Citations

Restless legs syndrome (RLS) is a common sleep‐related movement disorder characterised by an uncomfortable urge to move the legs that occurs during periods of inactivity. Although there have been many case reports on antipsychotic‐induced RLS, ziprasidone has never been reported as a cause of RLS. We present a case of a female patient with schizophrenia who presented with symptoms of RLS following the administration of high doses of ziprasidone added to quetiapine and valproate. The patient’s symptoms of RLS occurred following the administration and titration of ziprasidone to 160 mg, and were relieved upon reducing the dose to 120 mg/day. Other potential causative medications and differential diagnoses that could have caused similar symptoms were excluded. Clinicians should be aware of the potential for ziprasidone‐induced RLS. Dopamine and serotonin interaction could be the mechanism underlying ziprasidone‐induced RLS.

Abstract Vascular smooth muscle cells (VSMCs) in the normal arterial media continually express contractile phenotypic markers which are reduced dramatically in response to injury. Tripartite motif‐containing proteins are a family of scaffold proteins shown to regulate gene silencing, cell growth, and differentiation. We here investigated the biological role of tripartite motif‐containing 28 (TRIM28) and tripartite motif‐containing 27 (TRIM27) in VSMCs. We observed that siRNA‐mediated knockdown of TRIM28 and TRIM27 inhibited platelet‐derived growth factor (PDGF)‐induced migration in human VSMCs. Both TRIM28 and TRIM27 can regulate serum response element activity and were required for maintaining the contractile gene expression in human VSMCs. At the same time, TRIM28 and TRIM27 knockdown reduced the expression of PDGF receptor‐β (PDGFRβ) and the phosphorylation of its downstream signaling components. Immunoprecipitation showed that TRIM28 formed complexes with TRIM27 through its N‐terminal RING‐B boxes‐Coiled‐Coil domain. Furthermore, TRIM28 and TRIM27 were shown to be upregulated and mediate the VSMC contractile marker gene and PDGFRβ expression in differentiating human bone marrow mesenchymal stem cells. In conclusion, we identified that TRIM28 and TRIM27 cooperatively maintain the endogenous expression of PDGFRβ and contractile phenotype of human VSMCs.

TPS8118 Background: Effective DLBCL adjuvant therapy after first-line chemotherapy is needed as high-risk DLBCL is associated with a poor 4-year overall survival (OS) rate (Sehn et al, Blood 2007;109:1857-61). In a phase II study of the oral mammalian target of rapamycin inhibitor everolimus in relapsed, aggressive non-Hodgkin lymphoma, DLBCL patients (n=47) had a 30% overall response rate (Witzig et al, Leukemia 2011;25:341-7). Methods: PILLAR-2 is an ongoing international, randomized, double-blind, phase 3 study designed to compare everolimus efficacy and safety with that of placebo in poor-risk DLBCL patients who achieved complete response (CR) with first-line rituximab-based chemotherapy (R-chemo) (ClinicalTrials.gov: NCT00790036; sponsor: Novartis Pharmaceuticals). Eligibility criteria include age ≥18 years; confirmed stage II bulky, III, or IV DLBCL and International Prognostic Index 3-5 at diagnosis; confirmed CR per revised International Workshop Response Criteria for malignant lymphoma (Cheson et al, J Clin Oncol 2007;25:579-86) after first-line R-chemo regimen completed 6-14 weeks before study drug start; Eastern Cooperative Oncology Group performance status ≤2; no ongoing or post–R-chemo radiation; and no myelosuppressive chemotherapy or biologic therapy within 3 weeks. Patients are randomized 1:1 to everolimus 10 mg once daily or matching placebo and treated for 12 months or until disease relapse, unacceptable toxicity, or death. Radiologic tumor assessment is performed at baseline, every 12 weeks during years 1 and 2, every 24 weeks during years 3 and 4, and annually thereafter until start of new anticancer therapy or 5 years after last patient randomization. The primary endpoint is disease-free survival (DFS). Secondary endpoints are OS, lymphoma-specific survival, and safety. Expected enrollment is 687 patients. Final analysis will be performed when 279 DFS events occur; survival follow-up will continue until 338 deaths occur and the last randomized patient has been followed for ≥5 years. Currently, 422 patients are enrolled. The data monitoring committee last reviewed the trial in July 2011 and recommended that it continue as planned.

6028 Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N=22) from 2.9 m for P (N=26) (Wald p=0.07), compared with 4.6 m for C (N=12) and 3.5 m for P (n=13) among the PTEN null/PIK3CA mutated (Wald p=0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.

2579 Background: HA, a glycosaminoglycan, accumulates in ~25% of solid tumors and is associated with poor prognosis. Tumors that accumulate HA develop high interstitial fluid pressure (IFP) and become resistant to chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA and increased efficacy of chemotherapy. Methods: This ongoing phase 1 study was designed to assess safety, tolerability, PK, PD, and the maximum tolerated dose (MTD) of PEGPH20 as a single agent in patients with treatment-refractory solid tumors. IV PEGPH20 was administered in a twice weekly or a once weekly dosing schedule with oral dexamethasone (dex) pre-and post dose. Biomarkers included tumor histochemistry to detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. Results: Fifteen patients have been enrolled into the study. Dose administration ranged from 0.5 µg/kg to 5 µg/kg. Musculoskeletal events (MSEs) were the most common and dose limiting toxicities. To date, up to 3 µg/kg twice weekly IV infusions of PEGPH20 were well tolerated with manageable Grade 1 MSEs in most patients. MTD has not been reached. Plasma concentrations of PEGPH20 showed dose proportional exposure with a terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor biopsies from 2 colon patients demonstrated 23-60% reduction in tumor HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 in one patient each. Doses of ≤3 µg/kg were tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels > 3 µg/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in dose-dependent systemic exposure and is tolerated with concomitant dex treatment. HA catabolites in plasma demonstrated the in vivo enzymatic activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI and FDG-PET images confirmed PD activity. Increased tumor perfusion by PEGPH20 may enhance drug delivery to tumor. Combination studies of PEGPH20 with cytotoxic chemotherapy are planned.

Abstract Importance: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections outbreak in China is now a global issue. There is only a limited understanding of the clinical characteristics of patients with SARS-CoV-2 infections is available.Objective:To describe the characteristics, management strategies, and outcomes of critically ill patients with SARS-CoV-2 infection.Design, Setting, and Patients: This is aretrospective, multi-center case series of 50 critically ill patients with confirmed SARS-CoV-2 infection who were admitted at Zhongnan Hospital of Wuhan University and Wuhan Pulmonary Hospital in Wuhan, China, from January 8 to February 9, 2020.Exposures:Documented Corona Virus Disease, 2019 (COVID-19).Main Outcome Measures: Demographic, clinical, laboratory, imaging data were collected along with management strategies, complications and outcomes of enrolled individuals. Results Fifty critically ill patients with SARS-CoV-2 infections were enrolled. Their median age was 62 (range, 29-92) [IQR,49.5-69.0] years, 68% were male, and 28 (56%) patients had comorbidities, the most common being hypertension. In this cohort, 20(40%) patients survived ,16(32%) patients died, and the rest remained hospitalized. The invasive mechanical ventilator was used in 36(72%) patients with 15(30%) of them requiring prone positioning, and 17(34%) switched to ECMO. The compliance scores of lungs (Cstat)on the day of ICU admission among survivors were higher than those in non-survivors [42.0(18.0-47.0), vs. 19.5(14.0-24.2), p=0.038].The blood IL-6 levels and neutrophils counts at the first day of ICU admission were significantly higher in non-survivors compared to survivors [123.7(85.3-228.8), vs. 20.2(6.8-67.2) ng/ml, p=0.025 for IL-6, and 20.2(6.8-67.2) vs. 4.01(1.99-7.05) × 10⁹/L, p=0.02 for neutrophils counts].The heart rates, PaCO2, lung injury scale (LIS), and positive end-expiratory pressure levels were constantly higher for 10 days in non-survivors than those who survived (p<0.05). The frequency of vasopressor uses and neuromuscular blockers was higher in non-survivors from day 1 to day 10 compared to survivors (p<0.05). In the whole cohort, the most common complications were ARDS (97%), shock (44%), arrhythmia (38%), acute cardiac injury (26%), and acute kidney injury (22%). A secondary bacterial infection was noted in 17(34%) patients. Univariate analysis indicated that lower lung complianceand higher neutrophil counts at the day of ICU admission were related to higher mortality (p-0.03, and 0.04, respectively)ConclusionWe demonstrated that SARS-CoV-2 infection-related critical illness predominantly affected old individuals with comorbidities and characterized by severe hypoxemic respiratory failure, often requiring prolonged mechanical ventilation and rescue therapies. Low lung compliance and persistently elevated PaCO2 indicated poor outcomes.

Senescent cells accumulate with aging and at etiological sites of multiple diseases, including those accounting for most morbidity, mortality, and health costs. Senescent cells do not replicate, can release factors that cause tissue dysfunction, and yet remain viable. The discovery of senolytic drugs, agents that selectively eliminate senescent cells, created a new route for alleviating age‐related dysfunction and diseases. As anticipated for agents targeting fundamental aging mechanisms that are ‘root cause’ contributors to multiple disorders, potential applications of senolytics are protean. We review the discovery of senolytics, strategies for translation into clinical application, and promising early signals from clinical trials.

Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. Dose escalation is complete and a recommended Ph 2 dose has been determined. We report Ph 1 safety and efficacy results of REGN1979 in patients (pts) with R/R B-NHL previously treated with anti-CD20 Abs, including pts with progressive disease after anti-CD19 CAR T-cell (CAR T) therapy. Methods Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total). Results As of June 3, 2019, 96 pts (diffuse large cell B-cell lymphoma [DLBCL] [n=53], follicular lymphoma [FL] grade [Gr] 1-3a [n=25], mantle cell lymphoma [n=6], marginal zone lymphoma [n=6], or other [FL Gr 3b, FL unknown, FL ungraded, or Waldenström macroglobulinemia ] [n=6]) were treated with REGN1979 0.03-320 mg and received a median of 9 doses (range 1-24). Pts had a median of 3 prior lines of therapy (range 1-11); 12 pts with prior CAR T therapy were included in the safety analysis of which 6 were included in the efficacy analysis. Twenty-four pts remain on treatment; 18 completed treatment; 54 discontinued early (35 due to progressive disease [PD]). No pts with B-NHL experienced a DLT. The most common treatment-emergent adverse events (AEs) were pyrexia (n=74), CRS (n=55), chills (n=49), infections and infestations (n=47), fatigue (n=36), increased C-reactive protein (n=32), and anemia (n=32). Seven pts experienced Gr 3 CRS. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Most common Gr 3 or 4 AEs were anemia (n=19), decreased lymphocytes/lymphopenia (n=19), infections and infestations (n=18), decreased neutrophils/neutropenia (n=17), and hypophosphatemia/decreased blood phosphorus (n=16). No pts had seizures or grade 4/5 neurologic AEs. Gr 3 neurologic AEs included depressed level of consciousness (unrelated), somnolence, and syncope (n=1 each). Neurological events were transient and none required permanent treatment termination. Five pts discontinued due to AEs: Gr 3 hemolysis; Gr 3 fatigue; Gr 2 and Gr 3 pneumonia; and Gr 3 neck abscess (1 each). Eleven pts died on study: PD (n=6), gastric perforation (n=1), cardiac arrest (n=1), lung infection (n=1), multi-organ failure (n=1), pneumonia (n=1). The Table and Figure show efficacy and duration of response for R/R DLBCL by dose level. Pts who had opportunity for response assessment at Week 12 were included in the analysis of response. Emerging data suggest increasing efficacy with higher doses in R/R DLBCL, with 5 of 8 pts treated at 80/160/320 mg achieving CR; at these doses 2 of 3 pts achieved CR after failure of CAR T therapy. Data also suggest increasing efficacy with increasing doses in R/R FL, but maximum efficacy appears to be achieved at lower doses than in DLBCL; in pts with FL Gr 1-3a treated at ≥5 mg, the ORR was 93% (13/14), and the CR rate was 71.4% (10/14). REGN1979 concentrations in serum increased linearly with dose during the first five weeks. Elevated levels of serum cytokines were observed, mostly in week 1, and no correlation was observed with clinical efficacy. Immunohistological analysis of malignant lymph node tissue demonstrated that pts with high and low CD20 expression achieved clinical response. Relapse among responders was seen with either maintenance or loss of CD20 expression, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions/Summary Tolerability of REGN1979 has been demonstrated at doses up to the final dose level of 320 mg weekly, with no observed DLTs in pts with B-NHL. No pts discontinued due to neurologic AE. Activity was observed broadly in heavily pretreated R/R B-NHL pts treated with REGN1979. With increasing dose, more resistant tumors such as R/R DLBCL are showing benefit, even in pts with prior CAR T therapy failure. Based on these efficacy findings, a global Ph 2 study is underway to evaluate REGN1979 monotherapy in R/R FL Gr 1-3a, R/R DLBCL, and other R/R B-NHL subtypes. Disclosures Bannerji: AbbVie, Inc: Consultancy, travel support; Gilead: Other: travel support; Gilead: Other: travel support; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Celgene: Consultancy; Celgene: Consultancy; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support. Allan:Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Arnason:Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Brown:AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Invectys: Other: other; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Kite: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharma: Research Funding; Janssen: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Regeneron: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment. O'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Martin:I-MAB: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhu:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ibrahim:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Aina:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Deering:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Murphy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinreich:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The data described in the abstract will report on use REGN1979 in a Phase 1 clinical trial of patients with B-NHL.

Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int'l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study). Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of &lt;1% and the 95% CI of the difference included zero. Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 5% were thrombocytopenia, neutropenia, anemia, febrile neutropenia, and leukopenia). As of the data cutoff, median follow up was 5.2 months ( IQR 3.5-8.0) with 101 patients evaluable for response . Preliminary response analysis of all evaluable patients showed best responses of complete response (CR) in 12 patients (11.9%), marrow (m)CR in 46 (45.5%) including 14 patients (13.9%) with mCR + hematological improvement (HI), hematologic improvement (HI) in 7 (6.9%) resulting in an objective response rate (CR+mCR+ HI) in 65 patients (64%). In addition, of all 133 treated patients, 16 patients (12%) underwent hematopoietic cell transplant. Updated response data will be presented at the meeting. Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Griffiths:New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Persimmune: Consultancy; Partner Therapeutics: Consultancy; Boston Scientific: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial. Yee:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Zeidan:Ariad: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Astellas: Honoraria; Seattle Genetics: Honoraria; Cardinal Health: Honoraria; Novartis: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; BeyondSpring: Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Dao:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria; France Foundation: Honoraria. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Canada: Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Fazal:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Research Funding; Astra Zeneca: Research Funding; Gilead Sciences: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Roboz:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Keer:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

580 Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.