Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Therapy With Sorafenib
Overview
- Phase
- Phase 3
- Intervention
- Ramucirumab
- Conditions
- Hepatocellular Carcinoma
- Sponsor
- Eli Lilly and Company
- Enrollment
- 399
- Locations
- 17
- Primary Endpoint
- Overall Survival (OS)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety and efficacy of ramucirumab in participants with hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein. Participants will be randomized to ramucirumab or placebo in a 2:1 ratio (Main Global Cohort and China Maximized Extended Enrollment [MEE] Cohort). Participants may also receive ramucirumab if eligible to be enrolled in Open-Label Expansion (OLE) Cohort.
Investigators
Eligibility Criteria
Inclusion Criteria
- •A diagnosis of HCC based on histopathologic findings, or a diagnosis of cirrhosis and a tumor with classical HCC imaging characteristics.
- •Sorafenib was the only systemic therapy for HCC and was discontinued for disease progression or intolerance (Main Global and MEE Cohorts only).
- •The participant received ≤2 prior systemic therapy regimen, excluding prior sorafenib or chemotherapy, for the treatment of HCC (OLE Cohort only).
- •≥1 measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 that has not been previously treated with locoregional therapy. A participant with a lesion(s) that has previously been treated with locoregional therapy is also eligible, if the lesion has documented progression after locoregional treatment and is measureable.
- •Child-Pugh score \<7 (Child-Pugh Class A).
- •Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy.
- •Baseline AFP ≥400 nanograms/milliliter.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Resolution of all clinically significant toxic effects of prior therapy.
- •Total bilirubin ≤1.5 times upper limit of normal value (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤5 × ULN.
Exclusion Criteria
- •Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
- •Concurrent malignancy. Participants with carcinoma in situ of any origin and participants with prior malignancies in remission may be eligible with sponsor approval.
- •Previous brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
- •History of or current hepatic encephalopathy or clinically meaningful ascites.
- •Ongoing or recent hepatorenal syndrome.
- •Liver transplant (Main Global and MEE cohorts only; Participants with prior liver transplant may be eligible for OLE cohort).
- •Hepatic locoregional therapy following prior systemic therapy or within 28 days prior to randomization.
- •Major surgical procedure, traumatic injury, non-healing wound, or peptic ulcer ≤28 days prior to randomization.
- •Received radiation to any nonhepatic (for example, bone) site within 14 days prior to randomization.
- •Placement of a subcutaneous venous access device within 7 days prior to the first dose of study treatment unless the procedure is judged of low risk of bleeding.
Arms & Interventions
Ramucirumab + Best Supportive Care (BSC)
8 milligrams per kilogram (mg/kg) ramucirumab administered as an intravenous (IV) injection on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Ramucirumab
Placebo + BSC
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Ramucirumab
Placebo + BSC
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Placebo
Open Label Ramucirumab + BSC
8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Ramucirumab
Ramucirumab MEE Cohort + BSC
8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Ramucirumab
Placebo MEE Cohort + BSC
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Ramucirumab
Placebo MEE Cohort + BSC
Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met.
Intervention: Placebo
Outcomes
Primary Outcomes
Overall Survival (OS)
Time Frame: From Date of Randomization to Death from Any Cause (Up to 28 Months)
OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive.
Secondary Outcomes
- Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire(From Randomization through End of Study (Up to 28 Months))
- Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS)(From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months))
- Percentage of Participants With Anti-Ramucirumab Antibodies(Predose Cycle 1: 7 Days prior to First Infusion, Cycle 4: 3 Days Prior to Infusion, Cycle 7 through Follow Up (Up to 28 Months))
- Time to Deterioration of Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8)(From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months))
- Progression Free Survival (PFS)(From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months))
- Time to Radiographic Progression(From Randomization to Objective Progression (Up to 28 Months))
- Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)(From Randomization to Objective Progression (Up to 28 Months))
- Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion(Predose, Weeks 2, 6, 12 and 18, Day 1; Up to 3 Days Before Infusion (14-Day Cycles))
- PK: Serum Concentration Maximum (Cmax) After 1st, 2nd, 4th, 7th and 10th Ram Infusion(Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles))