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

Primary Purpose

Carcinoma, Hepatocellular

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Mapatumumab
Placebo
Sorafenib
Sponsored by
Human Genome Sciences Inc., a GSK Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Carcinoma, Hepatocellular focused on measuring advanced hepatocellular carcinoma, Mapatumumab, HGS1012, sorafenib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site
  • GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Sorafenib plus mapatumumab

Sorafenib plus Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
December 7, 2010
Last Updated
November 28, 2018
Sponsor
Human Genome Sciences Inc., a GSK Company
Collaborators
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT01258608
Brief Title
Study of Mapatumumab in Combination With Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
February 8, 2011 (Actual)
Primary Completion Date
May 31, 2013 (Actual)
Study Completion Date
November 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Human Genome Sciences Inc., a GSK Company
Collaborators
GlaxoSmithKline

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Hepatocellular
Keywords
advanced hepatocellular carcinoma, Mapatumumab, HGS1012, sorafenib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
101 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sorafenib plus mapatumumab
Arm Type
Experimental
Arm Description
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
Arm Title
Sorafenib plus Placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Mapatumumab
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Normal saline solution for intravenous infusion will be administered as placebo for mapatumumab
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Intervention Description
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.
Primary Outcome Measure Information:
Title
Time to Progression-Blinded Independent Central Review (BICR) Assessment
Description
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.
Time Frame
Randomization to maximum of 24.1 months
Secondary Outcome Measure Information:
Title
Time to Progression-Investigator Assessment
Description
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.
Time Frame
Randomization to maximum of 52.9 months
Title
Median Overall Survival
Description
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.
Time Frame
Randomization to maximum of 52.9 months
Title
Progression Free Survival-BICR Assessment
Description
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.
Time Frame
Randomization to maximum of 24.1 months
Title
Progression Free Survival-Investigator Assessment
Description
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.
Time Frame
Randomization to maximum of 52.9 months
Title
Percentage of Participants With Objective Response-BICR Assessment
Description
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.
Time Frame
Randomization to maximum of 24.1 months
Title
Percentage of Participants With Objective Response-Investigator Assessment
Description
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.
Time Frame
Randomization to maximum of 52.9 months
Title
Percentage of Participants With Disease Control-BICR Assessment
Description
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.
Time Frame
Randomization to maximum of 24.1 months
Title
Percentage of Participants With Disease Control-Investigator Assessment
Description
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.
Time Frame
Randomization to maximum of 52.9 months
Title
Time to Response-BICR Assessment
Description
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
Time Frame
Randomization to maximum of 24.1 months
Title
Duration of Response-BICR Assessment
Description
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.
Time Frame
Randomization to maximum of 24.1 months
Title
Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Start of study treatment to maximum of 52.9 months
Title
Number of Participants With Severe AEs
Description
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.
Time Frame
Start of study treatment to maximum of 52.9 months
Title
Number of Participants With Worst Toxicity Grade-chemistry Parameters
Description
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.
Time Frame
Enrolment to maximum of 52.9 months
Title
Number of Participants With Worst Toxicity Grade-hematology Parameters
Description
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.
Time Frame
Enrolment to maximum of 52.9 months
Title
Number of Participants With Anti-mapatumumab Antibodies
Description
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.
Time Frame
Randomization to maximum of 24.1 months
Title
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Description
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.
Time Frame
Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
Title
Change From Baseline in Heart Rate
Description
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.
Time Frame
Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
Title
Change From Baseline in Temperature
Description
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.
Time Frame
Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
Title
Change From Baseline in Respiratory Rate
Description
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.
Time Frame
Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
Title
Change From Baseline in Weight
Description
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.
Time Frame
Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
Title
Serum Concentration of Mapatumumab
Description
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.
Time Frame
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
GSK Investigational Site
City
Shreveport
State/Province
Louisiana
ZIP/Postal Code
71103
Country
United States
Facility Name
GSK Investigational Site
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
GSK Investigational Site
City
Tupelo
State/Province
Mississippi
ZIP/Postal Code
38801
Country
United States
Facility Name
GSK Investigational Site
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07103
Country
United States
Facility Name
GSK Investigational Site
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033-0850
Country
United States
Facility Name
GSK Investigational Site
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033-
Country
United States
Facility Name
GSK Investigational Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
GSK Investigational Site
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Facility Name
GSK Investigational Site
City
Muenchen
State/Province
Bayern
ZIP/Postal Code
81377
Country
Germany
Facility Name
GSK Investigational Site
City
Frankfurt
State/Province
Hessen
ZIP/Postal Code
60590
Country
Germany
Facility Name
GSK Investigational Site
City
Hannover
State/Province
Niedersachsen
ZIP/Postal Code
30625
Country
Germany
Facility Name
GSK Investigational Site
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
GSK Investigational Site
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
GSK Investigational Site
City
Olsztyn
ZIP/Postal Code
10-228
Country
Poland
Facility Name
GSK Investigational Site
City
Poznan
ZIP/Postal Code
61-878
Country
Poland
Facility Name
GSK Investigational Site
City
Szczecin
ZIP/Postal Code
71-730
Country
Poland
Facility Name
GSK Investigational Site
City
Warszawa
ZIP/Postal Code
02-507
Country
Poland
Facility Name
GSK Investigational Site
City
Warszawa
ZIP/Postal Code
04-125
Country
Poland
Facility Name
GSK Investigational Site
City
San Juan
ZIP/Postal Code
00927
Country
Puerto Rico
Facility Name
GSK Investigational Site
City
Bucuresti
ZIP/Postal Code
022328
Country
Romania
Facility Name
GSK Investigational Site
City
Cluj-Napoca
ZIP/Postal Code
400015
Country
Romania
Facility Name
GSK Investigational Site
City
Craiova
ZIP/Postal Code
200385
Country
Romania
Facility Name
GSK Investigational Site
City
Iasi
ZIP/Postal Code
700483
Country
Romania
Facility Name
GSK Investigational Site
City
Ekaterinburg
ZIP/Postal Code
620036
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Kazan
ZIP/Postal Code
420029
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Krasnoyarsk
ZIP/Postal Code
660133
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Moscow
ZIP/Postal Code
115478
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Moscow
ZIP/Postal Code
125284
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Moscow
ZIP/Postal Code
195067
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Pyatigorsk
ZIP/Postal Code
357502
Country
Russian Federation
Facility Name
GSK Investigational Site
City
St-Petersburg
ZIP/Postal Code
194017
Country
Russian Federation
Facility Name
GSK Investigational Site
City
St. Petersburg
ZIP/Postal Code
198255
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Tomsk
ZIP/Postal Code
634050
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Yaroslavl
ZIP/Postal Code
150054
Country
Russian Federation
Facility Name
GSK Investigational Site
City
Dnipropetrovsk
ZIP/Postal Code
49044
Country
Ukraine
Facility Name
GSK Investigational Site
City
Donetsk
ZIP/Postal Code
83092
Country
Ukraine
Facility Name
GSK Investigational Site
City
Kharkiv
ZIP/Postal Code
61070
Country
Ukraine
Facility Name
GSK Investigational Site
City
Kyiv
ZIP/Postal Code
03022
Country
Ukraine
Facility Name
GSK Investigational Site
City
Kyiv
ZIP/Postal Code
03039
Country
Ukraine
Facility Name
GSK Investigational Site
City
Lviv
ZIP/Postal Code
79031
Country
Ukraine
Facility Name
GSK Investigational Site
City
Uzhhorod
ZIP/Postal Code
88014
Country
Ukraine
Facility Name
GSK Investigational Site
City
Zaporizhia
ZIP/Postal Code
69032
Country
Ukraine

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Citations:
PubMed Identifier
26802147
Citation
Ciuleanu T, Bazin I, Lungulescu D, Miron L, Bondarenko I, Deptala A, Rodriguez-Torres M, Giantonio B, Fox NL, Wissel P, Egger J, Ding M, Kalyani RN, Humphreys R, Gribbin M, Sun W. A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma. Ann Oncol. 2016 Apr;27(4):680-7. doi: 10.1093/annonc/mdw004. Epub 2016 Jan 22.
Results Reference
background
Links:
URL
https://www.clinicalstudydatarequest.com
Description
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.
Available IPD and Supporting Information:
Available IPD/Information Type
Study Protocol
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
200149
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Informed Consent Form
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
200149
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Statistical Analysis Plan
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
200149
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Clinical Study Report
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
200149
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
200149
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Dataset Specification
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
200149
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register

Learn more about this trial

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

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