A Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Ramucirumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 1. 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. Creatinine clearance ≥60 milliliters/minute. Urinary protein is ≤1+ on dipstick or routine urinalysis or 24-hour urine demonstrating <1 gram of protein. Absolute neutrophil count ≥1.0 × 10^9/Liter, hemoglobin ≥9 grams/deciliter, and platelets ≥75 × 10^9/Liter. International Normalized Ratio (INR) ≤1.5 and a partial thromboplastin time (PTT) ≤5 seconds above the ULN. Surgically sterile, postmenopausal, or compliant with a highly effective contraceptive method. If a woman of childbearing potential, a negative serum pregnancy test prior to randomization. Willing to provide blood for research. The participant has provided signed informed consent prior to any study specific procedures and is amenable to compliance with protocol schedules and testing. 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. Enrolled in a clinical trial involving an investigational product or unapproved use of a drug or in medical research judged not to be scientifically or medically compatible with this study. Discontinued from study treatment from another clinical trial within 28 days prior to randomization. Known allergy to any of the treatment components. Uncontrolled hypertension. Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, <6 months prior to randomization. Any bleeding episode considered life-threatening, or any Grade 3 or 4 gastrointestinal bleeding episode in the 3 months prior to randomization requiring intervention. Esophageal or gastric varices that require intervention or represent high bleeding risk. Participants with evidence of portal hypertension or prior bleeding must have had endoscopic evaluation within 3 months prior to randomization. Gastrointestinal perforation or fistulae within 6 months prior to randomization. Symptomatic congestive heart failure (New York Heart Association II-IV), unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia. Pregnant or breast-feeding. Any medical or psychiatric condition that may increase the risk associated with study participation or may interfere with the interpretation of study results. Conditions include but are not limited to: Human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. Active or uncontrolled clinically serious infection. (Participants with chronic viral hepatitis are eligible.) Ongoing or recent history of drug abuse. Uncontrolled hereditary or acquired thrombotic or bleeding disorder. Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection. Therapeutic dose anticoagulation with warfarin, low molecular-weight heparin, or similar agents. Chronic therapy with nonsteroidal anti-inflammatory agents or other anti-platelet agents. Aspirin at doses up to 100 milligrams/day is permitted. The participant received prior immunotherapy and is experiencing or has experienced any of the following (OLE cohort only): Any clinically significant Grade ≥3 immune-related adverse event (irAE) Any grade neurologic or ocular irAE Any grade immune-related pneumonitis, cardiomyopathy, or hepatitis The participant received prior immunotherapy and at the time of study enrollment, requires steroids or other immunosuppressive agents (OLE cohort only).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab + Best Supportive Care (BSC)<br>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. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;|
| Placebo Comparator: Placebo + BSC<br>Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;Drug: Placebo<br>* Administered IV<br>|
| Experimental: Open Label Ramucirumab + BSC<br>8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;|
| Experimental: Ramucirumab MEE Cohort + BSC<br>8 mg/kg ramucirumab administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;|
| Placebo Comparator: Placebo MEE Cohort + BSC<br>Placebo administered IV on day 1 of each 14 day cycle. Participants may continue treatment until discontinuation criteria are met. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;Drug: Placebo<br>* Administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | From Date of Randomization to Death from Any Cause (Up to 28 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Progression-free survival is defined as time from the date of randomization to the date of first observation of objective progression or death from any cause. | From Randomization to Objective Progression or Death from Any Cause (Up to 28 Months) | 
| Time to Radiographic Progression | Time to radiographic progression is defined as the time from the date of randomization to the date of first observation of objective 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) | Objective response rate is defined as the percentage of participants who achieve a best overall response of complete response (CR) + partial response (PR). ORR = CR + PR. CR is the disappearance of all non-target lesions and normalisation of tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. Best overall response is classified based on the overall responses assessed by study investigators according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1. | From Randomization to Objective Progression (Up to 28 Months) | 
| Pharmacokinetics (PK): Minimum Serum Concentration (Cmin) Before 2nd, 4th, 7th, and 10th Infusion | PK Cmin of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations. | 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 | PK Cmax of Ramucirumab Blood samples were collected at specified time points, and in the event of an infusion-related reaction, for assessment of ramucirumab serum concentrations. | Weeks 0, 2, 6, 12 and 18, Day 1; 1 hour to 1.5 hours Post End of Infusion (14 day-Cycles) | 
| Percentage of Participants With Anti-Ramucirumab Antibodies | Percentage of participants with positive treatment emergent anti-drug antibodies was summarized by treatment group. A treatment-emergent ADA (TEADA) was defined as: having a negative ADA at baseline and an ADA titer greater than or equal to 1:20 (that is (i.e.), greater than 2-fold from the minimal required dilution of 1:10) any time post baseline (i.e., treatment-induced); or a 4-fold or greater change in ADA titer from baseline for participants that had a detectable ADA titer at baseline (i.e., treatment boosted). | 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) | The FACT Hepatobiliary Symptom Index (FHSI-8) is a instrument with specific focus regarding the most frequent and concerning symptoms experienced by participants with hepatobiliary malignancies, including lack of energy, nausea, pain, weight loss, pain in back, fatigue, jaundice, stomach pain or discomfort. The (FHSI-8) questionnaire was used to assess the time to deterioration of FSHI-8 total score issued from the date of randomization to the first date observing deterioration, with the deterioration threshold defined as a decrease ≥ 3-points from baseline. In case of no deterioration, the participants were censored at the time of the last FSHI-8 item recording. FHSI-8 total score ranges from 0 to 32 where 0 is a severely symptomatic participant and the highest score indicates an asymptomatic participant. Kaplan-Meier method Hazard ratio was used to estimate (Ramucirumab versus Placebo) and 95% Confidence Interval (CI) (Wald) were estimated from un-stratified/stratified Cox model. | From Randomization to the First Date of Deterioration Observation (≥ 3-point decrease) (Up to 28 Months) | 
| Change From Baseline in EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire | The EQ-5D-5L is a nonspecific and standardized instrument for use as a measure of self-reported health status (EuroQol Group 1990; Herdman et al. 2011). Participants completed the 5-level (no problems, slight problems, moderate problems, severe problems, and extreme problems), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. A unique EQ-5D-5L health state scale ranges from 0 to 100 and is defined by combining 1 level from each of the 5 dimensions. Participants indicated their current health status by marking on a continuum ranging from 100 (best imaginable health state) to 0 (worst imaginable health state). | From Randomization through End of Study (Up to 28 Months) | 
| Time to Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) | Time to deterioration in ECOG PS is defined as the time from the date of randomization to the first date observing ECOG PS 2 (ie, deterioration from baseline status of 0 [fully active] or 1 [restricted in physically strenuous activity but ambulatory and able to carry out light work]). Participants without PS deterioration were censored at their last documented assessments of 0 or 1. Assessments included ECOG Performance Status (PS): 2- Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours, 3 -Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours, 4 -Completely disabled, cannot carry on any self-care. Totally confined to bed or chair, 5- Dead. | From Randomization through First Date of Deterioration Observation (ECOG PS≥2) (Up to 28 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver cancer