A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours

Hong, David S.; Kurzrock, Razelle; Mulay, Marilyn; Wu, Benjamin; Bass, Michael; Zhong, Zhandong Don; Friberg, Greg; Rosen, Lee S.

doi:10.18632/oncotarget.2568

Cited by 13 publications

(10 citation statements)

References 41 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although trebananib monotherapy has a favorable toxicity profile and the addition of trebananib to cytotoxic chemotherapy was well tolerated [ 13 ], combinations with other anti-angiogenic drugs have proven to be much more challenging. The AEs observed with the trebananib and bevacizumab combination included fatigue, diarrhea, nausea and epistaxis, whereas those of combining with motesanib were hypertension, diarrhea, fatigue and gastrointestinal upset [ 20 ]. Trebananib plus sorafenib led to diarrhea, palmar-plantar erythrodysesthesia syndrome, alopecia, hypertension and fatigue [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It has undergone early phase human clinical trials in several cancers, including metastatic breast cancer. However, it remains unclear whether inhibition of the angiopoietin pathway will affect survival outcomes in breast cancer [11-13]. …”

Section: Introductionmentioning

confidence: 99%

Angiopoietin pathway gene expression associated with poor breast cancer survival

Ramanathan

Olex

Dozmorov

et al. 2017

Breast Cancer Res Treat

View full text Add to dashboard Cite

Purpose Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a “big data” approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA). Methods A total of 888 patients with adequate gene expression, disease-free survival (DFS) and overall survival (OS) data were selected for analysis. DFS and OS were calculated for patients with high and low expression of angiopoietin and VEGF pathway genes using TCGA data. Gene-specific thresholds to dichotomize patients into high and low expression were determined and survival plots were generated. Results The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology and survival. High Ang2 gene expression was associated with not only decreased DFS (p=0.05), but also decreased OS (p<0.05). High co-expression of Ang2 and its receptor Tie2 was associated with both decreased DFS and OS (p<0.05). There was strong correlation between angiopoietin and VEGF pathway genes. While high expression of VEGFA alone was not associated with survival, high co-expression with Ang2 was associated with decreased OS. Conclusions This study validates TCGA as a representative database providing genomic data and survival outcomes in breast cancer. Our TCGA data supports the angiopoietin pathway as a key mediator in the pathologic angiogenic switch in breast cancer.

show abstract

“…For example, two studies indicate that Ang-2 levels are elevated in SCLC compared to healthy controls and this increases an independent predictor for shorter OS (34,35). Trebananib, an angiopoietin inhibitor, has been combined with the VEGF inhibitors Bev or motesanib in a phase 1b trial in various solid tumors; only 2 enrolled patients had SCLC and none achieved a partial response to treatment (36). On the other hand, several studies and a recent systematic review and meta-analysis support both the predictive and prognostic capacity of basic FGF (bFGF) overexpression in SCLC (37)(38)(39).…”

Section: Angiogenesis In Sclcmentioning

confidence: 99%

Targeting angiogenesis in small cell lung cancer

Stratigos

Matikas

Voutsina

et al. 2016

Transl. Lung Cancer Res.

View full text Add to dashboard Cite

Small cell lung cancer (SCLC) is a highly aggressive and lethal malignancy. Despite high initial response rates to systemic chemotherapy, the disease eventually relapses; further treatment only modestly improves outcomes and overall survival (OS) for patients with extensive stage disease is less than one year.Little progress has been made during the past decades, with no new drugs approved. Consequently, the development of novel strategies is an unmet need. The inhibition of angiogenesis, a defining characteristic of cancer, has demonstrated modest efficacy in several human malignancies, including non-small cell lung cancer (NSCLC). However, results from clinical trials in SCLC have been disappointing, and no anti-angiogenic agent has received regulatory approval due to lack of clinical efficacy. The elucidation of underlying mechanisms responsible for tumor resistance to angiogenic therapy and the simultaneous blockade of multiple elements that play a role in angiogenesis need to be further explored.

show abstract

A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours

Cited by 13 publications

References 41 publications

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)

Angiopoietin pathway gene expression associated with poor breast cancer survival

Targeting angiogenesis in small cell lung cancer

Contact Info

Product

Resources

About