Citations

Abstract Background: Myelofibrosis with myeloid metaplasia (MMM) currently has limited therapeutic options. BAY 43-9006 (sorafenib; Bayer Pharmaceuticals) is a oral multikinase inhibitor with both inhibitory properties against the Raf/ MEK survival pathway and VEGF that are a potential therapeutic targets for the myeloproliferation and apoptotic resistance seen in this disorder. We evaluated the activity of this agent through inhibition of aberrant in vitro myeloid colony growth, as we have previously successfully utilized in this disorder (Leukemia2003;17(5):849). Methods: Peripheral blood mononuclear cells (PBMC) were isolated and plated on the Methocult™ (StemCell Technologies) colony assay media. Dilutions of BAY 43-9006 (0–10 μM) (Phase I trial sustained concentrations of 10 μM (JCO2005;23:965) was added for either a 24 hour incubation, or for 14 days. Myeloid colonies were then quantified according to standards established by the manufacturer. Subsequent assays were performed combining BAY 43-9006 with the pro-apoptotic agents arsenic trioxide (ATO) or adaphostin (ADA) (both at 1.25μM). Finally, immunoblotting was performed on protein extracted from treated primary MMM cells to quantify the downregulation of Mcl-1 (shown to be crucial for the pro-apoptotic effects of BAY 43-9006; Yu et. al. Oncogene 2005). Results: PBMC were isolated from 12 MMM patients and 10 controls (normal n=5, other myeloproliferative (MPD) n=5). Twenty-four hour exposure of cells to the agent was insufficient to suppress aberrant colony growth. Continuous exposure (for 14 days) of the agent led to a median inhibitory concentration-50% (IC50) of 12 μM for MMM (compared to 7.1μM for normals, and 5μM for MPD controls). Although no specificity could be deduced from these latter results, 4 MMM patients had an IC50 of <10μM (range 1.25 to 8.6μM). In contrast, the other 8 patients were quite resistant IC50 of > 10μM (higher than clinically achievable ranges). Subsequently we evaluated whether there might be benefit to use of BAY43-9006 in combination with a pro-apoptotic agent (i.e. ATO or ADA). No significant activity was seen combining ADA with BAY43-9006. When BAY43-9006 was combined with ATO, the median IC 50 for the BAY compound decreased to 2μM (range 1.25 to 16), however there was not a significant increase in colony inhibition over ATO alone. In order to evaluate whether the lack of activity of BAY43-9006 observed in colony formation assays was secondary to a lack of downregulation of the established target Mcl-1, we immunoblotted for Mcl-1 (after in vitro incubation) in a subset of MMM patients. Western blots demonstrated successful downregulation of Mcl-1 by Bay 43-9006 in MMM samples, even in samples with clear in vitro resistance to the drug (i.e. IC50 > 10 μM). Conclusions: The multi-kinase inhibitor BAY43-9006 appears to have minimal activity against primary cells isolated from MMM patients. Although, suppression of aberrant colony growth was noted in a subset of patients the sensitivities would not support specificity when compared to controls. Although BAY 43-9006 was observed to down regulate the anti-apoptotic target Mcl-1, in patient samples, no detectable inhibition of colony formation was observed in 8/12 MMM samples. These preliminary results do not appear to support a clinical trial of BAY 43-9006 in MMM, however combination of this multi-kinase inhibitor with other pro-apoptotic agents should be evaluated.

9513 Background: The need for more research in N/V control is exemplified by agents that are costly, interfere with cytochrome P450 metabolism, and inadequately address delayed N/V. Based on pilot data, there was justification for evaluating whether gabapentin could improve the prevention of delayed N/V from highly emetogenic chemotherapy (HEC). Methods: Patients (pts) about to receive HEC were randomized to prophylactic treatment with 20 mg of dexamethasone (dex) and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by either gabapentin (gaba) 300 mg BID and dex or placebo (plac) and dex. Gaba/plac was started the evening of the day of chemotherapy and continued through day 5 of the first chemotherapy cycle. Dex was given at 8 mg BID days 2-3, then 4 mg BID for day 4, in both arms. The primary endpoint was complete response (CR), defined as no emesis and no rescue medications day 2-6, using a nausea and vomiting diary. The percent of CR were compared in each group by Fisher’s exact test. Secondary outcomes included the Functional Living Index-Emesis (FLIE), satisfaction, and a side effect questionnaire. Results: 430 pts were enrolled in this study between 5/2009 and 2/2011. 47% of pts in the gaba arm and 41% in the plac arm had a CR (p=.23). At some time during days 2-6, 30% in the gaba and plac arms experienced emesis, and 45% and 53% in the gaba and plac arms, respectively, took rescue medication. Mean diary nausea scores over days 2-6 ranged from 0.9 – 1.2 (gaba arm) and 1.0-1.3 (plac arm)(7 = the worst); mean number of diary emetic episodes ranged from 0.1 -0.3 (gaba arm) and 0.1-0.2 (plac arm). The FLIE was not significantly different between arms. Mean vomiting satisfaction was 9.1 in both arms and for nausea was 8.3 for gaba, 8.1 for plac (10= totally satisfied). There were no significant differences in toxicities by CTCAE provider grading or by self-report. Conclusions: In this study, gaba did not improve delayed N/V. Overall, there was little emesis and nausea severity was low. Patients were satisfied with the control of their N/V, irrespective of arm. The use of standard prophylactic guidelines that include a 5HT3RA and dex provided good control of N/V for most patients. Clinical trial information: NCT00880191.

577 Background: BAY 43–9006 targets the ras/raf signaling pathway and inhibits VEGFR-2, VEGFR-3 and or PDGFR-β growth factors. A study was conducted to assess anti-tumor activity and the toxicity profile in patients (pts) with metastatic breast cancer (MBC). Methods: A two-stage phase II study was conducted with pts with MBC who had measurable disease and were candidates for 1 st or 2 nd line chemotherapy and had previously received an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic setting. Pts started with a dose of 400 mg twice daily on days 1–28 of each 4 week cycle. Based on interval adverse events (AEs), a dose reduction was considered as 400 mg given one time daily. Primary endpoint was tumor response defined as a complete or partial response (PR) according to RESIST. The study required 40 pts, but was to be terminated if 0 or 1 responses occurred among 1 st 20 eligible pts. Results: 23 pts enrolled with a median age of 54 (range 37–70) but 3 were declared ineligible. All 23 pts were included in all analyses except efficacy analysis as stated per protocol. Fifteen (65%) had visceral metastasis; 22 (96%) had prior anthracycline treatment (tx); 16 (70%) had prior taxane tx.; 10 (44%) had received prior chemotherapy for metastatic disease and 14 (61%) had a prior relapse free interval of 12 months (mos) or more. Pts received tx for a median of 2 cycles (range 1–8) with a median follow-up of 7.2 mos. Dose reductions were due to dermatitis/skin rash (3), hand/foot skin reaction (2), hypertension (1) and cramping hands/feet (1). No grade 4 AEs occurred and grade 3 AEs included acne (2), hand/foot skin reaction (1), neutropenia (1), cough (1), wound infection (1), and prolonged PTT (1). Among the 20 pts eligible for efficacy analysis one pt (5%; 95% CI 0.5–20.5%) achieved a PR with duration of 3.6 mos and one pt achieved stable disease for at least 6 mos. The 6-month overall survival rate was 81% and the progression-free survival rates were 53% at 2 mos, 24% at 4 mos and 6% at 6 mos. Median time to progression was 2 mos. Based on the lack of sufficient response, we did not proceed with the 2nd stage of this study. Conclusion: Treatment with oral BAY 43–9006, while well tolerated, does not have sufficient activity to warrant further testing as a single agent in this disease setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

4578 Background: Gemcitabine is commonly used in patients with cholangiocarcinoma with a response rate of 20–30% and median overall survival of 6–10 months. Pemetrexed’s mechanism of action and tolerability in patients with hepatic dysfunction makes it a potential agent for cholangiocarcinoma. Methods: Patients with unresectable, previously untreated biliary tract cancers were eligible for participation. Patients received pemetrexed 500 mg/m2 IV over 10 minutes and gemcitabine 800 mg/m2 IV at 10 mg/m2/minute on days 1 and 15 of an every 4 week schedule with vitamin B12 and folate supplementation. The primary end-point is 6-month survival with a planned accrual of 59 patients. Results: 58 eligible patients are included in this analysis. 93% had metastatic disease. Median age was 61 (range: 40 - 81). Median follow-up was 6.5 months (range: 3.3 - 23.2). Median of 3 cycles of treatment was given (range: 1 - 10). Reasons for stopping treatment included disease progression (57%), adverse events (20%), refusal (17%), death on- study (4%), and other medical problems (2%). 6-month survival was 52% (95% CI: 40 - 68%). Median survival was 6.3 months (95% CI: 5.4 - 8.0 months) and median time-to-progression was 3.8 months (2.4 - 5.0). 46 of 58 patients (79%) experienced at least one grade 3+ AE (at least possible attribution), and 26 patients (45%) experienced at least one grade 4 AE (at least possible attribution), most of which were due to grade 4 neutropenia. Conclusions: This study shows similar results to what would be expected with gemcitabine alone. The addition of pemetrexed, as with other agents, has not significantly enhanced the activity of gemcitabine. Supported by NIH Grant CA25224- 18. [Table: see text] No significant financial relationships to disclose.

APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans.

The Center for Disease Control and Prevention ranks diabetes mellitus (DM) as the seventh leading cause of death in the USA. The most prevalent forms of DM include Type 2 DM, Type 1 DM, and gestational diabetes mellitus (GDM). While the acute problem of diabetic hyperglycemia can be clinically managed through dietary control and lifestyle changes or pharmacological intervention with oral medications or insulin, long-term complications of the disease are associated with significant morbidity and mortality. These long-term complications involve nearly all organ systems of the body and share common pathologies associated with endothelial cell abnormalities. To better understand the molecular mechanisms underlying DM as related to future long-term complications following hyperglycemia, we have undertaken a study to determine the frequency that GDM did or did not occur in the second pregnancy of women who experienced GDM in their first pregnancy between 2013 and 2018 at Mayo Clinic, Rochester, MN. Within the five-year period of the study, the results indicate that 7,330 women received obstetrical care for pregnancy during the study period. Of these, 150 developed GDM in their first pregnancy and of these, 42 (28%) had a second pregnancy. Of these 42 women, 20 again developed GDM and 22 did not develop GDM in their second pregnancy within the study period. Following the occurrence of GDM in the first pregnancy, the study (1) established the number of women with and without GDM in the second pregnancy and (2) confirmed the feasibility to study diabetic metabolic memory using maternal placental tissue from GDM women. These studies represent Phase I of a larger research project whose goal is to analyze epigenetic mechanisms underlying true diabetic metabolic memory using endothelial cells isolated from the maternal placenta of women with and without GDM as described in this article.

Uproleselan (GMI-1271) is a novel antagonist of E-selectin, an adhesion molecule expressed on endothelial cells. E-selectin is expressed transiently in the normal vasculature during an inflammatory response and constitutively in the bone marrow (BM). Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand (E-sel-L), on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. In preclinical models, blockade of E-selectin with uproleselan disrupts the activation of cell survival pathways and enhanced the efficacy of chemotherapy across multiple AML tumor models. Furthermore, uproleselan protected against chemotherapy-induced mucositis by regulating macrophage trafficking to the site of injury in the gut lining. A previous phase I/II study of uproleselan added to chemotherapy in patients with untreated AML (older adults ≥60 yrs) and relapsed/refractory AML (≥ 18yrs) showed promising remission rates (CR/CRi) and survival outcomes, and reduced rates of mucositis. In the newly diagnosed older patients, high remission rates were achieved overall (CR/CRi 72%) and for the high risk subgroup with sAML (CR/CRi 69%). In this phase 2/3 study, we will test the addition of uproleselan to a standard daunorubicin/cytarabine regimen in older adults with previously untreated AML. The study will enroll patients age ≥ 60 yrs with untreated acute myeloid leukemia. Patients with acute promyelocytic leukemia, activating mutations in FLT3, or evidence of central nervous system involvement are excluded. Subjects are randomized to 7+3 induction (cytarabine + daunorubicin) +/- uproleselan. Subjects achieving a CR/CRi may receive up to 3 cycles of consolidation with intermediate dose cytarabine 2 gm/m2 IV d1-5 +/- uproleselan. The primary phase II objective is to compare the event-free survival (EFS). A sample size of 262 patients was selected for the phase II to detect an improvement in median EFS from 7 months to 11 months (HR= 0.64) with > 95% power, using a log rank test. The phase III primary objective will compare overall survival (OS). For the phase III, a sample size of 335 evaluable patients per arm (670 total inclusive of patients enrolled in phase II) will provide >90% power to detect an improvement in median OS from 12 months to 16 months (HR= 0.75), using a log-rank test. Correlative studies will measure E-selectin ligand on AML blasts and soluble E-selectin and will also measure minimal residual disease after remission induction by multiparameter flow cytometry. A comprehensive geriatric assessment will identify baseline measures associated with EFS and develop a risk model to predict OS among older adults receiving intensive AML therapy. The study is endorsed by SWOG and ECOG-ACRIN and opened to enrollment on 1/16/2019. Figure Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Strickland:Jazz: Consultancy; Sunesis Pharmaceuticals: Research Funding; Pfizer: Consultancy; Kite: Consultancy; Astellas Pharma: Consultancy; AbbVie: Consultancy. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Novartis, Agios, Arog: Research Funding. OffLabel Disclosure: Uproleselan in AML

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to App NL-G-F knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.