Study of Mapatumumab in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. Sorafenib, a multikinase inhibitor, is the standard of care for treatment of patients with advanced hepatocellular carcinoma (HCC). The mechanisms of sorafenib and mapatumumab action suggest that these agents could interact synergistically. This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects with advanced hepatocellular carcinoma.

Official Title
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A Randomized, Multi-Center, Blinded, Placebo-Controlled Study Of Mapatumumab ([HGS1012], A Fully Monoclonal Antibody To TRAIL-R1) In Combination With Sorafenib As A First-Line Therapy In Subjects With Advanced Hepatocellular Carcinoma

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Mapatumumab
* Drug: Placebo
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Child-Pugh Class A. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial chemoembolization is not considered appropriate Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced computerized tomography (CT), with use of multislice scanners, or contrast enhanced dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the following criteria: located in the liver; can be accurately measured in at least 1 dimension; well delineated area of viable, hypervascular (contrast enhancement in the arterial phase) tumor that is >2 centimeter (cm) in the axial plane; suitable for repeat measurement; OR not previously treated with locoregional or systemic treatment unless the lesion shows a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that is >2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical enhancement as a result of the previous intervention, then it cannot be selected as a target lesion) Radiologic eligibility (measurable disease) must be must be confirmed by the BICR prior to randomization. Adequate bone marrow, renal and liver function as defined in the protocol. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale Age 18 years or older Have the ability to understand the requirements of the study, provide written informed consent (including consent for the use and disclosure of research-related health information), and comply with the study and follow-up procedures. Exclusion Criteria: Any co-morbid condition that in the judgment of the investigator renders the subject at high risk of treatment complications or reduces the possibility of assessing clinical effect. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal therapy, biological therapy (including but not limited to monoclonal antibodies, small molecules or other immunotherapy) to treat hepatocellular carcinoma. History of organ allograft. Previously received mapatumumab or sorafenib. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 4 weeks before enrollment or not recovered from such treatments. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, immunotherapy, radiofrequency ablation) or other investigational agents during the study treatment period. Major surgery (i.e., the opening of a major body cavity, requiring the use of general anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of vascular access device) within 2 weeks before enrollment; or not yet recovered from the effects of the surgery. Systemic steroids within 1 week before enrollment except steroids used as part of an antiemetic regimen or maintenance-dose steroids for non-cancerous disease. Hepatic encephalopathy, per the investigator's evaluation. History of clinically significant gastrointestinal bleeding requiring procedural intervention (e.g., variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial embolization, topical coagulation therapy) within 4 weeks before enrollment. Gastrointestinal disease resulting in an inability to take oral medication or a requirement for intravenous hyperalimentation. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks before enrollment. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids. Known human immunodeficiency virus infection. Unstable angina, myocardial infarction, cerebrovascular accident, >= Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure within 6 months before enrollment. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. Uncontrolled hypertension (systolic blood pressure >150 millimeters of mercury [mmHg] or diastolic pressure >90 mmHg despite optimal medical management). Using and unable to discontinue use of concomitant strong CYP3A4 inducers (e.g., including but not limited to St. John's Wort, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic for the 24 months before enrollment) must have a negative serum pregnancy test at screening. All non-sterile or non-postmenopausal females must practice a medically accepted method of contraception over the course of the study and for 60 days after the last dose of study agent. Males who do not agree to use effective contraception during the study and for a period of 60 days following the final dose of study agent. Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s) or subject is receiving other investigational agents. Acute or chronic severe renal insufficiency (glomoerular filtration rate <30 milliliters [mL]/minute/1.73 square meters) or acute renal insufficiency of any severity due to the hepato-renal syndrome. Hepatitis B virus deoxyribonucleic acid (DNA) levels >2,000 international units/mL.

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: Sorafenib plus mapatumumab<br>Mapatumumab 30 milligrams (mg)/kilogram (kg) intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity | Drug: Mapatumumab<br>* Mapatumumab will be supplied as a lyophilized formulation in 10 mL vials containing 100 mg mapatumumab for intravenous infusion at the dose of 30 mg/kg.<br>Drug: Sorafenib<br>* Sorafenib will be supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 200 mg of sorafenib, to be administered 400 mg (2 x 200 mg tablets) orally twice daily.<br>|
| Placebo Comparator: Sorafenib plus Placebo<br>Placebo intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity | Drug: Placebo<br>* Normal saline solution for intravenous infusion will be administered as placebo for mapatumumab<br>Drug: Sorafenib<br>* Sorafenib will be supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 200 mg of sorafenib, to be administered 400 mg (2 x 200 mg tablets) orally twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression-Blinded Independent Central Review (BICR) Assessment | Time to progression is defined as the time from randomization to radiologic disease progression based on blinded independent review (BICR) of imaging scans using modified Response Evaluation Criteria in Solid Tumors assessment (mRECIST) for hepatocellular carcinoma. The primary analysis was performed using Kaplan Meier methods. The median time to progression is reported with one-sided 90% confidence interval. Analysis was performed on the modified Intent to Treat (mITT) Population which comprised of all randomized participants who received at least part of 1 dose of study agent (mapatumumab/placebo and/or sorafenib) with participants analyzed according to the groups to which they were randomized. NA indicates upper limit was not measurable as one-sided confidence interval is presented. | Randomization to maximum of 24.1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression-Investigator Assessment | Time to progression is defined as the time from randomization to radiologic disease progression. The primary analysis was performed using Kaplan Meier methods based on application of mRECIST for hepatocellular carcinoma to investigator assessments. The median time to progression is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented. | Randomization to maximum of 52.9 months | 
| Median Overall Survival | Overall survival is defined as time from randomization to death from any cause. The analysis was performed using Kaplan Meier methods. The median overall survival is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented. | Randomization to maximum of 52.9 months | 
| Progression Free Survival-BICR Assessment | Progression free survival is defined as time from randomization to radiologic disease progression or death from any cause. The analysis was performed using Kaplan Meier methods using BICR assessment of imaging scans. The median progression free survival is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented. | Randomization to maximum of 24.1 months | 
| Progression Free Survival-Investigator Assessment | Progression free survival is defined as time from randomization to radiologic disease progression or death from any cause. The analysis was performed using Kaplan Meier methods based on application of mRECIST for hepatocellular carcinoma to investigator assessments. The median progression free survival is reported with one-sided 90% confidence interval. NA indicates upper limit was not measurable as one-sided confidence interval is presented. | Randomization to maximum of 52.9 months | 
| Percentage of Participants With Objective Response-BICR Assessment | Objective response rate is defined as the percentage of participants with complete response+partial response according to mRECIST criteria for hepatocellular carcinoma using BICR assessment of imaging scans. The percentage of participants with objective response is reported along with 95% confidence interval. | Randomization to maximum of 24.1 months | 
| Percentage of Participants With Objective Response-Investigator Assessment | Objective response rate is defined as the percentage of participants with complete response+partial response according to mRECIST criteria for hepatocellular carcinoma to investigator assessments. The percentage of participants with objective response is reported along with 95% confidence interval. | Randomization to maximum of 52.9 months | 
| Percentage of Participants With Disease Control-BICR Assessment | Disease control rate is the percentage of participants with complete response+partial response+stable disease according to mRECIST criteria for hepatocellular carcinoma. The end point was based on BICR assessment of imaging scans. The percentage of participants with disease control is presented along with 95% confidence interval. | Randomization to maximum of 24.1 months | 
| Percentage of Participants With Disease Control-Investigator Assessment | Disease control rate is the percentage of participants with complete response+partial response+stable disease according to mRECIST criteria for hepatocellular carcinoma to investigator assessments. The percentage of participants with disease control is presented along with 95% confidence interval. | Randomization to maximum of 52.9 months | 
| Time to Response-BICR Assessment | Time to response is defined as time from randomization to first partial response or complete response in responders only. Complete Response (CR): Disappearance of intratumoral arterial enhancement in all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions | Randomization to maximum of 24.1 months | 
| Duration of Response-BICR Assessment | Duration of response is defined as time from first PR or CR to radiologic disease progression; in responders only. CR: Disappearance of intratumoral arterial enhancement in all target lesions. PR: At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the Baseline sum of the diameters of target lesions. Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started. | Randomization to maximum of 24.1 months | 
| Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any unfavorable or unintended sign, symptom, or disease that is temporally associated with the use of a study agent but is not necessarily caused by the study agent. An SAE is an adverse event resulting in any of the following outcomes: death, life-threatening, inpatient hospitalization, prolongation of an existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or other medically important events that may jeopardize the participant or may require intervention to prevent one of the other outcomes mentioned before. A treatment-emergent AE is an AE that emerged during treatment, having been absent pre-treatment, or worsened relative to the pre-treatment state. As-Treated Population comprised of participants who received at least part of 1 dose of study agent analyzed according to the treatment that they actually received. | Start of study treatment to maximum of 52.9 months | 
| Number of Participants With Severe AEs | An AE is any unfavorable or unintended sign, symptom, or disease that is temporally associated with the use of a study agent but is not necessarily caused by the study agent. Severity of AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life -threatening consequences; urgent intervention indicated. Grade 5 represents death related to AE. Severe AE is defined as AEs classified by investigator as severe (causing inability to carry out usual activities), life threatening or fatal using NCI-CTCAE Version 4.0 grading. | Start of study treatment to maximum of 52.9 months | 
| Number of Participants With Worst Toxicity Grade-chemistry Parameters | Blood samples were collected for the evaluation of following chemistry parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), amylase, bilirubin, gamma glutamyl transferase (GGT), calcium, potassium, magnesium, albumin, sodium and creatinine. Laboratory toxicities were graded based on the NCI-CTCAE version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life -threatening consequences; urgent intervention indicated. Number of participants with worst toxicity grades for any abnormalities observed in any chemistry parameters during the study is presented. | Enrolment to maximum of 52.9 months | 
| Number of Participants With Worst Toxicity Grade-hematology Parameters | Blood samples were collected for assessment of the following hematology parameters: activated partial thromboplastin time (APTT), hemoglobin, international normalized ratio (INR), lymphocytes, neutrophils, platelets and white blood cells (WBC). Laboratory toxicities were graded based on the NCI-CTCAE version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life -threatening consequences; urgent intervention indicated. Number of participants with worst toxicity grades for any abnormalities observed in any hematology parameters during the study is presented. | Enrolment to maximum of 52.9 months | 
| Number of Participants With Anti-mapatumumab Antibodies | Blood samples were collected for the assessment of serum antibodies. The presence of anti-mapatumumab antibodies was assessed using a validated electrochemiluminescent immunoassay. The assay incorporated a tiered testing approach which used screening and confirmation steps. The anti-drug antibody (ADA) confirmed positive participants were separated into transient or persistent antibody positives. Persistent positive refers to positive immunogenic response at 2 or more assessments or at the final assessment. Transient positive refers to positive immunogenic response at only 1 assessment and negative at the final assessment. | Randomization to maximum of 24.1 months | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP were obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point. | Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days) | 
| Change From Baseline in Heart Rate | Heart rate was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point. | Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days) | 
| Change From Baseline in Temperature | Temperature was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point. | Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days) | 
| Change From Baseline in Respiratory Rate | Respiratory rate was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose.Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point. | Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days) | 
| Change From Baseline in Weight | Weight was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time point. | Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days) | 
| Serum Concentration of Mapatumumab | Blood samples were collected for determination of serum mapatumumab concentration at the indicated time points. NA indicates standard deviation could not be calculated as only one participant was analyzed at the specified time points. | Day1 pre-dose(Cycle 1,2,4,5,6,8,9,10,12,14,16,17,18,20,22,24,26,28,30,32,34);end of infusion (Cycle 1);Day8 pre-dose(Cycle 1);Day15 pre-dose (Cycle 1,2);Day21(Cycle 2,4,6,8,9,12,14,16,18,20,22,24,26,28,30,32,34);Cycle 99(end of treatment) (21-day cycles) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced hepatocellular carcinoma, Mapatumumab, HGS1012, sorafenib