Hepatocellular Carcinoma
Conditions
Keywords
Hepatocellular carcinoma (HCC), recombinant human immunoglobulin G, subclass 1 (IgG1) monoclonal antibody (MAb), Hepatocellular Carcinoma (HCC) following First-Line Therapy With Sorafenib
Brief summary
This is a Phase 3 multicenter, randomized study evaluating the safety and efficacy of ramucirumab DP plus BSC as a double-blind, placebo-controlled (placebo plus BSC) comparison. Approximately 544 participants, at least 18 years of age, with Child-Pugh score \< 7 and diagnosed with hepatocellular carcinoma will be randomized. Participants must have received sorafenib as first-line systemic treatment for hepatocellular carcinoma (HCC), and must have discontinued sorafenib prior to entering the study. Hypothesis: This sample size will allow differentiation of the expected increase in median overall survival (OS), from 8 months in the placebo arm to 10.67 months in the ramucirumab arm. Upon registration and completion of screening procedures, eligible participants with HCC who have disease progression during or following first-line therapy with sorafenib, or were intolerant to this agent, will be randomized to receive either ramucirumab DP or placebo. The treatment regimen will be continued until radiographic or symptomatic progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the participant, or investigator decision.
Interventions
BIOLOGICALPlacebo
8 mg/kg IV every 2 weeks
BIOLOGICALRamucirumab DP (IMC-1121B)
8 milligrams/kilogram (mg/kg) intravenous (IV) every 2 weeks
OTHERBSC
Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator.
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
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 * Child-Pugh score of \<7 (Child-Pugh Class A only) * Barcelona Clinic Liver Cancer (BCLC) Stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy * Diagnosis of HCC (excluding fibrolamellar carcinoma) in the absence of histologic or cytologic confirmation * There are either clinical, laboratory, or radiographic findings consistent with a diagnosis of liver cirrhosis * Has a liver mass measuring at least 2 centimeters (cm) with characteristic vascularization seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium * At least 1 measurable or evaluable lesion that is viable \[that is (i.e.), is vascularized\], and has not been previously treated with locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable progression following locoregional therapy * Previously treated with sorafenib and has discontinued sorafenib treatment at least 14 days prior to randomization. Participants may have experienced: * Radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy, or * Discontinuation of sorafenib due to an adverse drug reaction, despite dose reduction by 1 level and BSC * The participant has received sorafenib as the only systemic therapeutic intervention. Any hepatic locoregional therapy that has been administered prior to sorafenib is allowed, but not following sorafenib. Radiation to metastatic sites \[for example (e.g.), bone\] following sorafenib therapy is permitted. * Resolution of clinically significant toxicity of any anti-cancer therapy to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events volume 4.0 (NCI-CTCAE v. 4.0). Adequate Organ Function defined as: * Total bilirubin \<3.0 milligrams/deciliter (mg/dL) \[51.3 micromole/liter (µmol/L)\], aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN) * Serum creatinine ≤1.2 × ULN or calculated creatinine clearance \>50 milliliters/minute (mL/min) * Absolute neutrophil count (ANC) ≥1.0 × 10\^3/microliter (μL) (1.0 × 10\^9/liter (L)\]), hemoglobin ≥9 grams/deciliter (g/dL) \[5.58 millimoles/liter (mmol/L)\], and platelets ≥75 × 10\^3/µL (75 × 10\^9/L) * International Normalized Ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤5 seconds above ULN. Participants receiving prophylactic low-dose anticoagulant therapy are eligible provided that INR ≤1.5 and PTT ≤5 seconds above the ULN * The participant's urinary protein is ≤1+ on dipstick or routine urinalysis. If urine dipstick or routine analysis indicates ≥2+ proteinuria, then a 24-hour urine must be collected and must demonstrate \<1000 milligrams (mg) of protein in 24 hours to allow participation in the study
Exclusion criteria
* Major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to randomization * Hepatic locoregional therapy within 28 days prior to randomization * Radiation to any nonhepatic (e.g., bone) site within 14 days prior to randomization * Sorafenib within 14 days prior to randomization * Received any investigational therapy or non-approved drug within 28 days prior to randomization * Received any previous systemic therapy with vascular endothelial growth factor (VEGF) inhibitors or vascular endothelial growth factor receptor (VEGFR) inhibitors (including investigational agents) other than sorafenib for treatment of HCC * Fibrolamellar carcinoma * Received any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte colony-stimulating factors (G-CSF) within 14 days prior to randomization * Therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or similar agents. Participants receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria (INR ≤1.5 and PTT ≤5 seconds above the ULN) are met * Receiving ongoing therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g., indomethacin, ibuprofen, naproxen, nimesulide, celecoxib, etoricoxib, or similar agents) or other antiplatelet agents (e.g., clopidogrel, ticlopidine, prasugrel, dipyridamole, picotamide, indobufen, anagrelide, triflusal). Aspirin (ASA) at doses up to 100 milligrams/day (mg/day) is permitted * Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia * Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization * Uncontrolled arterial hypertension systolic ≥150 / diastolic ≥90 millimeters of mercury (mm Hg) despite standard medical management * Grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to randomization requiring transfusion, endoscopic or operative intervention (participants with any bleeding episode considered life-threatening during the 3 months prior to randomization are excluded, regardless of transfusion or intervention status) * Esophageal or gastric varices that require immediate intervention (e.g., banding, sclerotherapy) or represent a high bleeding risk. Participants with evidence of portal hypertension (including splenomegaly) or any prior history of variceal bleeding must have had endoscopic evaluation within the 3 months immediately prior to randomization. Participants with evidence of portal hypertension are eligible for study participation if endoscopic evaluation does not indicate esophageal or gastric varices that require immediate intervention or represent a high bleeding risk; however, these eligible participants must receive supportive therapy (e.g., beta blocker therapy) according to institutional standards and clinical guidelines during study participation * Central nervous system (CNS) metastases or carcinomatous meningitis * History of or current hepatic encephalopathy or current clinically meaningful ascites
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization to death from any cause (up to 37 months) | OS was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the end of the follow-up period or were lost to follow-up were censored on the last date the participant was known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | Baseline to the date of first evidence of confirmed CR or PR (up to 37 months) | ORR was defined, using RECIST v1.1 criteria, as the percentage of participants who achieved a best overall response of CR or PR. CR was defined as the disappearance of all lesions and any intratumor arterial enhancement in target lesions, the normalization of the tumor marker level and all lymph nodes short axis reduced to \<10 mm. PR was defined as ≥30% decrease in the SOD of target lesions, including the short axes of any target lymph nodes, taking as reference the baseline SOD of target lesions, no new lesions and stable nontarget lesions. Percentage of participants was calculated as: (number of participants with CR or PR / number of participants randomized) \* 100. |
| Time to Radiographic Progression (TTP) | Randomization to PD (up to 36 months) | TTP was defined as the time from randomization to the first radiographically documented PD. PD was defined, using RECIST v1.1 criteria, as ≥20% increase in SOD of target lesions, taking as reference smallest sum on study (including baseline sum if it was the smallest). Sum must show an absolute increase of ≥5 mm. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. Participants without PD were censored at the day of the last adequate tumor assessment. Progression occurred immediately after ≥2 missed tumor assessments and were censored at the day of the last adequate tumor assessment prior to the missing assessments. Participants who began new anticancer therapy were censored at the day of their last adequate tumor assessment prior to start of new anticancer therapy. |
| Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), and end of treatment (up to 34 months) | The FHSI-8 is a self-administered 8-item questionnaire that measures a participant's symptoms in the domains of jaundice, stomach pain/discomfort weight loss, and fatigue. Participants rated each item on a 5-point scale from 0 (not at all) to 4 (very much). Item scores were calculated as outlined in the FACIT manual. FHSI-8 total score was the sum of each item's score with a total score ranging from 0 (highly symptomatic) to 32 (asymptomatic). |
| Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), end of treatment (up to 34 months) | The EQ-5D is a self-reported, 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire related to the participant's current health state. Each question was scored using a 3 level scale (no problems, some problems, or extreme problems). EQ-5D health state was defined by combining responses from each of the 5 dimensions into a weighted health-state index score according to the United Kingdom (UK) population based algorithm where 0 = death and 1 = perfect health. |
| Progression-Free Survival (PFS) | Randomization to PD (up to 36 months) | PFS was defined as time from date of randomization until date of objectively determined progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death from any cause. PD was defined as ≥20% increase in sum of diameters (SOD) of target lesions, taking as reference smallest sum on study (including baseline sum if it was smallest). Sum must show a ≥5 millimeter (mm) increase. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. In primary analysis, participants alive and without PD were censored at day of last adequate tumor assessment; progression or deaths without progression occurring immediately after ≥2 missed tumor assessments, were censored at day of the last adequate tumor assessment prior to missing assessments; participants who began new anticancer therapy were censored at day of the last adequate tumor assessment prior to start of new anticancer therapy. |
| Maximum Concentration (Cmax) of Ramucirumab, Cycle 1 | 1 hour following the completion of Cycle 1 (14-day cycle) infusion | — |
| Cmax of Ramucirumab, Cycle 4 | 1 hour following completion of Cycle 4 (14-day cycles) infusion | — |
| Cmax of Ramucirumab, Cycle 7 | 1 hour following completion of Cycle 7 (14-day cycles) infusion | — |
| Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)] | Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles) | Participants were considered positive for anti-ramucirumab antibodies \[anti-drug antibodies (ADA)\] if the post-treatment sample had an increase of at least 4-fold in titer from the pretreatment values. If the pretreatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence of ADA. |
| Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | Baseline to study completion (up to 37 months) | The number of participants with serious AEs (SAEs), other non-serious AEs and participants who died. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. |
Countries
Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Finland, France, Germany, Hong Kong, Hungary, Israel, Italy, Japan, Netherlands, Norway, Philippines, Portugal, Romania, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, United States
Participant flow
Pre-assignment details
Participants who died due to any cause or were alive and on study at conclusion but off treatment were considered to have completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab (IMC-1121B) + BSC Ramucirumab 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator. | 283 |
| Placebo + BSC Placebo: 8 mg/kg IV infusion every 2 weeks. BSC: Palliative and supportive care for disease-related symptoms and toxicity associated with treatment as deemed medically necessary and appropriate in the opinion of the investigator. | 282 |
| Total | 565 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 6 |
| Overall Study | Withdrawal by Subject | 13 | 8 |
Baseline characteristics
| Characteristic | Ramucirumab (IMC-1121B) + BSC | Placebo + BSC | Total |
|---|---|---|---|
| Age, Continuous | 62.9 years STANDARD_DEVIATION 11.56 | 62.5 years STANDARD_DEVIATION 11.1 | 62.7 years STANDARD_DEVIATION 11.33 |
| Age, Customized <65 years | 150 participants | 162 participants | 312 participants |
| Age, Customized ≥65 years | 133 participants | 120 participants | 253 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 20 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 253 Participants | 260 Participants | 513 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 131 Participants | 135 Participants | 266 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 7 Participants | 15 Participants |
| Race (NIH/OMB) White | 139 Participants | 137 Participants | 276 Participants |
| Region of Enrollment Australia | 3 participants | 8 participants | 11 participants |
| Region of Enrollment Austria | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Belgium | 3 participants | 5 participants | 8 participants |
| Region of Enrollment Brazil | 15 participants | 12 participants | 27 participants |
| Region of Enrollment Bulgaria | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Canada | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Czech Republic | 11 participants | 9 participants | 20 participants |
| Region of Enrollment Finland | 0 participants | 3 participants | 3 participants |
| Region of Enrollment France | 32 participants | 27 participants | 59 participants |
| Region of Enrollment Germany | 19 participants | 21 participants | 40 participants |
| Region of Enrollment Hong Kong | 14 participants | 10 participants | 24 participants |
| Region of Enrollment Hungary | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Israel | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Italy | 33 participants | 18 participants | 51 participants |
| Region of Enrollment Japan | 45 participants | 48 participants | 93 participants |
| Region of Enrollment Korea, Republic of | 28 participants | 42 participants | 70 participants |
| Region of Enrollment Netherlands | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Norway | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Philippines | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Portugal | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Romania | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Spain | 9 participants | 12 participants | 21 participants |
| Region of Enrollment Sweden | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Switzerland | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Taiwan | 33 participants | 25 participants | 58 participants |
| Region of Enrollment Thailand | 5 participants | 1 participants | 6 participants |
| Region of Enrollment United States | 17 participants | 20 participants | 37 participants |
| Sex: Female, Male Female | 47 Participants | 40 Participants | 87 Participants |
| Sex: Female, Male Male | 236 Participants | 242 Participants | 478 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 254 / 277 | 235 / 276 |
| serious Total, serious adverse events | 124 / 277 | 92 / 276 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at the end of the follow-up period or were lost to follow-up were censored on the last date the participant was known to be alive.
Time frame: Randomization to death from any cause (up to 37 months)
Population: Intent-to-treat (ITT) Population: All randomized participants. Participants censored: Ramucirumab+BSC (Ram)=65, Placebo+BSC (Pl)=58.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Overall Survival (OS) | 9.17 months |
| Placebo + BSC | Overall Survival (OS) | 7.62 months |
p-value: 0.139195% CI: [0.717, 1.046]Log Rank
Secondary
Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score
The EQ-5D is a self-reported, 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire related to the participant's current health state. Each question was scored using a 3 level scale (no problems, some problems, or extreme problems). EQ-5D health state was defined by combining responses from each of the 5 dimensions into a weighted health-state index score according to the United Kingdom (UK) population based algorithm where 0 = death and 1 = perfect health.
Time frame: Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), end of treatment (up to 34 months)
Population: Randomized participants who had an EQ-5D score at baseline and the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Cycle 10 (n=71, 45) | -0.054 units on a scale | Standard Deviation 0.212 |
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Cycle 4 (n=166, 145) | -0.038 units on a scale | Standard Deviation 0.189 |
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Cycle 16 (n=47, 25) | -0.062 units on a scale | Standard Deviation 0.214 |
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | End of Treatment (n=166, 190) | -0.129 units on a scale | Standard Deviation 0.29 |
| Placebo + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | End of Treatment (n=166, 190) | -0.144 units on a scale | Standard Deviation 0.28 |
| Placebo + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Cycle 16 (n=47, 25) | -0.012 units on a scale | Standard Deviation 0.085 |
| Placebo + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Cycle 4 (n=166, 145) | -0.046 units on a scale | Standard Deviation 0.245 |
| Placebo + BSC | Change From Baseline in European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score | Cycle 10 (n=71, 45) | 0.003 units on a scale | Standard Deviation 0.148 |
Secondary
Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)
The FHSI-8 is a self-administered 8-item questionnaire that measures a participant's symptoms in the domains of jaundice, stomach pain/discomfort weight loss, and fatigue. Participants rated each item on a 5-point scale from 0 (not at all) to 4 (very much). Item scores were calculated as outlined in the FACIT manual. FHSI-8 total score was the sum of each item's score with a total score ranging from 0 (highly symptomatic) to 32 (asymptomatic).
Time frame: Baseline, Prior to infusion on Day 1 of Cycle 4, Cycle 10, and Cycle 16 (14-day cycles), and end of treatment (up to 34 months)
Population: Randomized participants who had FHSI-8 at baseline and the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | End of Treatment (n=169, 199) | -2.44 units on a scale | Standard Deviation 5.561 |
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Cycle 4 (n=166, 147) | -1.26 units on a scale | Standard Deviation 3.164 |
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Cycle 16 (n=47, 24) | -0.97 units on a scale | Standard Deviation 4.095 |
| Ramucirumab (IMC-1121B) + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Cycle 10 (n=70, 45) | -1.28 units on a scale | Standard Deviation 3.989 |
| Placebo + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | End of Treatment (n=169, 199) | -2.86 units on a scale | Standard Deviation 5.618 |
| Placebo + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Cycle 16 (n=47, 24) | 0.75 units on a scale | Standard Deviation 3.768 |
| Placebo + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Cycle 4 (n=166, 147) | -0.81 units on a scale | Standard Deviation 4.623 |
| Placebo + BSC | Change From Baseline in the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) | Cycle 10 (n=70, 45) | -0.01 units on a scale | Standard Deviation 4.378 |
Secondary
Cmax of Ramucirumab, Cycle 4
Time frame: 1 hour following completion of Cycle 4 (14-day cycles) infusion
Population: Participants who received Cycle 4 of Ram and had Cmax results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Cmax of Ramucirumab, Cycle 4 | 189.5 µg/mL | Geometric Coefficient of Variation 39.1 |
Secondary
Cmax of Ramucirumab, Cycle 7
Time frame: 1 hour following completion of Cycle 7 (14-day cycles) infusion
Population: Participants who received Cycle 7 of Ram and had Cmax results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Cmax of Ramucirumab, Cycle 7 | 184.4 µg/mL | Geometric Coefficient of Variation 56.3 |
Secondary
Maximum Concentration (Cmax) of Ramucirumab, Cycle 1
Time frame: 1 hour following the completion of Cycle 1 (14-day cycle) infusion
Population: Participants who received Cycle 1 of Ram and had Cmax results.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Maximum Concentration (Cmax) of Ramucirumab, Cycle 1 | 149.6 micrograms/milliliter (µg/mL) | Geometric Coefficient of Variation 36.9 |
Secondary
Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died
The number of participants with serious AEs (SAEs), other non-serious AEs and participants who died. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Baseline to study completion (up to 37 months)
Population: Participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | SAEs | 123 participants |
| Ramucirumab (IMC-1121B) + BSC | Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | Other Non-SAEs | 254 participants |
| Ramucirumab (IMC-1121B) + BSC | Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | Died | 215 participants |
| Placebo + BSC | Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | SAEs | 92 participants |
| Placebo + BSC | Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | Other Non-SAEs | 235 participants |
| Placebo + BSC | Number of Participants With Adverse Events (AEs) and the Number of Participants Who Died | Died | 220 participants |
Secondary
Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)]
Participants were considered positive for anti-ramucirumab antibodies \[anti-drug antibodies (ADA)\] if the post-treatment sample had an increase of at least 4-fold in titer from the pretreatment values. If the pretreatment value was not detected or was not present, a 1:20 post-treatment titer was required to indicate treatment emergence of ADA.
Time frame: Prior to treatment and 1 hour post end of infusion for Cycles 1, 4 and 7 (14-day cycles)
Population: Participants who received at least 1 dose of study drug and had post-treatment ADA analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)] | 10 participants |
| Placebo + BSC | Number of Participants With Treatment Emergent Positive Anti-Ramucirumab Response [Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)] | 7 participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
ORR was defined, using RECIST v1.1 criteria, as the percentage of participants who achieved a best overall response of CR or PR. CR was defined as the disappearance of all lesions and any intratumor arterial enhancement in target lesions, the normalization of the tumor marker level and all lymph nodes short axis reduced to \<10 mm. PR was defined as ≥30% decrease in the SOD of target lesions, including the short axes of any target lymph nodes, taking as reference the baseline SOD of target lesions, no new lesions and stable nontarget lesions. Percentage of participants was calculated as: (number of participants with CR or PR / number of participants randomized) \* 100.
Time frame: Baseline to the date of first evidence of confirmed CR or PR (up to 37 months)
Population: ITT Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 7.1 percentage of participants |
| Placebo + BSC | Percentage of Participants With Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0.7 percentage of participants |
p-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Progression-Free Survival (PFS)
PFS was defined as time from date of randomization until date of objectively determined progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or death from any cause. PD was defined as ≥20% increase in sum of diameters (SOD) of target lesions, taking as reference smallest sum on study (including baseline sum if it was smallest). Sum must show a ≥5 millimeter (mm) increase. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. In primary analysis, participants alive and without PD were censored at day of last adequate tumor assessment; progression or deaths without progression occurring immediately after ≥2 missed tumor assessments, were censored at day of the last adequate tumor assessment prior to missing assessments; participants who began new anticancer therapy were censored at day of the last adequate tumor assessment prior to start of new anticancer therapy.
Time frame: Randomization to PD (up to 36 months)
Population: ITT Population: All randomized participants. Participants censored: Ram=43, Pl=19.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Progression-Free Survival (PFS) | 2.79 months |
| Placebo + BSC | Progression-Free Survival (PFS) | 2.10 months |
p-value: <0.000195% CI: [0.522, 0.75]Log Rank
Secondary
Time to Radiographic Progression (TTP)
TTP was defined as the time from randomization to the first radiographically documented PD. PD was defined, using RECIST v1.1 criteria, as ≥20% increase in SOD of target lesions, taking as reference smallest sum on study (including baseline sum if it was the smallest). Sum must show an absolute increase of ≥5 mm. Appearance of ≥1 new lesions and unequivocal progression of existing non-target lesions were considered progression. Participants without PD were censored at the day of the last adequate tumor assessment. Progression occurred immediately after ≥2 missed tumor assessments and were censored at the day of the last adequate tumor assessment prior to the missing assessments. Participants who began new anticancer therapy were censored at the day of their last adequate tumor assessment prior to start of new anticancer therapy.
Time frame: Randomization to PD (up to 36 months)
Population: ITT Population: All randomized participants. Participants censored: Ram=86, Pl=52.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) + BSC | Time to Radiographic Progression (TTP) | 3.48 months |
| Placebo + BSC | Time to Radiographic Progression (TTP) | 2.63 months |
p-value: <0.000195% CI: [0.487, 0.722]Log Rank