Carcinoma, Hepatocellular
Conditions
Brief summary
The main purpose of this study is to determine if the advised dose of ramucirumab is safe to be taken with chemotherapy treatment in participants with advanced liver tumors.
Interventions
BIOLOGICALRamucirumab
Administered IV.
DRUGFOLFOX4
Administered IV.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histological or cytological diagnosis of hepatocellular carcinoma (HCC) or imaging findings consistent with HCC in a participant with liver cirrhosis and alpha-fetoprotein \> 200 nanogram per milliliter * At least 1 measurable or non-measurable lesion * Child-Pugh A * Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy * Eastern Cooperative Oncology Group Performance Status of 0 or 1 * Have not received previous systemic therapy for advanced HCC * Have resolution to Grade ≤1 of all clinically significant toxic effects of prior locoregional therapy * Adequate organ function including: Absolute neutrophil coun t≥1.5×109/liter (L), hemoglobin ≥9 gram/deciliter, and platelets ≥90×109/L; Total bilirubin level ≤1.5 the upper limit of the normal range (ULN), aspartate transaminase and alanine transaminase ≤5 ULN, albumin \>28 gram/L; Serum creatinine level ≤1.5 ULN; or calculated serum creatinine clearance ≥50 milliliter/minute; International Normalized Ratio≤1.5 and partial thromboplastin time ≤5 seconds above ULN * The urinary protein is ≤ 1+. If ≥ 2+ proteinuria, the 24-hour urine protein is \<1000 milligram * An estimated life expectancy of at least 12 weeks
Exclusion criteria
* Received any investigational therapy or non-approved drug within 28 days prior to enrollment * Undergone major surgery within 28 days prior to enrollment, or undergone central venous access device placement within 7 days prior to enrollment * Undergone hepatic locoregional therapy within 28 days prior to enrollment * Undergone radiation to any nonhepatic site within 14 days prior to enrollment * Prior liver transplant * Fibrolamellar carcinoma or cholangiocellular carcinoma * Received any transfusion, blood component preparation, erythropoietin, albumin preparation, or granulocyte-colony stimulating factors within 14 days prior to enrollment * Receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents * Receiving ongoing therapy with nonsteroidal anti-inflammatory agents or other antiplatelet agents. * Known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness * Active or uncontrolled clinically serious infection * Uncontrolled thrombotic or hemorrhagic disorder * Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to enrollment * History of gastrointestinal perforation or obstruction * History of or current hepatic encephalopathy or current clinically meaningful ascites * Known allergy to monoclonal antibody, fluorouracil, oxaliplatin or their excipients * Interstitial pneumonia or interstitial fibrosis of the lung * Central nervous system metastases or carcinomatous meningitis * Known history of dihydropyrimidine dehydrogenase deficiency * Symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia * Experienced any arterial thromboembolic event * Uncontrolled arterial hypertension * Grade 3-4 venous thromboembolic events occurring within 3 months prior to enrollment * Experienced any grade 3-4 gastrointestinal bleeding or any variceal bleeding episode in the 3 months prior to enrollment requiring transfusion, endoscopic or operative intervention * Esophageal or gastric varices that require immediate intervention or represent a high bleeding risk * Pre-existing grade ≥ 2 motor or sensory neuropathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | Baseline through study completion (Up To 8 Months) | A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab | Cycle 1 and Cycle 3: 0,1.0,1.5,2.0,3.0,5.0,24.0,48.0,168.0,336.0 hours | Maximum Concentration (Cmax) |
| PK:Area Under the Concentration-Time Curve (AUC[0-∞]) of Ramucirumab | Cycle 1 and Cycle 3: 0,1.0,1.5,2.0,3.0,5.0,24.0,48.0,168.0,336.0 hours | Area under the concentration-time curve. |
| Number of Participants With Anti-Ramucirumab Antibodies | Baseline through 6.1 Months | — |
| Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) | Response to Disease Progression or Death (Up To 7 Months) | Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version\[v\] 1.1) criteria.CR was defined as the disappearance of all target and non-target lesions and all target and non-target lymph nodes were non-pathological or normal in size \[\<10 millimeter (mm) short axis\]. PR is at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease(PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest).In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Percentage of participants with CR or PR= (number of participants whose best overall response was CR or PR)/(number of participants treated)\*100. |
Countries
Taiwan
Participant flow
Pre-assignment details
Participants completed the study if they completed 3 cycles or discontinued due to a DLT during the DLT assessment period.
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab + FOLFOX4 8 milligram/kilogram (mg/kg) ramucirumab given intravenously (IV) on Day 1 followed by FOLFOX4 (folinic acid + fluorouracil + oxaliplatin chemotherapy regimen) given IV on Day 1 of 2 week cycles:
FOLFOX4 every 2 weeks:
85 milligram per square meter (mg/m²) oxaliplatin IV on Day 1 200 mg/m² folinic acid(FA) IV on days 1 and 2 400 mg/m² 5-FU bolus on days 1 and 2 600 mg/m2 5-FU 22-h continuous infusion on Days 1 and 2
Participants may continue to receive treatment until discontinuation criteria are met. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Ramucirumab + FOLFOX4 |
|---|---|
| Age, Continuous | 55.56 years STANDARD_DEVIATION 11.06 |
| Barcelona Clinic Liver Cancer (BCLC) Classification Missing | 0 Participants |
| Barcelona Clinic Liver Cancer (BCLC) Classification Stage A | 0 Participants |
| Barcelona Clinic Liver Cancer (BCLC) Classification Stage B | 1 Participants |
| Barcelona Clinic Liver Cancer (BCLC) Classification Stage C | 7 Participants |
| Barcelona Clinic Liver Cancer (BCLC) Classification Stage D | 0 Participants |
| Basis of Initial Pathological Diagnosis Biochemical Assay and Imaging | 2 Participants |
| Basis of Initial Pathological Diagnosis Cytological | 1 Participants |
| Basis of Initial Pathological Diagnosis Histopathological | 3 Participants |
| Disease Stage Stage I | 0 Participants |
| Disease Stage Stage II | 1 Participants |
| Disease Stage Stage III | 4 Participants |
| Disease Stage Stage IV | 1 Participants |
| Disease Stage Unknown | 0 Participants |
| Duration of Disease (months) | 0.345 months |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 4 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 4 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status >2 | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Taiwan | 8 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
| Viral hepatitis B Test Negative | 0 Participants |
| Viral hepatitis B Test Positive | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 5 / 8 |
Outcome results
Primary
Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration
A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline through study completion (Up To 8 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + FOLFOX4 | Number of Participants With One or More Serious Adverse Event(s) (SAEs) Considered by the Investigator to be Related to Study Drug Administration | 4 Participants |
Secondary
Number of Participants With Anti-Ramucirumab Antibodies
Time frame: Baseline through 6.1 Months
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ramucirumab + FOLFOX4 | Number of Participants With Anti-Ramucirumab Antibodies | 0 Participants |
Secondary
Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])
Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST, version\[v\] 1.1) criteria.CR was defined as the disappearance of all target and non-target lesions and all target and non-target lymph nodes were non-pathological or normal in size \[\<10 millimeter (mm) short axis\]. PR is at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease(PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including the baseline sum if that is the smallest).In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Percentage of participants with CR or PR= (number of participants whose best overall response was CR or PR)/(number of participants treated)\*100.
Time frame: Response to Disease Progression or Death (Up To 7 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + FOLFOX4 | Percentage of Participants With Best Response of Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) | 25 percentage of Participants |
Secondary
Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab
Maximum Concentration (Cmax)
Time frame: Cycle 1 and Cycle 3: 0,1.0,1.5,2.0,3.0,5.0,24.0,48.0,168.0,336.0 hours
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab + FOLFOX4 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab | Cycle 1 | 155 ug/mL(microgram / milliliter) | Geometric Coefficient of Variation 25 |
| Ramucirumab + FOLFOX4 | Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab | Cycle 3 | 190 ug/mL(microgram / milliliter) | Geometric Coefficient of Variation 29 |
Secondary
PK:Area Under the Concentration-Time Curve (AUC[0-∞]) of Ramucirumab
Area under the concentration-time curve.
Time frame: Cycle 1 and Cycle 3: 0,1.0,1.5,2.0,3.0,5.0,24.0,48.0,168.0,336.0 hours
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ramucirumab + FOLFOX4 | PK:Area Under the Concentration-Time Curve (AUC[0-∞]) of Ramucirumab | Cycle 1 | 940 microgram*day / milliliter)(ug*day/mL) | Geometric Coefficient of Variation 24 |
| Ramucirumab + FOLFOX4 | PK:Area Under the Concentration-Time Curve (AUC[0-∞]) of Ramucirumab | Cycle 3 | 1190 microgram*day / milliliter)(ug*day/mL) | Geometric Coefficient of Variation 25 |