Hepatocellular Carcinoma
Conditions
Keywords
Liver disease, Neoplasms, Liver neoplasms, Carcinoma, Hepatocellular
Brief summary
A study to determine how long ramucirumab (IMC-1121B) will stop cancer from growing in participants with liver cancer that cannot be treated with surgery.
Detailed description
Inhibition of angiogenesis is considered a promising approach to the treatment of cancer. Members of the vascular endothelial growth factor (VEGF) family and the VEGF receptor-2 (VEGFR-2) are important mediators of angiogenesis and are likely important therapeutic targets in advanced hepatocellular cancer (HCC). Angiogenesis appears integral to HCC development and pathogenesis. Angiogenesis inhibition has been efficacious in both in vitro and in vivo HCC models and results of clinical studies also suggest potential to inhibit disease growth. Ramucirumab is a fully human monoclonal antibody (MAb) that specifically binds to the extracellular domain of VEGFR-2 with high affinity. Phase 1 studies currently nearing completion have demonstrated safety and tolerability at clinically relevant doses, with preliminary evidence of clinical efficacy in a variety of human cancers.
Interventions
BIOLOGICALRamucirumab (IMC-1121B)
Participants will receive ramucirumab (IMC-1121B) at 8 milligrams per kilogram (mg/kg) administered over 1 hour every other week (every 14 days). Treatment will continue until there is evidence of disease progression, intolerable toxicity, or other withdrawal criteria are met.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant must have histologically-confirmed, unresectable HCC * The participant has at least one unidimensionally-measurable target lesion \[≥ 2 centimeters (cm) with conventional techniques, or ≥ 1 cm by spiral computed tomography (CT) or magnetic resonance imaging (MRI)\], as defined by Response Evaluation Criteria in Solid Tumors (RECIST). Target lesion(s) must not lay within a previously irradiated, ablated, or chemoembolized area. If a target lesion does lie in such an area, there must be evidence of growth on successive imaging studies, including tumor hypervascularity, in order for such a lesion to be considered a target lesion * The participant has a Cancer of the Liver Italian Programme (CLIP) score of 0-3 * The participant has a Child-Pugh Classification score of A or B (liver dysfunction) * The participant has provided signed informed consent
Exclusion criteria
* The participant has received prior systemic chemotherapy, biologic or anti-angiogenic therapy, or investigational systemic therapy for HCC * The participant has had bleeding from esophageal or gastric varices during the 3 months prior to study participation. Note: If the participant has any history of known esophageal varices, or evidence of esophageal varices on CT/MRI, the participant must undergo endoscopic evaluation prior to study entry (minimally invasive capsule esophageal endoscopy is an acceptable initial modality). The participant with endoscopically detected esophageal varices is eligible provided he/she meets all other entry criteria. The participant with any history or current evidence of esophageal varices must receive oral beta-blocker therapy throughout participation while on study, he/she may receive optimal endoscopic therapy as determined by the consulting gastroenterologist or hepatologist, and must undergo regular endoscopic follow-up throughout participation while on study * The participant has acute hepatitis * The participant has central nervous system (CNS) metastases or carcinomatous meningitis * The participant has poorly-controlled hypertension \[in other words (ie), blood pressure in abnormal range despite medical management\]
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) in Participants With Unresectable Hepatocellular Cancer Treated With the Monoclonal Antibody Ramucirumab | First dose to date of progressive disease or death due to any cause [every 3 cycles up to 18 months (1 cycle=2 weeks)] | PFS was defined as the time from the first day of therapy to the first evidence of disease progression or death from any cause. As classified according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Participants who were alive and without disease progression and participants who did not progress and were subsequently lost to follow-up were censored at the last objective tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | First dose to death due to any cause up to 37.5 months | Overall survival (OS) was the duration from first dose to death due to any cause. OS was censored at last contact date for participants who were alive at the end of follow-up period or lost to follow-up. |
| Percentage of Participants With Complete Response or Partial Response (Objective Response Rate) | First dose to date of objective progressive disease (PD) or death up to 18 months | Objective response rate (ORR) was defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). As classified according to Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria, CR was the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeters (mm) and normalization of tumor marker level of non-target lesions. PR was having at least a 30% decrease in sum of longest diameter of target lesions. |
| Time to Progression | First dose to date of PD [every 3 cycles up to 18 months (1 cycle=2 weeks)] | The time from first day of therapy to the first date of objective evidence of progressive disease (PD) by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD was defined as having at least a 20% increase in sum of longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of new lesion. Time to PD was censored at the date of death or study discontinuation. |
| Number of Participants With Serum Anti-Ramucirumab Antibodies | Prior to dosing at baseline, Cycles 4 and 7, and 30 days after end of therapy (1 cycle=2 weeks) | — |
| Number of Participants With Drug-Related Treatment-Emergent Adverse Events | First dose to 37.5 months | Data presented are the number of participants who experienced treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade 3 or higher TEAEs, or adverse events (AEs) leading to discontinuation of treatment that were considered by the investigator to be related to ramucirumab. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section. |
| Duration of Response | Time of first response (CR or PR) to disease progression, or death due to any cause [every 3 cycles up to 18 months (1 cycle=2 weeks)] | Duration of response was the interval from the date of initial documented response \[complete response (CR) or partial response (PR)\] to the first documented date of disease progression, initiation of other (or additional) antitumor therapy was first reported, or death due to any cause. As classified according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, CR was the disappearance of all target lesions, PR was having at least a 30% decrease in the sum of the longest diameter of target lesions, and disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Data were censored for participants who did not progress or die. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab (IMC-1121B) Ramucirumab (IMC-1121B): 8 milligrams per kilogram (mg/kg) administered intravenously over 1 hour, every 2 weeks. Treatment continued until there was evidence of disease progression, intolerable toxicity, or other withdrawal criteria were met. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Ramucirumab (IMC-1121B) |
|---|---|
| Age, Customized >=65 years | 15 participants |
| Age, Customized Between 18 and 65 years | 27 participants 10.7 |
| Barcelona Stage A | 2 participants |
| Barcelona Stage B | 4 participants |
| Barcelona Stage C | 36 participants |
| Child-Pugh Score A | 31 participants |
| Child-Pugh Score B | 11 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Extrahepatic Metastasis Status Absent | 10 participants |
| Extrahepatic Metastasis Status Present | 32 participants |
| Hepatitis B and C Status Hepatitis B and C Negative | 15 participants |
| Hepatitis B and C Status Hepatitis B and C Positive | 2 participants |
| Hepatitis B and C Status Hepatitis B Positive | 3 participants |
| Hepatitis B and C Status Hepatitis C Positive | 19 participants |
| Macrovascular Invasion Absent | 32 participants |
| Macrovascular Invasion Missing | 1 participants |
| Macrovascular Invasion Not Available | 2 participants |
| Macrovascular Invasion Present | 7 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants |
| Race/Ethnicity, Customized Asian | 4 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Race Other: Black and Asian | 1 participants |
| Race/Ethnicity, Customized Race Other: Greek | 1 participants |
| Race/Ethnicity, Customized Race Other: Hispanic | 1 participants |
| Race/Ethnicity, Customized White | 32 participants |
| Region of Enrollment United States | 42 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 42 |
| serious Total, serious adverse events | 24 / 42 |
Outcome results
Primary
Progression Free Survival (PFS) in Participants With Unresectable Hepatocellular Cancer Treated With the Monoclonal Antibody Ramucirumab
PFS was defined as the time from the first day of therapy to the first evidence of disease progression or death from any cause. As classified according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Participants who were alive and without disease progression and participants who did not progress and were subsequently lost to follow-up were censored at the last objective tumor assessment.
Time frame: First dose to date of progressive disease or death due to any cause [every 3 cycles up to 18 months (1 cycle=2 weeks)]
Population: Intent-to-treat population: Participants who received at least 1 dose of ramucirumab. The number of participants censored was 13.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) | Progression Free Survival (PFS) in Participants With Unresectable Hepatocellular Cancer Treated With the Monoclonal Antibody Ramucirumab | 4.0 months |
Secondary
Duration of Response
Duration of response was the interval from the date of initial documented response \[complete response (CR) or partial response (PR)\] to the first documented date of disease progression, initiation of other (or additional) antitumor therapy was first reported, or death due to any cause. As classified according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria, CR was the disappearance of all target lesions, PR was having at least a 30% decrease in the sum of the longest diameter of target lesions, and disease progression was having at least a 20% increase in the sum of the longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of a new lesion. Data were censored for participants who did not progress or die.
Time frame: Time of first response (CR or PR) to disease progression, or death due to any cause [every 3 cycles up to 18 months (1 cycle=2 weeks)]
Population: Participants who received at least 1 dose of ramucirumab and had a CR or PR. The number of participants censored 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) | Duration of Response | 14.1 months |
Secondary
Number of Participants With Drug-Related Treatment-Emergent Adverse Events
Data presented are the number of participants who experienced treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade 3 or higher TEAEs, or adverse events (AEs) leading to discontinuation of treatment that were considered by the investigator to be related to ramucirumab. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events section.
Time frame: First dose to 37.5 months
Population: Intent-to-treat population: Participants who received at least 1 dose of ramucirumab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramucirumab (IMC-1121B) | Number of Participants With Drug-Related Treatment-Emergent Adverse Events | Related TEAE | 41 participants |
| Ramucirumab (IMC-1121B) | Number of Participants With Drug-Related Treatment-Emergent Adverse Events | Related SAE | 9 participants |
| Ramucirumab (IMC-1121B) | Number of Participants With Drug-Related Treatment-Emergent Adverse Events | Related Grade 3 or higher TEAE | 14 participants |
| Ramucirumab (IMC-1121B) | Number of Participants With Drug-Related Treatment-Emergent Adverse Events | Related AE leading to discontinuation | 6 participants |
Secondary
Number of Participants With Serum Anti-Ramucirumab Antibodies
Time frame: Prior to dosing at baseline, Cycles 4 and 7, and 30 days after end of therapy (1 cycle=2 weeks)
Population: Intent-to-treat population: Participants who received at least 1 dose of ramucirumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab (IMC-1121B) | Number of Participants With Serum Anti-Ramucirumab Antibodies | 6 participants |
Secondary
Overall Survival
Overall survival (OS) was the duration from first dose to death due to any cause. OS was censored at last contact date for participants who were alive at the end of follow-up period or lost to follow-up.
Time frame: First dose to death due to any cause up to 37.5 months
Population: Intent-to-treat population: Participants who received at least 1 dose of ramucirumab. The number of participants censored was 10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) | Overall Survival | 12.0 months |
Secondary
Percentage of Participants With Complete Response or Partial Response (Objective Response Rate)
Objective response rate (ORR) was defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). As classified according to Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria, CR was the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeters (mm) and normalization of tumor marker level of non-target lesions. PR was having at least a 30% decrease in sum of longest diameter of target lesions.
Time frame: First dose to date of objective progressive disease (PD) or death up to 18 months
Population: Intent-to-treat population: Participants who received at least 1 dose of ramucirumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab (IMC-1121B) | Percentage of Participants With Complete Response or Partial Response (Objective Response Rate) | 9.5 percentage of participants |
Secondary
Time to Progression
The time from first day of therapy to the first date of objective evidence of progressive disease (PD) by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD was defined as having at least a 20% increase in sum of longest diameter of target lesions and/or unequivocal progression of a non-target lesion and/or detection of new lesion. Time to PD was censored at the date of death or study discontinuation.
Time frame: First dose to date of PD [every 3 cycles up to 18 months (1 cycle=2 weeks)]
Population: Intent-to-treat population: Participants who received at least 1 dose of ramucirumab. The number of participants censored was 20.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab (IMC-1121B) | Time to Progression | 4.2 months |