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A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer.

ABSTRACT: PURPOSE: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. PATIENTS AND 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. CONCLUSION: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.

SUBMITTER: Rosen LS

PROVIDER: S-EPMC3432706 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer.

Rosen Lee S LS Hurwitz Herbert I HI Wong Michael K MK Goldman Jonathan J Mendelson David S DS Figg William D WD Spencer Shawn S Adams Bonne J BJ Alvarez Delia D Seon Ben K BK Theuer Charles P CP Leigh Bryan R BR Gordon Michael S MS

Clinical cancer research : an official journal of the American Association for Cancer Research 20120705 17

<h4>Purpose</h4>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.<h4>Patients and methods</h4>Patients received escalating doses of intravenous TRC105 until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.<h4>Results</h4>Fifty patients were treated with escalating doses of ...[more]

PMID: 22767667

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Project description: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.

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:The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder. Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI). Regorafenib 80 mg daily plus cetuximab 200 mg/m2 loading dose, followed by 150 mg/m2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high. clinicaltrials.gov NCT02095054FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).

Dataset Information

A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer.

Publications

A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer.

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