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

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.

High prevalence of malnutrition and nutrition impact symptoms in older patients with cancer: Results of a Brazilian multicenter study

“…This is in line with findings from 2 recent studies conducted in Japan, which showed that no appetite was the most prevalent symptom in patients with cancer, with a prevalence ranging from 20% to 24.4% . However, in 2 other studies conducted in patients with advanced cancer, the prevalence of no appetite varied between 53% and 57%, which is even higher than that found in our study …”

“…35,36 However, in 2 other studies conducted in patients with advanced cancer, the prevalence of no appetite varied between 53% and 57%, which is even higher than that found in our study. [37][38][39] Nausea was higher in patients with gynecological cancer, and similar findings were reported in a conductive study at Aga Khan University Hospital, Pakistani, where 1 of the most common adverse effects was nausea (33.3%) in patients who received pelvic radiotherapy for gynecological cancer. 40 Conversely, repeated vomiting is 1 of the symptoms used to diagnose upper digestive cancer, because it is considered an alarm symptom.…”

Cervical cancer cell–derived angiopoietins promote tumor progression

“…20 A recent study revealed that antibodies inhibiting the interaction between Ang-1, Ang-2, and Tie-2 receptor, such as AMG 380 and AMG 780, offered greater superiority in inhibiting tumor growth, viable tumor fraction, and tumor EC proliferation for advanced solid tumors compared with antibody solely interrupting the binding of Ang-2 and Tie-2. 29 Moreover, clinical trials for multiple solid tumors indicated that dual inhibition of Ang-1 and -2 had more advantages than only blocking Ang-2/Tie signaling. 30,31 We found that Ang-1 and -2 were highly expressed in cervical cancer cells and downregulating Ang-1 and -2 inhibited tumor growth, suggesting that dual inhibition of Ang-1 and -2 may be a potential anti-angiogenic pharmaceutical target for the treatment of cervical cancer.…”

Ang-2 but not Ang-1 expression in perivascular soft tissue tumors

“…Directed anti-angiopoietin therapies are possible (including Trebananib, AMG 386), and have been investigated as antiangiogenic therapies in epithelial, [18][19][20][21][22] hematopoietic, 23 and mesenchymal malignancies. 24 The most promising results for Trebananib therapy appear to be in ovarian cancer (reviewed in 18).…”