Athenex (United States)

Poor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. This multi-center phase Ib open-label safety and activity study involved elderly patients with relapsed or refractory AML, or who declined standard chemotherapy. Twenty-four patients averaging 74years of age were enrolled. The majority previously received hypomethylating agents. Five doses were tested: 40mg (n = 1), 80mg (n = 2), 120mg (n = 8), 140mg (n = 12), and 160mg (n = 1). Seven patients were treated for 12days or less, nine for 15-29days, five for 33-58days, and three for 77-165days. One patient receiving 120mg for 165days had reduced splenomegaly and survived 373days. Another had no evidence of disease progression for 154days. One patient receiving 160mg for 12days remained treatment-free for about 18months. Dose-limiting toxicities occurred in eight patients at: 120mg (transaminitis, hyperbilirubinemia), 140mg (mucositis, allergic reaction, transaminitis, acute kidney injury), and 160mg (mucositis). The maximum tolerated dose for KX2-391 was 120mg once daily. KX2-391 bone marrow concentrations were approximately similar to plasma concentrations. This is the first study to evaluate the safety of KX2-391 in elderly patients with AML. Further studies are warranted, including alternative dosing phase I trials evaluating shorter courses at higher doses and phase II trials. (Clinical Trial Registration:The study was registered at ClinicalTrials.gov: NCT01397799 (July 20, 2011)).

BACKGROUNDTreXTAM® is a combination of the key regulatory cytokine transforming growth factor beta (TGFβ) and all trans retinoic acid (ATRA) microencapsulated for oral delivery to immune structures of the gut. It is in development as a novel treatment for inflammatory bowel disease (IBD).AIMTo measure TGFβ levels in blood and tissue after oral administration of encapsulated TGFβ.METHODSAnimals were orally administered encapsulated TGFβ by gavage. Levels of drug substance in blood and in gut tissues at various times after administration were measured by ELISA.RESULTSWe made the surprising discovery that oral administration of TreXTAM dramatically (approximately 50%) and significantly (P = 0.025) reduced TGFβ levels in colon, but not small intestine or mesenteric lymph nodes. Similarly, levels in rat serum after 25 d of thrice weekly dosing with either TreXTAM, or microencapsulated TGFβ alone (denoted as TPX6001) were significantly (P < 0.01) reduced from baseline levels. When tested in the SCID mouse CD4+CD25- adoptive cell transfer (ACT) model of IBD, oral TPX6001 alone provided only a transient benefit in terms of reduced weight loss.CONCLUSIONThese observations suggest a negative feedback mechanism in the gut whereby local delivery of TGFβ results in reduced local and systemic levels of the active form of TGFβ. Our findings suggest potential clinical implications for use of encapsulated TGFβ, perhaps in the context of IBD and/or other instances of fibrosis and/or pathological TGFβ signaling.

2569Background: Paclitaxel has poor oral bioavailability due to active excretion by p-glycoprotein (Pgp) on intestinal epithelial cells. An oral formulation would reduce IV access, avoid allergic r...

Context:KDT501 is an isohumulone drug that has demonstrated beneficial effects on metabolic parameters in mice.Objective:This study was intended to examine potential improvements in metabolism in humans.Design and Setting:Changes in carbohydrate and lipid metabolism, along with inflammatory markers, were evaluated in prediabetic humans in a clinical research center.Participants:Nine obese patients participated. All had prediabetes or normal glucose tolerance plus three features of metabolic syndrome.Intervention:All participants were treated with escalating doses of KDT501 to a maximum dose of 1000 mg every 12 hours for a total of 28 days.Outcome Measures:Changes in carbohydrate metabolism were measured with oral glucose tolerance, homeostatic model of insulin resistance, and euglycemic clamp; changes in plasma lipids and response to a lipid tolerance test; and changes in plasma inflammatory markers.Results:The drug was well tolerated. After KDT501 treatment, plasma triglycerides were reduced at 4 hours during a lipid tolerance test. Furthermore, plasma adiponectin and high-molecular-weight adiponectin increased significantly, and plasma tumor necrosis factor-α decreased significantly. There were no significant changes in oral glucose tolerance test results or insulin sensitivity measures.Conclusions:Despite the small sample size and the short duration of therapy, KDT501 administration reduced measures of systemic inflammation and improved postmeal plasma triglyceride levels, which may be beneficial in participants with insulin resistance or metabolic syndrome.

Src kinase is elevated in breast tumors that are ER/PR negative and do not overexpress HER2, but clinical trials with Src inhibitors have shown little activity. The present study evaluated preclinical efficacy of a novel peptidomimetic compound, KX-01 (KX2-391), that exhibits dual action as an Src and pretubulin inhibitor. KX-01 was evaluated as a single-agent and in combination with paclitaxel in MDA-MB-231, MDA-MB-157, and MDA-MB-468 human ER/PR/HER2-negative breast cancer cells. Treatments were evaluated by growth/apoptosis, isobologram analysis, migration/invasion assays, tumor xenograft volume, metastasis, and measurement of Src, focal adhesion kinase (FAK), microtubules, Ki67, and microvessel density. KX-01 inhibited cell growth in vitro and in combination with paclitaxel resulted in synergistic growth inhibition. KX-01 resulted in a dose-dependent inhibition of MDA-MB-231 and MDA-MB-157 tumor xenografts (1 and 5 mg/kg, twice daily). KX-01 inhibited activity of Src and downstream mediator FAK in tumors that was coincident with reduced proliferation and angiogenesis and increased apoptosis. KX01 also resulted in microtubule disruption in tumors. Combination of KX-01 with paclitaxel resulted in significant regression of MDA-MB-231 tumors and reduced metastasis to mouse lung and liver. KX-01 is a potently active Src/pretubulin inhibitor that inhibits breast tumor growth and metastasis. As ER/PR/HER2-negative patients are candidates for paclitaxel therapy, combination with KX-01 may potentiate antitumor efficacy in management of this aggressive breast cancer subtype.

Based on the observations of teachers and other adults in the framework of our school concept, this study follows the development of a young boy during his first three school years. Jerry is gifted in many fields and shows a complex range of interests. Although he was among the youngest in his class coming into the school, Jerry was more cognitively mature than most. He was socially reserved at the beginning, but his social skills developed significantly during the period in question. Inventing different kinds of creative activities, where he could use his skills and still stay in the same age group, proved to be an effective method and resulted in a much more socially engaged and satisfied child. The experience with Jerry reminds us that gifted children are first of all children and then gifted, but also that significant differences exist between them and the general population.

A Protein kinase targeted.A number of these molecules are broad-spectrum kinase inhibitors.B Staurosporine class represents examples of broad-spectrum kinase inhibitors.PCD, preclinical development.These compounds may have progressed to phase I clinical trials.