An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer

Michael S. Gordon, Francisco Robert, Daniela Matei, David S. Mendelson, Jonathan W. Goldman, E. Gabriela Chiorean, Robert M. Strother, Ben K. Seon, William D. Figg, Cody J. Peer, Delia Alvarez, Bonne J. Adams, Charles P. Theuer, Lee S. Rosen

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish
Pages (from-to)5918-5926
Number of pages9
JournalClinical Cancer Research
Volume20
Issue number23
DOIs
StatePublished - Dec 1 2014

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Anti-Idiotypic Antibodies
Neoplasms
Vascular Endothelial Growth Factor A
Endoglin
TRC105
Bevacizumab
Vascular Endothelial Growth Factor Receptor
Glioblastoma
Tumor Burden
Proteinuria
Renal Cell Carcinoma
Sarcoma
Protein-Tyrosine Kinases
Headache
Disease Progression
Hepatocellular Carcinoma
Research Design
Endothelial Cells
Pharmacokinetics
Immunoglobulin G

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. / Gordon, Michael S.; Robert, Francisco; Matei, Daniela; Mendelson, David S.; Goldman, Jonathan W.; Chiorean, E. Gabriela; Strother, Robert M.; Seon, Ben K.; Figg, William D.; Peer, Cody J.; Alvarez, Delia; Adams, Bonne J.; Theuer, Charles P.; Rosen, Lee S.

In: Clinical Cancer Research, Vol. 20, No. 23, 01.12.2014, p. 5918-5926.

Research output: Contribution to journalArticle

Gordon, MS, Robert, F, Matei, D, Mendelson, DS, Goldman, JW, Chiorean, EG, Strother, RM, Seon, BK, Figg, WD, Peer, CJ, Alvarez, D, Adams, BJ, Theuer, CP & Rosen, LS 2014, 'An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer', Clinical Cancer Research, vol. 20, no. 23, pp. 5918-5926. https://doi.org/10.1158/1078-0432.CCR-14-1143
Gordon, Michael S. ; Robert, Francisco ; Matei, Daniela ; Mendelson, David S. ; Goldman, Jonathan W. ; Chiorean, E. Gabriela ; Strother, Robert M. ; Seon, Ben K. ; Figg, William D. ; Peer, Cody J. ; Alvarez, Delia ; Adams, Bonne J. ; Theuer, Charles P. ; Rosen, Lee S. / An open-label phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) with bevacizumab in patients with advanced cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 23. pp. 5918-5926.
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AU - Matei, Daniela

AU - Mendelson, David S.

AU - Goldman, Jonathan W.

AU - Chiorean, E. Gabriela

AU - Strother, Robert M.

AU - Seon, Ben K.

AU - Figg, William D.

AU - Peer, Cody J.

AU - Alvarez, Delia

AU - Adams, Bonne J.

AU - Theuer, Charles P.

AU - Rosen, Lee S.

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N2 - Purpose: 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. Experimental Design: 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.

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