Kate Owen

Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia

In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low‐dose cytosine arabinoside (LDAC) in patients aged ≥60 years with acute myeloid leukemia (AML).

Phase I Study Assessing the Safety and Tolerability of Barasertib (AZD1152) With Low-Dose Cytosine Arabinoside in Elderly Patients With AML

INTRODUCTION Barasertib is the pro-drug of barasertib-hydroxy-quinazoline pyrazole anilide, a selective Aurora B kinase inhibitor that has demonstrated preliminary anti-AML activity in the clinical setting. PATIENTS AND METHODS This Phase I dose-escalation study evaluated the safety and tolerability of barasertib, combined with LDAC, in patients aged 60 years or older with de novo or secondary AML. Barasertib (7-day continuous intravenous infusion) plus LDAC 20 mg (subcutaneous injection twice daily for 10 days) was administered in 28-day cycles. The MTD was defined as the highest dose at which ≤ 1 patient within a cohort of 6 experienced a dose-limiting toxicity (DLT) (clinically significant adverse event [AE] or laboratory abnormality considered related to barasertib). The MTD cohort was expanded to 12 patients. RESULTS Twenty-two patients (median age, 71 years) received ≥ 1 treatment cycle (n = 6, 800 mg; n = 13, 1000 mg; n = 3, 1200 mg). DLTs were reported in 2 patients (both, National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 stomatitis/mucositis; 1200 mg cohort). The most common AEs were infection (73%), febrile neutropenia (59%), nausea (50%), and diarrhea (46%). Barasertib plus LDAC resulted in an overall response rate (International Working Group criteria) of 45% (n = 10/22; according to investigator opinion). CONCLUSION The MTD of 1000 mg barasertib in combination with LDAC in older patients with AML was associated with acceptable tolerability and preliminary anti-AML activity.

Potent and specific inhibition of the biological activity of the type-II transmembrane serine protease matriptase by the cyclic microprotein MCoTI-II

Matriptase is a type-II transmembrane serine protease involved in epithelial homeostasis in both health and disease, and is implicated in the development and progression of a variety of cancers. Matriptase mediates its biological effects both via as yet undefined substrates and pathways, and also by proteolytic cleavage of a variety of well-defined protein substrates, several of which it shares with the closely-related protease hepsin. Development of targeted therapeutic strategies will require discrimination between these proteases. Here we have investigated cyclic microproteins of the squash Momordica cochinchinensis trypsin-inhibitor family (generated by total chemical synthesis) and found MCoTI-II to be a high-affinity (Ki 9 nM) and highly selective (> 1,000-fold) inhibitor of matriptase. MCoTI-II efficiently inhibited the proteolytic activation of pro-hepatocyte growth factor (HGF) by matriptase but not by hepsin, in both purified and cell-based systems, and inhibited HGF-dependent cell scattering. MCoTI-II also selectively inhibited the invasion of matriptase-expressing prostate cancer cells. Using a model of epithelial cell tight junction assembly, we also found that MCoTI-II could effectively inhibit the re-establishment of tight junctions and epithelial barrier function in MDCK-I cells after disruption, consistent with the role of matriptase in regulating epithelial integrity. Surprisingly, MCoTI-II was unable to inhibit matriptase-dependent proteolytic activation of prostasin, a GPI-anchored serine protease also implicated in epithelial homeostasis. These observations suggest that the unusually high selectivity afforded by MCoTI-II and its biological effectiveness might represent a useful starting point for the development of therapeutic inhibitors, and further highlight the role of matriptase in epithelial maintenance.

Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia: Barasertib vs LDAC in AML

In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low‐dose cytosine arabinoside (LDAC) in patients aged ≥60 years with acute myeloid leukemia (AML).

Stage I of Phase II study assessing efficacy, safety and tolerability of barasertib (AZD1152) versus LDAC in elderly AML patients

In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low‐dose cytosine arabinoside (LDAC) in patients aged ≥60 years with acute myeloid leukemia (AML).