Abstract
SummaryBackground There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity. Methods Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2. Results Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL −1, and 8 at DL −2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2−/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment. Conclusions The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.Electronic supplementary materialThe online version of this article (doi:10.1007/s10637-015-0313-8) contains supplementary material, which is available to authorized users.
Highlights
Approved agents against the vascular endothelial growth factor (VEGF) pathway and its receptor (VEGFR), such as bevacizumab, aflibercept, and sunitinib, provide proof of principle of targeting angiogenesis
Angiopoietins (ANG) are a family of secreted ligands of Invest New Drugs (2016) 34:104–111 the endothelial receptor Tie2 that play a critical role in initiation of tumor angiogenesis, tumor inflammation and metastasis [2]
ANG-2 is believed to be the primary ANG involved in angiogenesis in malignant setting
Summary
Approved agents against the vascular endothelial growth factor (VEGF) pathway and its receptor (VEGFR), such as bevacizumab, aflibercept, and sunitinib, provide proof of principle of targeting angiogenesis. The efficacy of these anti-VEGF therapies is suboptimal and the duration of response is often short-lived. Angiopoietins (ANG) are a family of secreted ligands of Invest New Drugs (2016) 34:104–111 the endothelial receptor Tie that play a critical role in initiation of tumor angiogenesis, tumor inflammation and metastasis [2]. ANG-2 is believed to be the primary ANG involved in angiogenesis in malignant setting. It is frequently up-regulated at areas of angiogenesis within tumors. Elevated expression of this ligand is associated with more advanced disease and poor prognosis [7,8,9,10]. The function of ANG-4 is unclear, as it has a restricted pattern of expression in lung [11]
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