title: A phase II study of TRC105 in patients with hepatocellular carcinoma who have progressed on sorafenib.
abstract: BACKGROUND
  Endoglin is an endothelial cell membrane receptor essential for angiogenesis and highly expressed on the vasculature of many tumor types, including hepatocellular carcinoma (HCC). TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis, and complements VEGF inhibitors.
  
  
  OBJECTIVE
  The aim of this phase II study was to evaluate the efficacy of anti-endoglin therapy with TRC105 in patients with advanced HCC, post-sorafenib.
  
  
  METHODS
  Patients with HCC and compensated liver function (Childs-Pugh A/B7), ECOG 0/1, were enrolled to a single-arm, phase II study of TRC105 15 mg/kg IV every two weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal two-stage design was employed with a 50% four-month PFS target for progression to the second stage. Correlative biomarkers evaluated included DCE-MRI as well as plasma levels of angiogenic biomarkers and soluble CD105.
  
  
  RESULTS
  A total accrual of 27 patients was planned. However, because of lack of efficacy and in accordance with the Simon two-stage design, 11 patients were enrolled. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N = 3) and epistaxis (G1; N = 4). One patient had a confirmed partial response by standard RECIST criteria and biologic response on DCE-MRI but the four-month PFS was insufficient to proceed to the second stage of the study.
  
  
  CONCLUSIONS
  TRC105 was well tolerated in this HCC population following sorafenib. Although there was evidence of clinical activity, this did not meet prespecified criteria to proceed to the second stage. TRC105 development in HCC continues as combination therapy with sorafenib.
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Duffy
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Ulahannan
authors.affiliation: Genetics Branch, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cao
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: O E
authors.initials: OE
authors.lastname: Rahma
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: O V
authors.initials: OV
authors.lastname: Makarova-Rusher
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fioravanti
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: S
authors.initials: S
authors.lastname: Carey
authors.affiliation: Genetics Branch, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Radiology and Imaging Sciences, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Venkatesan
authors.affiliation: Molecular Imaging Department, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: B
authors.initials: B
authors.lastname: Turkbey
authors.affiliation: Molecular Imaging Department, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: P
authors.initials: P
authors.lastname: Choyke
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: J
authors.initials: J
authors.lastname: Trepel
authors.affiliation: Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Bollen
authors.affiliation: Biostatistics and Data Management, Center for Cancer Research, National Institutes of Health, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Greten
keywords: CD105; Hepatocellular carcinoma; angiogenesis; clinical trial; endoglin