PURPOSE The anti–B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma. PATIENTS AND METHODS In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/104 bone marrow cells by flow cytometry. RESULTS Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year. CONCLUSION In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.

BackgroundSingle nucleotide polymorphisms (SNPs) can lead to the susceptibility and onset of diseases through their effects on gene expression at the posttranscriptional level. Recent findings indicate that SNPs could create, destroy, or modify the efficiency of miRNA binding to the 3'UTR of a gene, resulting in gene dysregulation. With the rapidly growing number of published disease-associated SNPs (dSNPs), there is a strong need for resources specifically recording dSNPs on the 3'UTRs and their nucleotide distance from miRNA target sites. We present here miRdSNP, a database incorporating three important areas of dSNPs, miRNA target sites, and diseases.DescriptionmiRdSNP provides a unique database of dSNPs on the 3'UTRs of human genes manually curated from PubMed. The current release includes 786 dSNP-disease associations for 630 unique dSNPs and 204 disease types. miRdSNP annotates genes with experimentally confirmed targeting by miRNAs and indexes miRNA target sites predicted by TargetScan and PicTar as well as potential miRNA target sites newly generated by dSNPs. A robust web interface and search tools are provided for studying the proximity of miRNA binding sites to dSNPs in relation to human diseases. Searches can be dynamically filtered by gene name, miRBase ID, target prediction algorithm, disease, and any nucleotide distance between dSNPs and miRNA target sites. Results can be viewed at the sequence level showing the annotated locations for miRNA target sites and dSNPs on the entire 3'UTR sequences. The integration of dSNPs with the UCSC Genome browser is also supported.ConclusionmiRdSNP provides a comprehensive data source of dSNPs and robust tools for exploring their distance from miRNA target sites on the 3'UTRs of human genes. miRdSNP enables researchers to further explore the molecular mechanism of gene dysregulation for dSNPs at posttranscriptional level. miRdSNP is freely available on the web at http://mirdsnp.ccr.buffalo.edu.

ABSTRACT:Carbonyl reductase 1 (CBR1) reduces the anticancer drug doxorubicin into the cardiotoxic metabolite doxorubicinol. We documented the hepatic expression of CBR1 in samples from white and black donors. Concordance between ethnicity and geographical ancestry was examined with ancestry informative markers. Livers from blacks and whites showed similar CBR1 mRNA levels (CBR1 mRNA blacks ‫؍‬ 4.8 ؎ 4.3 relative -fold versus CBR1 mRNA whites ‫؍‬ 3.6 ؎ 3.6 relative -fold; p ‫؍‬ 0.217). CBR1 protein levels did not differ between both groups (CBR1 blacks

8007 Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.

ABSTRACT:Cancer patients with Down syndrome (DS) are susceptible to developing anthracycline-related cardiotoxicity. The pathogenesis of anthracycline-related cardiotoxicity has been linked to the intracardiac synthesis of alcohol metabolites by carbonyl reductase 1 (CBR1). CBR1 is located in the DS critical region (21q22.12). The expression of CBR1 in hearts from individuals with DS has not been characterized. This study documented CBR1 expression in hearts from donors with DS (n ‫؍‬ 4) and donors without DS (n ‫؍‬ 15). The DS samples showed 1.8-fold higher CBR1 mRNA levels compared to the non-DS samples (levels in DS samples were 3.3-relative fold, and those in non-DS were 1.8-relative fold; p ‫؍‬ 0.012). CBR1 protein levels were 1.9-fold higher in DS samples than in non-DS samples (13.5 ؎ 7.7 versus 7.2 ؎ 3.9 nmol/g cytosolic protein, respectively; p ‫؍‬ 0.029). CBR1 activity for daunorubicin was 1.7-fold higher in DS samples than in non-DS samples (3.8 ؎ 0.1 versus 2.3 ؎ 0.2 nmol daunol/min ⅐ mg, respectively; p ‫؍‬ 0.050). CBR1 1096G>A (rs9024) affects CBR1 activity, and one heart trisomic for the variant A allele (A/A/A) exhibited low enzymatic activity. These findings suggest that increased CBR1 expression in the hearts of individuals with DS may contribute to the risk of anthracycline-related cardiotoxicity.

Purpose The intracardiac synthesis of anthracycline alcohol metabolites (e.g., daunorubicinol) contributes to the pathogenesis of anthracycline-related cardiotoxicity. Cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- and without- DS. Methods Cardiac expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays using daunorubicin. The CBR1 polymorphism rs9024 was investigated by allelic discrimination with fluorescent probes. The contribution of CBRs/AKRs proteins to daunorubicin reductase activity was examined by multiple linear regression. Results CBR1 was the most abundant transcript (average relative expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most abundant protein (average relative expression; DS: 38%, non-DS: 35%). Positive associations between cardiac CBR1 protein levels and daunorubicin reductase activity were found for samples from donors with- and without- DS. Regression analysis suggests that sex, CBR1, AKR1A1, and AKR7A2 protein levels were significant contributors to cardiac daunorubicin reductase activity. CBR1 rs9024 genotype status impacts on cardiac CBR1 expression in non-DS hearts. Conclusions CBR1, AKR1A1, and AKR7A2 protein levels point to be important determinants for predicting the synthesis of cardiotoxic daunorubicinol in heart.

Purpose-Carbonyl reductase 1 (CBR1) reduces the anticancer anthracyclines doxorubicin and daunorubicin into the cardiotoxic metabolites doxorubicinol and daunorubicinol. We evaluated whether the cardioprotectant monoHER inhibits the activity of polymorphic CBR1.Methods-We performed enzyme kinetic studies with monoHER, CBR1 (CBR1 V88 and CBR1 I88) and anthracycline substrates. We also characterized CBR1 inhibition by the related flavonoids triHER and quercetin.Results-MonoHER inhibited the activity of CBR1 V88 and CBR1 I88 in a concentrationdependent manner. The IC 50 values of monoHER were lower for CBR1 I88 compared to CBR1 V88 for the substrates daunorubicin and doxorubicin (daunorubicin, IC 50-CBR1 I88: 164 μM vs. IC 50 -CBR1 V88: 219 μM; doxorubicin, IC 50 -CBR1 I88: 37 μM vs. IC 50 -CBR1 V88: 59 μM; p < 0.001). Similarly, the flavonoids triHER and quercetin exhibited lower IC 50 values for CBR1 I88 compared to CBR1 V88 (p < 0.001). MonoHER acted as a competitive CBR1 inhibitor when using daunorubicin as a substrate (Ki = 45 ± 18 μM). MonoHER acted as an uncompetitive CBR1 inhibitor for the small quinone substrate menadione (Ki = 33 ± 17 μM). Conclusions-The cardioprotectant monoHER inhibits CBR1 activity. CBR1 V88I genotype status and the type of anthracycline substrate dictate the inhibition of CBR1 activity.

Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/ day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/ CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL. K E Y W O R D S acute lymphoblastic leukemia, blinatumomab, clinical study, Japan, phase 1b, refractory, relapsed | 1315 KIYOI et al.