A Safety, Tolerability, and Pharmacokinetics Study of Onartuzumab as Single Agent or in Combination With Sorafenib in Participants With Advanced Hepatocellular Carcinoma

Study Overview
=================
Brief Summary
-----------------
This multicenter, open-label study will evaluate the maximum tolerated dose (MTD) and dose-limiting toxicities of onartuzumab as single agent or in combination with sorafenib in participants with advanced hepatocellular carcinoma. Participants in Cohort 1 will receive onartuzumab as single agent on Day 1 of each 21-day cycle. Participants in Cohorts 2 or 3 will receive onartuzumab on Day 1 of each 21-day cycle in combination with sorafenib 400 mg orally daily or twice daily. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Official Title
-----------------
A Phase Ib, Open-Label Study Evaluating The Safety, Tolerability, and Pharmacokinetics of Onartuzumab Given as a Single Agent and in Combination With Sorafenib in Patients With Advanced Hepatocellular Carcinoma (HCC)

Conditions
-----------------
Carcinoma, Hepatocellular

Intervention / Treatment
-----------------
* Drug: Onartuzumab
* Drug: Sorafenib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Cytologically or histologically confirmed diagnosis of hepatocellular carcinoma (HCC) Advanced or metastatic disease Not a candidate for curative treatments (that is, resection, transplantation) Child-Pugh class A liver function Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Life expectancy greater than (>) 3 months For participants who received prior adjuvant chemotherapy, a treatment-free interval of at least 6 months between the last chemotherapy cycle and Cycle 1 Day 1 Exclusion Criteria: Prior surgery or local therapy within 4 weeks prior to Cycle 1 Day 1, with the exception of palliative radiation therapy to the bone Brain metastasis or spinal cord compression not definitively treated with surgery and/or radiation Granulocyte count less than (<) 1500 per cubic millimeter (mm^3), platelet count < 75,000/mm^3, and hemoglobin < 8 gram per deciliter (g/dL) within 7 days prior to Cycle 1 Day 1 Total bilirubin greater than (>) 1.5 times the upper limit of normal (ULN) Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT), Alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (ALP) > 5 × ULN Serum creatinine > 1.5 × ULN or creatinine clearance < 60 cubic centimeter per minute (cc/min) by Cockcroft-Gault formula Significant history of cardiac disease within 6 months prior to Cycle 1 Day 1, myocardial infarction within the previous year, or current cardiac ventricular arrhythmias requiring medication Serious active infection, or other serious underlying medical conditions that would impair the ability of the participant to receive protocol treatment, with the exception of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections Known active infection with human immunodeficiency virus (HIV) or known HIV-seropositivity Inability to take oral medication or untreated malabsorption syndrome Pregnant or lactating women History of transplantation including organ, bone marrow transplantation, and peripheral blood stem cell transplantation with the exception of corneal transplantation Active bleeding diathesis (including active esophageal varices) or tumor rupture within 8 weeks prior to Cycle 1 Day1 that are not successfully treated Uncontrolled hypertension Treatment with any other investigational drug within 4 weeks of Cycle 1 Day

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (Onartuzumab)<br> | Drug: Onartuzumab<br>* Onartuzumab intravenous infusion at a starting dose of 10 or 15 milligram per kilogram body weight administered every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurs (maximum up to 31 months).<br>* Other names: RO5490258;|
| Experimental: Cohorts 2/3 (Onartuzumab + Sorafenib)<br> | Drug: Onartuzumab<br>* Onartuzumab intravenous infusion at a starting dose of 10 or 15 milligram per kilogram body weight administered every 3 weeks (Q3W) until disease progression or unacceptable toxicity occurs (maximum up to 31 months).<br>* Other names: RO5490258;Drug: Sorafenib<br>* Sorafenib 400 milligram (mg) tablets (2 tablets of 200 mg each) orally once daily or twice daily depending on the cohort assigned until disease progression or unacceptable toxicity occurs (maximum up to 31 months).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose-limiting Toxicities (DLT) |  | Maximum up to 42 days | 
| Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) |  | Up to approximately 31 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve (AUC) of Onartuzumab |  | Day 1 up to Day 15 of Cycle 1, Day 1 of Cycle 2, 3, 4, and every fourth cycle thereafter (maximum up to 31 months) | 
| Steady-state Plasma Concentrations of Sorafenib When Administered in Combination With Onartuzumab |  | Day 1 Cycles 1-2 | 
| Progression-free Survival (PFS) |  | Up to approximately 31 months | 
| Percentage of Participants With Objective Response |  | Up to approximately 31 months | 
| Duration of Response (DR) |  | Up to approximately 31 months | 
| Overall Survival (OS) |  | Up to approximately 31 months | 
| Percentage of Participants With Progression-free Survival at 4 Months (PFS4) |  | 4 months | 
| Number of Participants With Anti-therapeutic Antibodies (ATAs) Against Onartuzumab |  | Up to approximately 31 months |