participants | 7 Participants | 7 Participants | 3 Participants | 23 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 2 Participants | 5 Participants | 3 Participants | 14 Participants |
| Region of Enrollment United States | 12 Participants | 3 Participants | 6 Participants | 4 Participants | 25 Participants |
| Sex: Female, Male All randomized participants Female | 60 Participants | 26 Participants | 54 Participants | 22 Participants | 162 Participants |
| Sex: Female, Male All randomized participants Male | 46 Participants | 26 Participants | 48 Participants | 27 Participants | 147 Participants |
| Sex: Female, Male All randomized participants who received at least 1 dose of study drug Female | 59 Participants | 26 Participants | 54 Participants | 21 Participants | 160 Participants |
| Sex: Female, Male All randomized participants who received at least 1 dose of study drug Male | 45 Participants | 26 Participants | 48 Participants | 27 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 84 / 104 | 34 / 52 | 71 / 102 | 38 / 48 |
| other Total, other adverse events | 102 / 104 | 49 / 52 | 100 / 102 | 48 / 48 |
| serious Total, serious adverse events | 53 / 104 | 25 / 52 | 56 / 102 | 23 / 48 |
Outcome results
Primary
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.
Time frame: Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)
Population: All randomized participants. Censored participants: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 29; 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 34; Pooled Placebo = 25. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Progression Free Survival (PFS) | 6.47 Months |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Progression Free Survival (PFS) | 6.97 Months |
| Pooled Placebo | Progression Free Survival (PFS) | 6.64 Months |
p-value: 0.482180% CI: [0.904, 1.395]Log Rank
p-value: 0.641780% CI: [0.734, 1.153]Log Rank
Secondary
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.
Time frame: Baseline, Follow Up (Up To 48 Months)
Population: All randomized participants who received at least 1 dose of study drug with baseline and one post-baseline FACT-Hep Questionnaire.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | SWB | -0.26 Units on a Scale | Standard Error 0.36 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | HCS | -3.62 Units on a Scale | Standard Error 0.63 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FWB | -2.40 Units on a Scale | Standard Error 0.44 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | PWB | -2.75 Units on a Scale | Standard Error 0.43 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | TOI | -8.68 Units on a Scale | Standard Error 1.31 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FACT-Hep | -1.11 Units on a Scale | Standard Error 0.37 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | EWB | 0.23 Units on a Scale | Standard Error 0.31 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FWB | -1.34 Units on a Scale | Standard Error 0.44 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | PWB | -2.88 Units on a Scale | Standard Error 0.43 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | SWB | 0.22 Units on a Scale | Standard Error 0.36 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | EWB | 0.64 Units on a Scale | Standard Error 0.32 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | HCS | -2.32 Units on a Scale | Standard Error 0.64 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FACT-Hep | -0.74 Units on a Scale | Standard Error 0.37 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | TOI | -6.43 Units on a Scale | Standard Error 1.32 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | HCS | -0.68 Units on a Scale | Standard Error 0.63 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | SWB | 0.56 Units on a Scale | Standard Error 0.36 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | TOI | -3.01 Units on a Scale | Standard Error 1.3 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FACT-Hep | -0.09 Units on a Scale | Standard Error 0.37 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | FWB | -0.75 Units on a Scale | Standard Error 0.44 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | EWB | 0.93 Units on a Scale | Standard Error 0.31 |
| Pooled Placebo | Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) | PWB | -1.65 Units on a Scale | Standard Error 0.42 |
Comparison: PWBp-value: 0.06995% CI: [-2.28, 0.09]MMRM Model
Comparison: PWBp-value: 0.04295% CI: [-2.42, -0.04]MMRM Model
Comparison: SWBp-value: 0.11295% CI: [-1.83, 0.19]MMRM Model
Comparison: SWBp-value: 0.50595% CI: [-1.35, 0.67]MMRM Model
Comparison: EWBp-value: 0.11695% CI: [-1.56, 0.17]MMRM Model
Comparison: EWBp-value: 0.52195% CI: [-1.16, 0.59]MMRM Model
Comparison: FWBp-value: 0.00895% CI: [-2.87, -0.44]MMRM Model
Comparison: FWBp-value: 0.33595% CI: [-1.82, 0.62]MMRM Model
Comparison: HCSp-value: 0.00195% CI: [-4.69, -1.18]MMRM Model
Comparison: HCSp-value: 0.06895% CI: [-3.4, 0.12]MMRM Model
Comparison: FACT-Hepp-value: 0.05195% CI: [-2.04, 0]MMRM Model
Comparison: FACT-Hepp-value: 0.21295% CI: [-1.68, 0.38]MMRM Model
Comparison: TOIp-value: 0.00295% CI: [-9.3, -2.04]MMRM Model
Comparison: TOIp-value: 0.06695% CI: [-7.07, 0.22]MMRM Model
Secondary
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).
Time frame: Baseline, Follow Up (Up To 48 Months)
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score | 66.44 millimeter (mm) | Standard Deviation 22.8 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score | 66.57 millimeter (mm) | Standard Deviation 21.73 |
| Pooled Placebo | Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score | 69.08 millimeter (mm) | Standard Deviation 20.03 |
Secondary
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.
Time frame: Baseline, Follow Up (Up To 48 Months)
Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | 0.61 Units on a Scale | Standard Deviation 0.31 |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | 0.63 Units on a Scale | Standard Deviation 0.29 |
| Pooled Placebo | Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score | 0.66 Units on a Scale | Standard Deviation 0.27 |
Secondary
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.
Time frame: Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months)
Population: All randomized participants who received at least 1 dose of study drug with both baseline and at least one post baseline ADA assessments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | 3 Participants |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies | 0 Participants |
Secondary
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.
Time frame: Randomization to Date of Death from Any Cause (Up To 48 Months)
Population: All randomized participants. Censored participants: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 29; 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 34; Pooled Placebo = 25. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Overall Survival (OS) | 10.45 Months |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Overall Survival (OS) | 14.03 Months |
| Pooled Placebo | Overall Survival (OS) | 13.04 Months |
p-value: 0.08795% CI: [0.959, 1.862]Log Rank
p-value: 0.759995% CI: [0.669, 1.342]Log Rank
Secondary
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.
Time frame: Randomization to Disease Progression (Up To 30 Months)
Population: All randomized participants. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 31.1 Percentage of participants |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 19.6 Percentage of participants |
| Pooled Placebo | Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) | 32.7 Percentage of participants |
p-value: 0.87895% CI: [0.6, 1.9]Exact Cochran-Mantel-Haenszel
p-value: 0.02395% CI: [0.2, 0.9]Exact Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Randomization to Disease Progression (Up To 30 Months)
Population: All randomized participants. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | 81.1 Percentage of participants |
| 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | 83.3 Percentage of participants |
| Pooled Placebo | Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) | 78.2 Percentage of participants |
p-value: 0.6895% CI: [0.6, 2.4]Exact Cochran-Mantel-Haenszel
p-value: 0.49995% CI: [0.6, 2.6]Exact Cochran-Mantel-Haenszel
Secondary
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab
PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).
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)
Population: All participants who received at least one dose of study drug and had evaluable PK data. As per protocol, Cmin of merestinib was not measured.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 1 Day 8 (Week 1) | 46.2 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 32 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 2 Day 1 (Week 3) | 38.1 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 42 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 3 Day 1 (Week 6) | 54.1 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 43 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 4 Day 1 (Week 9) | 77.3 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 50 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 5 Day 1 (Week 12) | 82.9 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 35 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 7 Day 1 (Week 18) | 85.6 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 39 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 9 Day 1 (Week 24) | 82.7 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 35 |
| 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Cycle 13 Day 1 (Week 36) | 97.7 Microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 23 |
Secondary
PK: Plasma Concentration of Merestinib
PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.
Time frame: C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning
Population: Zero participants were analyzed as no data collected for summary analysis.