Clinical trial NCT01258608: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Hepatocellular
Keywords: advanced hepatocellular carcinoma
Mapatumumab
HGS1012
sorafenib
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2010-12-13
Enrollment: 101
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Time to Progression-Blinded Independent Central Review (BICR) Assessment
timeFrame: Randomization to maximum of 24.1 months
Secondary outcomes:
measure: Time to Progression-Investigator Assessment
timeFrame: Randomization to maximum of 52.9 months
measure: Median Overall Survival
timeFrame: Randomization to maximum of 52.9 months
measure: Progression Free Survival-BICR Assessment
timeFrame: Randomization to maximum of 24.1 months
measure: Progression Free Survival-Investigator Assessment
timeFrame: Randomization to maximum of 52.9 months
measure: Percentage of Participants With Objective Response-BICR Assessment
timeFrame: Randomization to maximum of 24.1 months
measure: Percentage of Participants With Objective Response-Investigator Assessment
timeFrame: Randomization to maximum of 52.9 months
measure: Percentage of Participants With Disease Control-BICR Assessment
timeFrame: Randomization to maximum of 24.1 months
measure: Percentage of Participants With Disease Control-Investigator Assessment
timeFrame: Randomization to maximum of 52.9 months
measure: Time to Response-BICR Assessment
timeFrame: Randomization to maximum of 24.1 months
measure: Duration of Response-BICR Assessment
timeFrame: Randomization to maximum of 24.1 months
measure: Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Start of study treatment to maximum of 52.9 months
measure: Number of Participants With Severe AEs
timeFrame: Start of study treatment to maximum of 52.9 months
measure: Number of Participants With Worst Toxicity Grade-chemistry Parameters
timeFrame: Enrolment to maximum of 52.9 months
measure: Number of Participants With Worst Toxicity Grade-hematology Parameters
timeFrame: Enrolment to maximum of 52.9 months
measure: Number of Participants With Anti-mapatumumab Antibodies
timeFrame: Randomization to maximum of 24.1 months
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
measure: Change From Baseline in Heart Rate
timeFrame: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
measure: Change From Baseline in Temperature
timeFrame: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
measure: Change From Baseline in Respiratory Rate
timeFrame: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
measure: Change From Baseline in Weight
timeFrame: Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
measure: Serum Concentration of Mapatumumab
timeFrame: 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)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: Shreveport
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Rochester
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Tupelo
country: United States
facility: GSK Investigational Site
state: Mississippi
city: Newark
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Hershey
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Hershey
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Gdansk
country: Poland
facility: GSK Investigational Site
city: Olsztyn
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Szczecin
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: Bucuresti
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca
country: Romania
facility: GSK Investigational Site
city: Craiova
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: Ekaterinburg
country: Russian Federation
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Krasnoyarsk
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Pyatigorsk
country: Russian Federation
facility: GSK Investigational Site
city: St-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Dnipropetrovsk
country: Ukraine
facility: GSK Investigational Site
city: Donetsk
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Lviv
country: Ukraine
facility: GSK Investigational Site
city: Uzhhorod
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhia
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.