title: A phase I study of TRC105 anti-endoglin (CD105) antibody in metastatic castration-resistant prostate cancer.
abstract: OBJECTIVE
  TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin (CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer (mCRPC).
  
  
  METHODS
  Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design.
  
  
  RESULTS
  A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor (VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction.
  
  
  CONCLUSIONS
  TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity.
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Fatima H
authors.initials: FH
authors.lastname: Karzai
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Apolo
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Cao
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Madan
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Adelberg
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Parnes
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: McLeod
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Harold
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Cody
authors.initials: C
authors.lastname: Peer
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Yunkai
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, MD, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015703:Antigens, CD / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000071063:Endoglin; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000453:epidemiology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D017430:Prostate-Specific Antigen; C579557:carotuximab
keywords: TRC105; angiogenesis inhibitors; anti CD105; endogolin; metastatic; prostate cancer