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Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer.

ABSTRACT: TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin-2 [Ang-2], insulin-like growth factor-binding protein-3 [IGFBP-3], plasminogen activator inhibitor-1 [PAI-1] total, platelet-derived growth factor [PDGF]-AA, PDGF-BB, thrombospondin-1 [TSP-1], and vascular endothelial growth factor [VEGF]-D). Meanwhile, seven markers were upregulated by C2D1 (E-Cadherin, soluble Endoglin [sEnd], E-Selectin, interleukin-6 [IL-6], osteopontin [OPN], TSP-2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang-2, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), IGFBP-1, IL-6, TSP-2, and vascular cell adhesion molecule-1 (VCAM-1). A statistical trend was also seen for increases of VEGF-A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma-based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang-2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105's anti-angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF-targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.

SUBMITTER: Liu Y

PROVIDER: S-EPMC4101749 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer.

Liu Yingmiao Y Starr Mark D MD Brady John C JC Dellinger Andrew A Pang Herbert H Adams Bonne B Theuer Charles P CP Lee Nam Y NY Hurwitz Herbert I HI Nixon Andrew B AB

Cancer medicine 20140214 3

TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantl ...[more]

PMID: 24574330

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Project description:BACKGROUND:TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC). SUBJECTS, MATERIALS, AND METHODS:Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design. RESULTS:Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-? receptor 3 correlated with overall response rate. CONCLUSION:TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064). IMPLICATIONS FOR PRACTICE:TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.

Project description:BackgroundBased on molecular biomarkers, anti-angiogenic drugs in combination with programmed cell death protein 1 (PD-1) antibodies can screen the potentially beneficial populations with hepatocellular carcinoma (HCC) and predict the efficacy after treatment. Therefore, we aimed to study predictive molecular biomarkers to improve the effectiveness of immuno-targeted combination therapy for HCC.Patients and methodsBaseline clinical data, blood samples, and imaging data of the first evaluation after two cycles of treatment were collected for 40 patients with advanced HCC who underwent combination therapy, and then these data were compared according to the efficacy. Since 15 patients had complete hematology samples, we additionally tested the T lymphocyte subpopulations of these 15 patients and also compared them according to the efficacy. In addition, we also selected five patients who benefited the most from the combination therapy and five patients with the worst curative effect for gene detection based on survival time and efficacy evaluation. Finally, the relationship between certain clinical characteristics, laboratory indicators, specific T lymphocyte subpopulations, gene mutations and the response of immuno-targeted combination therapy for HCC was evaluated.ResultsThe high levels of CD3+CD4+CD279+, CD3+CD8+CD45RO+CD62L+T lymphocytes and tumor mutational burden (TMB) were associated with good efficacy of the combination therapy (P=0.03, P<0.01 and P=0.03). The high levels of CD3+CD4+CD28+ T lymphocytes were associated with poor efficacy of the combination therapy (P=0.02). The high mutation frequency of TP53 and ARID1A appeared in the non-response cohort. In addition, amplification mutation of 11q13-CCND1, FGF3, FGF4, and FGF19 was found in a patient with hyperprogression (HP).ConclusionsThe certain clinical characteristics, laboratory indicators, specific T lymphocyte subpopulations, and gene mutations established in this paper were potential predictive biomarkers for HCC patients treated with combination therapy.

Dataset Information

Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer.

Publications

Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer.

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