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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
GlaxoSmithKline ( Human Genome Sciences Inc., a GSK Company )
ClinicalTrials.gov Identifier:
NCT01258608
First received: December 7, 2010
Last updated: August 28, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Carcinoma, Hepatocellular
Drug: Mapatumumab
Drug: Placebo
Drug: Sorafenib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Time to progression (TTP) [ Time Frame: From randomization until radiologic progressive disease (PD) is documented ] [ Designated as safety issue: No ]
    Disease response assessments will be done using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for HCC. TTP is defined as the time from randomization to radiologic disease progression based on blinded independent review of imaging scans


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: From the date of randomization until death from any cause ] [ Designated as safety issue: No ]
    OS is defined as time from randomization to death from any cause.

  • Progression-free survival (PFS) [ Time Frame: From randomization until radiologic PD or death is documented. ] [ Designated as safety issue: No ]
    Disease response assessments will be done using the mRECIST criteria for HCC. PFS is defined as time from randomization to disease progression or death from any cause.

  • Overall response [ Time Frame: From randomization until radiologic PD is documented ] [ Designated as safety issue: No ]
    Disease response assessments will be done using the mRECIST criteria for HCC. Overall response is defined as complete response (CR) + partial response (PR).

  • Disease control [ Time Frame: From randomization until radiologic PD is documented ] [ Designated as safety issue: No ]
    Disease response assessments will be done using the mRECIST criteria for HCC. Disease control is defined as CR + PR + stable disease (SD).

  • Time to response [ Time Frame: From randomization until radiologic PD is documented ] [ Designated as safety issue: No ]
    Disease response assessments will be done using the mRECIST criteria for HCC. Time to response is defined as time from randomization to first PR or CR in responders only.

  • Duration of response [ Time Frame: From randomization until radiologic PD is documented ] [ Designated as safety issue: No ]
    Disease response assessments will be done using the mRECIST criteria for HCC. Duration of response is defined as time from first PR or CR to disease progression in responders only.

  • Frequency and severity of adverse events (AEs) [ Time Frame: First dose of study drug until 30 days following cessation of study drug ] [ Designated as safety issue: No ]
    All AEs will be classified by system organ class and preferred term under the Medical Dictionary for Regulatory Activities (MedDRA) system of classification with a severity assigned according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 4.0)

  • Clinical laboratory tests [ Time Frame: For the duration on treatment and 30 days after the last dose ] [ Designated as safety issue: No ]
    Clinical laboratory tests will include CBC with differential, coagulation and chemistry parameters

  • Vital signs [ Time Frame: For the duration on treatment and 30 days after the last dose ] [ Designated as safety issue: No ]
    Vital signs will include blood pressure and heart rate parameters

  • Anti-mapatumumab antibody response [ Time Frame: Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter; and at least 30 days after the last dose. ] [ Designated as safety issue: No ]
    Blood samples for serum antibodies to mapatumumab will be obtained

  • Serum mapatumumab concentration [ Time Frame: Cycle 1 (Day 1 and Day 8), Day 1 of Cycles 2, 4 and 6 and thereafter each even cycle and at least 30 days after the last dose. ] [ Designated as safety issue: No ]
    Serum mapatumumab concentration data obtained from this study will be pooled with data obtained from other studies for use in a population PK analysis


Enrollment: 101
Study Start Date: February 2011
Estimated Study Completion Date: September 2014
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sorafenib plus mapatumumab
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
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.
Drug: Sorafenib
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.
Placebo Comparator: Sorafenib plus Placebo
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
Normal saline solution for intravenous infusion will be administered as placebo for mapatumumab
Drug: Sorafenib
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01258608

  Hide Study Locations
Locations
United States, Colorado
GSK Investigational Site
Aurora, Colorado, United States, 80045
United States, Louisiana
GSK Investigational Site
Shreveport, Louisiana, United States, 71103
United States, Minnesota
GSK Investigational Site
Rochester, Minnesota, United States, 55905
United States, Mississippi
GSK Investigational Site
Tupelo, Mississippi, United States, 38801
United States, New Jersey
GSK Investigational Site
Newark, New Jersey, United States, 07103
United States, Pennsylvania
GSK Investigational Site
Hershey, Pennsylvania, United States, 17033-0850
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
GSK Investigational Site
Pittsburgh, Pennsylvania, United States, 15232
Germany
GSK Investigational Site
Muenchen, Bayern, Germany, 81377
GSK Investigational Site
Frankfurt, Hessen, Germany, 60590
GSK Investigational Site
Hannover, Niedersachsen, Germany, 30625
GSK Investigational Site
Hamburg, Germany, 20246
Poland
GSK Investigational Site
Gdansk, Poland, 80-952
GSK Investigational Site
Olsztyn, Poland, 10-228
GSK Investigational Site
Poznan, Poland, 61-878
GSK Investigational Site
Szczecin, Poland, 71-730
GSK Investigational Site
Warszawa, Poland, 02-507
GSK Investigational Site
Warszawa, Poland, 04-125
Puerto Rico
GSK Investigational Site
San Juan, Puerto Rico, 00927
Romania
GSK Investigational Site
Bucuresti, Romania, 022328
GSK Investigational Site
Cluj-Napoca, Romania, 400015
GSK Investigational Site
Craiova, Romania, 200385
GSK Investigational Site
Iasi, Romania, 700483
Russian Federation
GSK Investigational Site
Ekaterinburg, Russian Federation, 620036
GSK Investigational Site
Kazan, Russian Federation, 420029
GSK Investigational Site
Krasnoyarsk, Russian Federation, 660133
GSK Investigational Site
Moscow, Russian Federation, 115478
GSK Investigational Site
Moscow, Russian Federation, 125284
GSK Investigational Site
Moscow, Russian Federation, 195067
GSK Investigational Site
Pyatigorsk, Russian Federation, 357502
GSK Investigational Site
St-Petersburg, Russian Federation, 194017
GSK Investigational Site
St. Petersburg, Russian Federation, 198255
GSK Investigational Site
Tomsk, Russian Federation, 634050
GSK Investigational Site
Yaroslavl, Russian Federation, 150054
Ukraine
GSK Investigational Site
Dnipropetrovsk, Ukraine, 49044
GSK Investigational Site
Donetsk, Ukraine, 83092
GSK Investigational Site
Kharkiv, Ukraine, 61070
GSK Investigational Site
Kyiv, Ukraine, 03039
GSK Investigational Site
Kyiv, Ukraine, 03022
GSK Investigational Site
Lviv, Ukraine, 79031
GSK Investigational Site
Uzhhorod, Ukraine, 88014
GSK Investigational Site
Zaporizhia, Ukraine, 69032
Sponsors and Collaborators
Human Genome Sciences Inc., a GSK Company
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline ( Human Genome Sciences Inc., a GSK Company )
ClinicalTrials.gov Identifier: NCT01258608     History of Changes
Other Study ID Numbers: 200149, HGS1012-C1103
Study First Received: December 7, 2010
Last Updated: August 28, 2014
Health Authority: Russia: Ministry of Health of Russian Federation
Ukraine: State Pharmacological Center - Ministry of Health
United States: Food and Drug Administration
Romania: National Medicines Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Germany: Paul-Ehrlich-Institut

Keywords provided by GlaxoSmithKline:
advanced hepatocellular carcinoma
Mapatumumab
HGS1012
sorafenib

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Adenocarcinoma
Digestive System Diseases
Digestive System Neoplasms
Liver Diseases
Liver Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Antibodies, Monoclonal
Sorafenib
Antineoplastic Agents
Enzyme Inhibitors
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014