A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma

AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM

Tax Evasion in Sales Cuts Registered by Electronic Cash Register

Tax evasion is a persistent problem of public finances. Sales cuts registered by electronic cash register (hereinafter referred to as "ECR") is part of tax evasion. The State, through constant changes in legislation, creates barriers against them, which are effective only in the short term. The paper is based on the documentation of administrative offences arising from demands and communications with the financial administration. It analyses the changes in the law relating to the elimination of tax evasion by recording sales of ECR and evaluates them. It applies a model approach for the identification of subjects and links in the system. Risky relationships between subjects are exposed and menas of their elimination are proposed. It emphasises the important position of ICT in ECR, identifies difficult places in hardware and software, and suggests areas for improvement

Molecular Characterization and Clinical Correlations of MEK1/2 Inhibition (AZD6244) in Relapse or Refractory Multiple Myeloma: Analysis From a Phase II Study

Abstract Abstract 306 Gene expression profiling previously defined 7 molecularly distinct multiple myeloma (MM) subgroups associated with clinical behavior. The MMSET/FGFR3 subgroup, harboring the t(4;14) translocation, and the MAF subgroup including t(14;16) (c-MAF), t(14,20) (MAF-B) and 8q24.3 (MAF-A), were associated with the shortest progression-free and overall survival. Recently, we demonstrated that MM cell lines of the MMSET/FGFR3 (MS) and MAF (MF) subgroups are dependent on MEK signaling for growth and survival. Inhibition of mitogen-activated protein (MAP) kinase pathway, by genetic or pharmacologic means, specifically decreased expression of MAF and its target genes. In addition, MEK inhibition enhances myeloma cell apoptosis in the presence of standard therapeutic agents due to the effects on the bone marrow microenvironment, suggesting that MEK inhibitors could kill cells resistant to conventional therapies. As part of our ongoing phase II multi-center clinical trial testing the MEK inhibitor AZD6244 in patients with relapsed or refractory MM, we have conducted extensive molecular profiling for a subset of patients, to characterize the underpinnings of MEK inhibition and its correlation with clinical outcomes. To date, of the 37 patients enrolled on trial, 12 patients consented to correlative sampling, including bone marrow aspirates performed at baseline and day 2 after initiation of AZD6244 treatment (75 mg twice daily, continuously on a 28 day cycle). CD138+ cells were purified using magnetic beads (Miltenyi) and subjected to RNA, DNA and protein extraction following standard procedures. qRT-PCR and RT-PCR was performed to detect the expression level of MAF genes (c-MAF, MAF-B, MAF-A ) and the presence of the JH-MMSET hybrid respectively. Nanopro-immunoassay was used to assess the level of total BIM, total and phospho-MEK1/2 and ERK1/2 pre- and post-treatment. Pyrosequencing was performed to detect the presence of mutations in RAS and BRAF genes. At this time, 11 patients have been molecularly characterized and included in this analysis. We found 3 (27%), 2 (18%) and 1 (9%) patients with a KRAS, NRAS, and BRAF mutation, respectively. Based on 8 patients analyzed to date, qRT-PCR showed that 4 (50%) over-expressed c-MAF or MAF-B genes; results from the MAF-A analysis are currently pending. RT-PCR detected the presence of JH-MMSET hybrid in one patient. At this time, we have detailed clinical data for 8 patients: one patient (MS) had a very good partial remission and the duration of response (DOR) was 8 months; one patient (MAF-B) had a partial remission with a DOR of 6 months; and two patients (one MAF-B, one with pending results) had stable disease with DORs of 5+ and 13 months. In these patients, high levels of phospho-ERK1/2 were detected at baseline, and were dramatically reduced after AZD6244 exposure. Also, MEK inhibition resulted in increased levels of total ERK1/2 and MEK1/2 as well as pro-apoptotic BIM. In subanalysis, CD138+ cells obtained from an extramedullar plasmacytoma in the patient carrying the MMSET translocation were treated in vitro with AZD6244; this resulted in undetectable levels of phospho-ERK1/2 post drug exposure. Among this group of relapsed MM patients, refractory to several lines of therapy and with molecular evidence for myeloma cells being MEK dependent, we found single drug AZD6244 to result in durable responses (up to 13 months). Our novel results provide molecular and clinical insight on MEK inhibition in MEK-dependent myeloma tumor cells, and support development of rational drug allocation in MM. Disclosures: No relevant conflicts of interest to declare

A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma

Abstract Abstract 2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mitogen-activated protein kinase, MEK 1/2 that has shown significant pre-clinical activity in multiple myeloma (MM) cells, both in vitro and in vivo, as well as a favorable clinical profile. The present phase II study was designed to determine the response rate for AZD6244 in patients with relapsed or refractory MM. The study utilized a two-stage Simon design to allow for early termination if there was strong evidence of regimen inactivity. Eligible patients were restricted to those with MM who have had at least 2 prior regimens. AZD6244 capsules (75 mg) were administered orally twice daily continuously for 28 day cycles. Response was evaluated after 3 cycles. To date, 37 patients have been enrolled (13 in the 1st stage and 24 in the 2nd stage). One subject enrolled in the 1st stage was not treated. Gender enrollment was balanced (male/female 18/19). The median age of treated patients was 65 years [range 43–81]. ECOG performance scores ranged from 0–2. The median number of prior therapies was 5 [range 2–11]. The most common treatment-related adverse events (occurring in 10–50% of patients) were leukopenia, acneiform rash and other skin/subcutaneous tissue manifestations, fatigue, limb edema, increased aspartate aminotransferase (AST), neutropenia, nausea, facial edema, vomiting, thrombocytopenia, increased creatine phosphokinase, and diarrhea. The most common grade 3 and 4 toxicities (CTCAE v4) included fatigue, peripheral sensory neuropathy, increased AST, neutropenia, nausea, hypotension, thrombocytopenia, increased alanine aminotransferase, and diarrhea. Five deaths have occurred: 2 associated with sepsis, 1 associated with acute kidney injury, all deemed possibly related to AZD6244; and 2 due to disease progression after discontinuation of study treatment. Two objective partial responses have been reported, the first of which justified expansion of the study to the 2nd stage. Twelve patients have had a best response of stable disease, 11 patients have had progressive disease, 1 patient withdrew after cycle 1 (unrelated to toxicity) and did not have response assessed, 3 patients died before response was assessed, and 7 patients are too early to evaluate. Accrual is ongoing to determine if the response threshold in the 2nd stage can be met. Correlative studies are ongoing and are designed to identify potential mechanisms of response/resistance to AZD6244, and to determine the effect of AZD6244 on the bone marrow microenvironment. These include, among others, assessment of pre- and post-treatment expression of phospho-MEK 1/2 and -ERK 1/2, and total levels of Bim. Fifteen patients consented to correlative sampling of bone marrow, blood and/or urine. Results and sample analysis are pending. It is concluded that AZD6244 has modest activity as a single agent in relapsed or refractory MM. This trial also provides a foundation for successor studies employing the MEK 1/2 inhibitor AZD6244 in combination with other agents in patients with MM. Disclosures: Voorhees: Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; MedImmune: Consultancy; Merck: Research Funding