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Abstract Abstract 677 Background: Activating mutations of NRAS and KRAS (‘RAS’) are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods: Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results: Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible. Conclusion: At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures: Borthakur: GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.

Abstract Abstract 731 Background: Treatment with bortezomib achieves high hematologic response rates and rapid and durable responses in AL patients (pts), providing the rationale for proteasome inhibition in this population. MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor (PI). In preclinical studies, MLN9708 has shown improved antitumor activity compared to bortezomib in a range of xenograft models. This phase 1 study (NCT01318902) assessed weekly doses of oral MLN9708 in pts with relapsed or refractory AL. Methods: Pts aged ≥18 years with relapsed or refractory AL after ≥1 prior therapy, cardiac biomarker stage I/II disease, and measurable major organ (heart/kidney) involvement, received increasing doses of oral MLN9708 (standard 3+3 dose escalation fixed doses of 4.0 and 5.5 mg), on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Pts with no major hematologic response (<PR) after 3 cycles received dexamethasone (dex; 40 mg, days 1–4). Two expansion cohorts of PI-naïve and PI-exposed pts were enrolled at the MTD. The primary objectives were to determine the safety, tolerability, and MTD. Secondary objectives included analysis of plasma pharmacokinetic (PK) and whole blood pharmacodynamic effects of MLN9708, and assessment of overall hematologic response rate, time to and duration of hematologic and organ response. Adverse events (AEs) were graded using NCI-CTCAE version 4.03. Blood samples were collected at multiple timepoints pre- and post-MLN9708 dosing for PK analysis during cycle 1. Hematologic response and amyloid-related organ assessments were performed according to standardized criteria. Results: At data cut-off (June 29, 2012) 16 pts had been enrolled and received ≥1 MLN9708 dose (safety population). The median age was 66.5 years (range 54–78) and 7 were male. Median number of prior therapies was 3 (range 1–7); 10 received prior transplant, 7 received prior bortezomib. Major organ involvement, defined by standard criteria, included heart, kidney, or both in 7/5/4 pts, respectively, with a median of 2 (range 1–5) involved organ systems, and Mayo cardiac biomarker risk stage was I, II, III in 6, 9, 1 pts. Five pts were treated in the 5.5 mg cohort and 11 pts were treated in the 4.0 mg (n=6 dose escalation; n=5 dose expansion) cohorts. Of the 11 pts treated at 4.0 mg, 4 were PI-naïve, 7 were PI-exposed. Pts received a median of 3 cycles (range 1–12); 5 pts received ≥5 cycles, and 8 pts remain on treatment. Dex was added in 4 pts (2 in each MLN9708 dose level). There were no on-study deaths. Pts discontinued due to disease progression (n=5), AE, withdrawal by pt, or unsatisfactory response (each n=1); 2 pts completed planned 1 year of therapy. One pt in the 4.0 mg cohort experienced a DLT of grade 3 thrombocytopenia. Two pts in the 5.5 mg dose cohort experienced DLTs: grade 3 diarrhea in 1 pt, and renal failure, respiratory failure (both grade 2), and cardiac arrest (grade 4) in another pt. The MTD was determined as 4.0 mg. AEs were reported in 14 pts. The most common drug-related AEs included nausea (n=5), diarrhea and thrombocytopenia (each n=4), abdominal pain and fatigue (each n=3). Grade ≥3 AEs (any cause) reported in >1 pt were thrombocytopenia (n=4), dyspnea (n=3), maculo-papular rash, dehydration, and abdominal pain (each n=2); all were grade 3. Preliminary response data are shown in the table. At data cut-off, one responder had progressed, and the median duration of hematologic response was 7.4 months (range 1.3–11.5+); 2 pts had cardiac organ response. Preliminary PK data showed that MLN9708 was rapidly absorbed, with a median Tmax of 1 hr (range 0.5–6). MLN9708 day 15 plasma Cmax was 73.6 ± 40.2 ng/mL (mean ± SD) and AUC0–168was 1250 ±530 ng*hr/mL (n=8 at 4.0 mg dose cohort). MLN9708 PK parameter values in this study appear similar to other MLN9708 studies in myeloma pts. Conclusions: These data suggest weekly oral administration of MLN9708 is feasible in pts with relapsed or refractory AL. The MLN9708 MTD was determined as 4.0 mg. Assessment is ongoing, with preliminary evidence of hematologic responses noted. A phase 3 study of MLN9708 plus dex versus physician's choice of treatment is planned (NCT01659658). Disclosures: Merlini: Millennium Pharmaceuticals, Inc.: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Onyx: Research Funding. Zonder:Celgene: Research Funding; Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Schonland:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Janssen Research & Development: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Research Funding. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Previous large registry studies have demonstrated inferior outcomes for simultaneous liver‐kidney transplantation (SLKT) recipients of grafts from donation after circulatory death (DCD) donors compared with those from donation after brain death (DBD) donors in the era from 2000 to 2010. Given the improving national results in liver transplantation alone using grafts from DCD donors, the present study aimed to investigate if results with DCD‐SLKT have improved in the modern era. Patients undergoing SLKT between 2000 and 2018 were obtained from the United Network for Organ Sharing Standard Analysis and Research file and divided into 2 eras based on the date of SLKT: era 1 (2000‐2010) and era 2 (2011‐2018). Improvement in DCD‐SLKT patient, liver graft, and kidney graft survival rates was seen between era 1 and era 2 (P < 0.001). Concurrently, there was a decrease in the proportion of critically ill (P = 0.02) and retransplant (P = 0.006) candidates undergoing DCD‐SLKT. When DCD‐SLKT in era 2 was compared with a propensity‐matched cohort of DBD‐SLKT in era 2, no differences in patient (P = 0.99), liver graft (P = 0.19), or kidney graft (P = 0.90) survival were observed. In addition, both bilirubin (0.5 versus 0.5 mg/dL; P = 0.86) and creatinine (1.2 versus 1.2 mg/dL; P = 0.68) at last follow‐up were not different between the DCD‐SLKT and DBD‐SLKT patients in era 2. In conclusion, in the most recent era, patients undergoing DCD‐SLKT were able to achieve similar outcomes compared with matched patients undergoing DBD‐SLKT. DCD‐SLKT represents a viable option for appropriately selected recipients.

Abstract Abstract 2462 Poster Board II-439 The eukaryotic translation initiation factor 5A (eIF5A) is highly conserved and the only known protein to contain the amino acid hypusine. Hypusinated eIF5A and deoxyhypusine synthase, one of the enzymes mediating eIF5A post-translational hypusination, have been identified as markers of neoplastic growth and metastasis, respectively. However, recent studies have indicated that, in its unhypusinated form, eIF5A is pro-apoptotic and thus functionally distinct from hypusine-modified eIF5A. SNS01 is a cancer gene therapy biologic targeted to the treatment of multiple myeloma. SNS01 is comprised of three components: a DNA vector containing a B-cell-specific (B29) promoter driving expression of a pro-apoptotic mutant of eIF5A (eIF5AK50R) that cannot be hypusinated; an siRNA that targets the native hypusinated eIF5A that promotes growth of cancer cells; and a synthetic polymer called polyethylenimine (PEI). RT-qPCR experiments demonstrated that treatment of the human myeloma cell line, KAS-6/1, with SNS01 results in a 90 % reduction in the expression of eIF5A mRNA (mediated by the siRNA) as well as the accumulation of ∼ 22,000 copies of the plasmid-derived eIF5AK50R mRNA per ng of total RNA. SNS01 was found to induce apoptosis in both IL-6-dependent (KAS-6/1) and IL-6-independent (U266) myeloma cell lines and was found to be more effective at inducing apoptosis than PEI nanoparticles carrying either the eIF5A siRNA or the eIF5AK50R plasmid alone. Apoptosis assays were used to optimize the ratio of DNA:siRNA in the nanoparticles and a ratio of 2:1 was found to be optimal for the induction of apoptosis in myeloma cells. The anti-tumoral activity of SNS01 was assessed in SCID mice bearing subcutaneous human multiple myeloma (KAS-6/1) tumors using twice-weekly intra-venous injections and a dose range between 0.15 mg/kg and 1.5 mg/kg. Control mice treated with PEI nanoparticles containing a non-expressing plasmid and a non-targeting siRNA had an average tumor volume of 284 mm3 at the time of sacrifice, whereas mice treated with 1.5 mg/kg or 0.75 mg/kg SNS01 exhibited significant tumor regression and had average tumor volumes of 13 mm3 (95 % inhibition; *p = 0.026) and 24.5 mm3 (91 % inhibition; *p = 0.03), respectively. In addition, for mice treated with 1.5 mg/kg SNS01, there was no evidence of tumors under the skin. Lower doses of SNS01 also demonstrated anti-tumoral activity with mice treated with 0.38 mg/kg and 0.15 mg/kg exhibiting a 73 % and 61 % inhibition of tumor growth, respectively. TUNEL-labeling revealed evidence of apoptotic cells in the treated tumors indicating that tumor regression occurs through the induction of apoptosis. Twice weekly dosing of SNS01 was found to be critical for effective tumor control. In a separate study, twice weekly dosing of SNS01 at 1.5 mg/kg was found to inhibit tumor growth by 88 % (p = 0.01) while once weekly dosing did not significantly reduce tumor burden. Since SNS01 is intended as a therapy for multiple myeloma, a bone marrow neoplasm, the biodistribution of PEI nanoparticles containing a GFP plasmid with the B-cell-specific B29 promoter and a fluorescently (DY547)-labeled siRNA was assessed following i.v. administration in Balb/c mice. The fluorescent siRNA was observed in the liver, lung, spleen, and bone marrow, while GFP expression was primarily observed in the bone marrow. In summary, our preclinical data indicate that systemic administration of SNS01 is an effective anti-cancer therapy in an animal model of multiple myeloma. Additionally, since PEI nanoparticles are taken up by cells of the bone marrow following systemic delivery, SNS01 may be an effective treatment option for multiple myeloma patients and is currently being evaluated for use in clinical trials. Disclosures: Taylor: Senesco Technologies Inc.: Patents & Royalties, stock options. Lust:Senesco Technologies Inc.: Research Funding. Dondero:Senesco Technologies Inc.: Employment, Equity Ownership, Patents & Royalties. Galton:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Donovan:Senesco Technologies Inc.: Research Funding. Thompson:Senesco Technologies Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Background: Electroacupuncture (EA) has been shown to improve complete spontaneous bowel movements (CSBMs), but the duration of its effects remains unknown. The objective of this study was to explore the duration of acupuncture effects after treatment and its associated factors for chronic severe functional constipation (CSFC). Methods: This was a secondary analysis of a multicenter, randomized, sham-acupuncture (SA) controlled trial that included 1075 participants with CSFC. The primary outcome, the duration of acupuncture effects after treatment, was the number of weeks during the 12-week follow-up period that participants were to meet the weekly CSBM responder criteria. A weekly CSBM responder was defined as a participant who had at least three CSBMs for a given week and an increase from baseline of at least one CSBM for that same week. We performed a retrospective multivariate analysis to explore potential factors associated with sustained acupuncture effects. Results: The duration of acupuncture effects in the EA group (5.5 weeks) was significantly higher than the duration of SA effects in the SA group (2.2 weeks) with a between-group difference of 3.2 weeks (95% CI, 2.77–3.78; p < 0.001). A younger age and higher baseline CSBMs per week [regression coefficient (RC) –0.06, 95% confidence interval (CI) (−0.06 to −0.04); RC 2.43, 95% CI 1.78–3.60; respectively] were associated with longer durations of acupuncture effects. Conclusions: EA had sustained post-treatment effects for CFSC. A significant association among a younger age, higher baseline CSBMs and sustained acupuncture effects was observed. Further research is needed to confirm the association. Trial registration: ClinicalTrials.gov (NCT01726504). Registered on 26 August 2012.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

INTRODUCTION: Double balloon enteroscopy (DBE) is an important tool for evaluation of obscure GI bleeding but is a limited resource given time and expertise required. Patient selection is important to help optimize diagnostic yield and subsequent successful management of small bowel bleeding. To maximize the efficiency of DBE performed, our endoscopy group established a screening protocol (Figure) prior to approval of any procedure. We developed a quality improvement project to assess the efficacy of this screening protocol and to evaluate which components of screening were most predictive for procedural success. METHODS: A retrospective chart review was performed on all patients who underwent anterograde or retrograde double balloon enteroscopy for suspected GI bleeding from January 2016 to December 2017. Our screening protocol was implemented on February 1 st , 2017. Data was obtained on patient demographics, clinical presentation, laboratory evaluation, and prior investigation for bleeding evaluation. Endoscopy outcomes were separated into procedural success, defined as lesion identified, and clinical success, defined as resolution of bleeding. Success rates were compared pre and post intervention. Regression analysis was performed to evaluate which components best predicted a successful procedure. RESULTS: We reviewed 114 DBE procedures in 89 patients, 53.5% male (n = 61) with a mean age of 62.8 + 13.3 years. Of these, 86% (n = 98) were performed prior to initiation of the screening protocol. Overall, there was no significant difference in procedural success pre and post intervention as defined by presence of recurrent bleeding, persistent anemia, or transfusion need (Table 1). On univariate analysis of clinical success, defined as lack of recurrent bleeding, gender, anticoagulation use, and presence of lesion on CE were significant (Table 2). Identification and intervention on a lesion during the balloon endoscopy did not impact future anemia, bleeding, or transfusion requirements. CONCLUSION: The patient screening protocol was successful in decreasing the number of procedures performed but did not improve our lesion detection rate on endoscopy and did not improve clinical outcomes as measured by rebleeding. Patients on anticoagulation and those who had prior lesions identified on capsule endoscopy had higher odds of rebleeding, indicating clinical failure. This data may help modify patient selection to maximize success of DBE procedures in the future.

Abstract Purpose: We hypothesized that integrated analysis of cancer types from different lineages would reveal novel molecularly defined subgroups with unique therapeutic vulnerabilities. On the basis of the molecular similarities between subgroups of breast and ovarian cancers, we analyzed these cancers as a single cohort to test our hypothesis. Experimental Design: Identification of transcriptional subgroups of cancers and drug sensitivity analyses were performed using mined data. Cell line sensitivity to Hsp90 inhibitors (Hsp90i) was tested in vitro. The ability of a transcriptional signature to predict Hsp90i sensitivity was validated using cell lines, and cell line- and patient-derived xenograft (PDX) models. Mechanisms of Hsp90i sensitivity were uncovered using immunoblot and RNAi. Results: Transcriptomic analyses of breast and ovarian cancer cell lines uncovered two mixed subgroups comprised primarily of triple-negative breast and multiple ovarian cancer subtypes. Drug sensitivity analyses revealed that cells of one mixed subgroup are significantly more sensitive to Hsp90i compared with cells from all other cancer lineages evaluated. A gene expression classifier was generated that predicted Hsp90i sensitivity in vitro, and in cell line- and PDXs. Cells from the Hsp90i-sensitive subgroup underwent apoptosis mediated by Hsp90i-induced upregulation of the proapoptotic proteins Bim and PUMA. Conclusions: Our findings identify Hsp90i as a potential therapeutic strategy for a transcriptionally defined subgroup of ovarian and breast cancers. This study demonstrates that gene expression profiles may be useful to identify therapeutic vulnerabilities in tumor types with limited targetable genetic alterations, and to identify molecularly definable cancer subgroups that transcend lineage.

Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that Robo2 deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKCς, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKCς, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of Robo2 and p53 rescued all the epithelial defects in kidneys compared with those in Robo2 -knockout kidneys. Taken together, the present results demonstrate that Robo2 deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.