title: A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer.
abstract: OBJECTIVE
  TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors.
  
  
  METHODS
  Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.
  
  
  RESULTS
  Fifty patients were treated with escalating doses of TRC105. The maximum tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concentrations that saturate CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 weeks. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 months.
  
  
  CONCLUSIONS
  TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 weeks, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clinical activity was seen in a refractory patient population. Ongoing clinical trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer.
authors: UCLA Department of Medicine, Los Angeles, CA90404, USA. lrosen@mednet.ucla.edu
authors: Lee S
authors: LS
authors: Rosen
authors: Herbert I
authors: HI
authors: Hurwitz
authors: Michael K
authors: MK
authors: Wong
authors: Jonathan
authors: J
authors: Goldman
authors: David S
authors: DS
authors: Mendelson
authors: William D
authors: WD
authors: Figg
authors: Shawn
authors: S
authors: Spencer
authors: Bonne J
authors: BJ
authors: Adams
authors: Delia
authors: D
authors: Alvarez
authors: Ben K
authors: BK
authors: Seon
authors: Charles P
authors: CP
authors: Theuer
authors: Bryan R
authors: BR
authors: Leigh
authors: Michael S
authors: MS
authors: Gordon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015703:Antigens, CD / Q000276:immunology; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced; D000071063:Endoglin; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C579557:carotuximab