title: An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer.
abstract: OBJECTIVE
  Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with bevacizumab.
  
  
  METHODS
  Patients (n = 38) with advanced solid tumors, Eastern Cooperative Group performance status 0-1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.
  
  
  RESULTS
  TRC105 and bevacizumab were well tolerated at their recommended single-agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over 2 days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizumab. Hypertension and proteinuria were observed, though not at rates expected for single-agent bevacizumab. Several patients who had previously progressed on bevacizumab or VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) treatment experienced reductions in tumor volume, including two partial responses by RECIST, and 6 remained without progression for longer periods than during their prior VEGF inhibitor therapy.
  
  
  CONCLUSIONS
  TRC105 was well tolerated with bevacizumab and clinical activity was observed in a VEGF inhibitor-refractory population. Ongoing clinical trials are testing TRC105 in combination with bevacizumab in glioblastoma and with VEGFR TKIs in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma.
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, Arizona. mgordon@azpoh.com.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.affiliation: University of Alabama, Birmingham, Alabama.
authors.forename: Francisco
authors.initials: F
authors.lastname: Robert
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Daniela
authors.initials: D
authors.lastname: Matei
authors.affiliation: Pinnacle Oncology Hematology, Scottsdale, Arizona.
authors.forename: David S
authors.initials: DS
authors.lastname: Mendelson
authors.affiliation: UCLA Department of Medicine, Los Angeles, California.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana. University of Washington, Seattle, Washington.
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strother
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Ben K
authors.initials: BK
authors.lastname: Seon
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.affiliation: Clinical Pharmacology Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Peer
authors.affiliation: TRACON Pharmaceuticals, San Diego, California.
authors.forename: Delia
authors.initials: D
authors.lastname: Alvarez
authors.affiliation: TRACON Pharmaceuticals, San Diego, California.
authors.forename: Bonne J
authors.initials: BJ
authors.lastname: Adams
authors.affiliation: TRACON Pharmaceuticals, San Diego, California.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Theuer
authors.affiliation: UCLA Department of Medicine, Los Angeles, California.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C579557:carotuximab