A Study of Ramucirumab (LY3009806) in Participants With Advanced Liver Cancer

Study Overview
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Brief Summary
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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.

Official Title
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Phase 1b Study of 5-FU/FA and Oxaliplatin (FOLFOX4) Plus Ramucirumab (LY3009806) in Patients With Advanced Hepatocellular Carcinoma

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Biological: Ramucirumab
* Drug: FOLFOX4


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab + FOLFOX4<br>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. | Biological: Ramucirumab<br>* Administered IV.<br>* Other names: LY3009806;Drug: FOLFOX4<br>* Administered IV.<br>* Other names: FOLFOX4 (leucovorin + fluorouracil + oxaliplatin);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline through study completion (Up To 8 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Concentration (Cmax) of Ramucirumab | Maximum Concentration (Cmax) | 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 | 
| PK:Area Under the Concentration-Time Curve (AUC[0-∞]) of Ramucirumab | Area under the concentration-time curve. | 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 | 
| 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 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. | Response to Disease Progression or Death (Up To 7 Months) |