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NCT01258608

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

Completed Phase 1, PHASE2 Results posted Last updated 19 December 2018
What this trial tests

Phase 1, PHASE2 trial testing Mapatumumab in Carcinoma, Hepatocellular in 101 participants. Completed in 29 November 2017.

Timeline
8 February 2011
Primary endpoint
31 May 2013
29 November 2017

Quick facts

Lead sponsorHuman Genome Sciences Inc., a GSK Company
PhasePhase 1, PHASE2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingdouble
Primary purposetreatment
Enrollment101
Start date8 February 2011
Primary completion31 May 2013
Estimated completion29 November 2017
Sites43 locations across Russia, Ukraine, Germany, Poland, Romania, Puerto Rico, United States

Drugs / interventions tested

Conditions studied

Sponsor

Human Genome Sciences Inc., a GSK Company — full company profile →

Who can join

18 and older, any sex, with Carcinoma, Hepatocellular. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Time to Progression-Blinded Independent Central Review (BICR) Assessment Primary · Randomization to maximum of 24.1 months

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/pl

GroupValue95% CI
Sorafenib+Placebo5.64.3 – NA
Sorafenib+Mapatumumab 30 mg/kg4.12.8 – NA
Time to Progression-Investigator Assessment Secondary · Randomization to maximum of 52.9 months

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.

GroupValue95% CI
Sorafenib+Placebo8.35.4 – NA
Sorafenib+Mapatumumab 30 mg/kg6.45.4 – NA
Median Overall Survival Secondary · Randomization to maximum of 52.9 months

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.

GroupValue95% CI
Sorafenib+Placebo10.18.9 – NA
Sorafenib+Mapatumumab 30 mg/kg10.07.3 – NA
Progression Free Survival-BICR Assessment Secondary · Randomization to maximum of 24.1 months

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.

GroupValue95% CI
Sorafenib+Placebo4.33.1 – NA
Sorafenib+Mapatumumab 30 mg/kg3.22.7 – NA
Progression Free Survival-Investigator Assessment Secondary · Randomization to maximum of 52.9 months

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.

GroupValue95% CI
Sorafenib+Placebo5.43.6 – NA
Sorafenib+Mapatumumab 30 mg/kg4.03.4 – NA
Percentage of Participants With Objective Response-BICR Assessment Secondary · Randomization to maximum of 24.1 months

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.

GroupValue95% CI
Sorafenib+Placebo12.54.2 – 26.8
Sorafenib+Mapatumumab 30 mg/kg17.97.5 – 33.5
Percentage of Participants With Objective Response-Investigator Assessment Secondary · Randomization to maximum of 52.9 months

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.

GroupValue95% CI
Sorafenib+Placebo7.82.2 – 18.9
Sorafenib+Mapatumumab 30 mg/kg14.66.1 – 27.8
Percentage of Participants With Disease Control-BICR Assessment Secondary · Randomization to maximum of 24.1 months

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.

GroupValue95% CI
Sorafenib+Placebo92.579.6 – 98.4
Sorafenib+Mapatumumab 30 mg/kg71.855.1 – 85.0
Percentage of Participants With Disease Control-Investigator Assessment Secondary · Randomization to maximum of 52.9 months

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.

GroupValue95% CI
Sorafenib+Placebo74.560.4 – 85.7
Sorafenib+Mapatumumab 30 mg/kg68.853.7 – 81.3
Time to Response-BICR Assessment Secondary · Randomization to maximum of 24.1 months

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

GroupValue95% CI
Sorafenib+Placebo4441 – 85
Sorafenib+Mapatumumab 30 mg/kg4841 – 188
Duration of Response-BICR Assessment Secondary · Randomization to maximum of 24.1 months

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

GroupValue95% CI
Sorafenib+Placebo12355 – 325
Sorafenib+Mapatumumab 30 mg/kg12742 – 372
Number of Participants With Treatment-emergent Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) Secondary · Start of study treatment to maximum of 52.9 months

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

Non-serious AEs
GroupValue95% CI
Sorafenib+Placebo47
Sorafenib+Mapatumumab 30 mg/kg49
SAEs
GroupValue95% CI
Sorafenib+Placebo27
Sorafenib+Mapatumumab 30 mg/kg21

Adverse events — posted to ClinicalTrials.gov

Time frame: Start of study treatment up to maximum of 52.9 months. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Sorafenib+Placebo
Serious: 27/51 (53%)
Deaths: 40/51
Sorafenib+Mapatumumab 30 mg/kg
Serious: 21/50 (42%)
Deaths: 39/50

Serious adverse events (43 terms)

ReactionSystemSorafenib+PlaceboSorafenib+Mapatumumab 30 m…
Hepatocellular carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Oesophageal varices haemorrhageGastrointestinal disorders
Hepatic failureHepatobiliary disorders
Gamma-glutamyltransferase increasedInvestigations
Acute myocardial infarctionCardiac disorders
Gastric haemorrhageGastrointestinal disorders
Upper gastrointestinal haemorrhageGastrointestinal disorders
General physical health deteriorationGeneral disorders
Blood bilirubin increasedInvestigations
HyperkalaemiaMetabolism and nutrition disorders
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
Disseminated intravascular coagulationBlood and lymphatic system disorders
Cardio-respiratory arrestCardiac disorders
Myocardial ischaemiaCardiac disorders
Atrial fibrillationCardiac disorders
Atrial flutterCardiac disorders
Atrioventricular blockCardiac disorders
Food poisoningGastrointestinal disorders
AscitesGastrointestinal disorders
Gastric ulcerGastrointestinal disorders
Gastric ulcer haemorrhageGastrointestinal disorders
Disease progressionGeneral disorders
FatigueGeneral disorders
HyperbilirubinaemiaHepatobiliary disorders
AppendicitisInfections and infestations
Other adverse events (49 terms — click to expand)

ReactionSystemSorafenib+PlaceboSorafenib+Mapatumumab 30 m…
Weight decreasedInvestigations
DiarrhoeaGastrointestinal disorders
Palmar-plantar erythrodysaesthesia syndromeSkin and subcutaneous tissue disorders
Lipase increasedInvestigations
HypertensionVascular disorders
FatigueGeneral disorders
Decreased appetiteMetabolism and nutrition disorders
AstheniaGeneral disorders
Aspartate aminotransferase increasedInvestigations
Gamma-glutamyltransferase increasedInvestigations
AnaemiaBlood and lymphatic system disorders
Abdominal painGastrointestinal disorders
Oedema peripheralGeneral disorders
Blood bilirubin increasedInvestigations
HypocalcaemiaMetabolism and nutrition disorders
Rash papularSkin and subcutaneous tissue disorders
NauseaGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
Amylase increasedInvestigations
ThrombocytopeniaBlood and lymphatic system disorders
VomitingGastrointestinal disorders
HyponatraemiaMetabolism and nutrition disorders
AscitesGastrointestinal disorders
Platelet count decreasedInvestigations
HypokalaemiaMetabolism and nutrition disorders
Pain in extremityMusculoskeletal and connective tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
HyperkeratosisSkin and subcutaneous tissue disorders
RashSkin and subcutaneous tissue disorders
PyrexiaGeneral disorders
HyperbilirubinaemiaHepatobiliary disorders
Blood alkaline phosphatase increasedInvestigations
Abdominal pain upperGastrointestinal disorders
HaemorrhoidsGastrointestinal disorders
StomatitisGastrointestinal disorders
HeadacheNervous system disorders
AlopeciaSkin and subcutaneous tissue disorders
PruritusSkin and subcutaneous tissue disorders
ConstipationGastrointestinal disorders
DyspepsiaGastrointestinal disorders

Most-reported serious reactions: Hepatocellular carcinoma, Oesophageal varices haemorrhage, Hepatic failure, Gamma-glutamyltransferase increased, Acute myocardial infarction, Gastric haemorrhage, Upper gastrointestinal haemorrhage, General physical health deterioration.

Data from ClinicalTrials.gov NCT01258608 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Developing TRAIL/TRAIL death receptor-based cancer therapies.
    Yuan X, Gajan A, Chu Q, Xiong H, et al · · 2018 · cited 200× · PMID 29541897 · DOI 10.1007/s10555-018-9728-y
  2. Death receptors as targets in cancer.
    Micheau O, Shirley S, Dufour F. · · 2013 · cited 151× · PMID 23638798 · DOI 10.1111/bph.12238
  3. The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials.
    Snajdauf M, Havlova K, Vachtenheim J, Ozaniak A, et al · · 2021 · cited 126× · PMID 33791337 · DOI 10.3389/fmolb.2021.628332
  4. The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer.
    Pimentel JM, Zhou JY, Wu GS. · · 2023 · cited 73× · PMID 37345089 · DOI 10.3390/cancers15102752
  5. Clinical trials in hepatocellular carcinoma: an update.
    Shen YC, Lin ZZ, Hsu CH, Hsu C, et al · · 2013 · cited 55× · PMID 24400222 · DOI 10.1159/000343850
  6. Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity.
    Siegemund M, Pollak N, Seifert O, Wahl K, et al · · 2012 · cited 52× · PMID 22495350 · DOI 10.1038/cddis.2012.29
  7. TRAIL-based gene delivery and therapeutic strategies.
    Zhong HH, Wang HY, Li J, Huang YZ. · · 2019 · cited 45× · PMID 31444476 · DOI 10.1038/s41401-019-0287-8
  8. Molecular therapies in hepatocellular carcinoma: what can we target?
    Galuppo R, Ramaiah D, Ponte OM, Gedaly R. · · 2014 · cited 37× · PMID 24573715 · DOI 10.1007/s10620-014-3058-x

Verify or expand the search:

Other recruiting trials for Carcinoma, Hepatocellular

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing