ALBERT

Description: Summary Purpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14C-guadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.

Description: Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved daily dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Intrapatient dose escalation was permitted. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: 43 patients were treated in 5 cohorts of 6 patients each plus a 13 patient expansion of cohort 5. The median age was 71.5 years (range 59-86), 30/43 (70%) were male, and median time from diagnosis was 273 days (range 5-3518). Prior therapies had been administered to 22/43 (51%) patients including 20 who had received prior HMA. The AUC for IV DAC 20 mg/m2 in all patients (n=43) had a mean (CV) of 171(37%) ng*hr/mL. The Cmax for IV DAC 20 mg/m2 had a mean (CV) of 179(36%) ng/mL. Doses of each component of ASTX727 were escalated as shown in Table 1. E7727 was escalated first from 40 to 100 mg in cohorts 1 to 3 then kept constant at cohorts 4 to 6. DAC doses were kept constant at 20 mg in cohorts 1 to 3 then escalated to 40 mg at cohort 4 and de-escalated to 30 mg at cohort 5. Dose dependent increases in AUC and Cmax occurred with escalating doses. DAC AUC values after oral ASTX727 approached then exceeded IV at 149% by cohort 4. DAC Cmax values after oral ASTX727 never exceeded IV in any Cohort. Mean % LINE-1 demethylation on cycle 1 Day 8±SE increased with dose escalation reaching 12.8%±3.8 by cohort 4. Lower DAC AUC and Cmax were observed after lowering the oral DAC dose from 40 to 30 mg in cohort 5 as shown in Table 1. One patient in cohort 4 had a dose limiting toxicity of thrombocytopenia and no Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common ≥ Grade 3 AEs regardless of relationship to the drug were thrombocytopenia (36%), anemia (30%), neutropenia (27%), and febrile neutropenia (21%). No drug-related Grade ≥ 3 gastrointestinal AEs were reported. A median of 5 cycles (range 1-23) were administered, 11 patients remain on therapy, and 14 (32%) have experienced objective clinical responses so far, including 5 Complete Response (CR), 4 marrow CR, and 5 Hematologic Improvement. Of 23 patients initially RBC dependent, 6 (26%), became independent and of 6 who were platelet dependent, 2(33%) became independent. Conclusions: ASTX727 (the combination of E7727 and DAC administered PO concomitantly) achieved the primary PK objective of emulating IV DAC 20 mg/m2 AUC levels with a similar safety profile. Day 8 LINE-1 demethylation in Cohort 4, overall clinical response and transfusion independence rates are consistent with those historically reported following DAC 20 mg/m2 IV for 5 days, even though 47% had received prior HMA therapy. ASTX727 has now proceeded to a randomized phase 2 study comparing IV DAC 20 mg/m2 IV daily for 5 days to oral ASTX727 at the doses of 35 mg DAC and 100 mg E7727 daily for 5 days in Int or HR MDS and CMML patients. Disclosures Odenike: Geron: Research Funding; Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ariad: Equity Ownership; Genoptix: Consultancy; Millenium/Takeda: Consultancy. Michaelis:Incyte: Honoraria; Pfizer: Equity Ownership; Celgene: Honoraria, Speakers Bureau. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Zhang:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs). Treatment with the HMAs decitabine (DAC) and azacitidine (AZA) requires 5 or 7 daily parenteral doses respectively every month with some patients remaining on treatment for extended periods. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and may allow exploring extended treatment schedules with lower doses of DAC. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the first Phase 1 results of a PK-guided FIH dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial with a 3+3 design. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. A data safety review committee evaluated safety, PK and PD on patients in each completed cohort and determined dosing for each component of ASTX727 at the next cohort. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: The Phase 1 portion of the trial completed dosing of 4 cohorts with 6 subjects each (24 subjects). The median age was 71 years (range 59-85), 15/24 (63%) were male, and median time from diagnosis was 307 days (range 5-3024). Prior therapies were administered to 10 patients including five who had received prior HMA. In cohorts 1-3 ASTX727 was given as a fixed oral DAC dose of 20 mg with escalating doses of oral E7727 at 40, 60, and 100 mg respectively. In cohort 4, the oral DAC dose was escalated to 40 mg while E7727 was kept at 100 mg. The Day 1 AUC for IV DAC 20 mg/m2 over all 4 cohorts had a mean (SD) value of 193(82) ng*hr/mL. After oral ASTX727 on Days 2-5, the mean DAC AUC as % of IV DAC AUC was 17, 19, 32, and 98% on Day 2 and 31, 41, 58 and 148% on Day 5, in cohorts 1-4 respectively (Figure). DAC AUC variability after oral ASTX727 was acceptable (CV% 35-53 across 4 cohorts). DAC Cmax values after oral ASTX727 approached IV (87%) in Cohort 4 on Day 5. Mean % LINE-1 demethylation on cycle 1 Day 8±SE was 6.8%±2.7; 8.6%±2.7; 9.5%±3.3; and 15.3%±3.4 from baseline for cohorts 1-4 respectively. No Dose Limiting Toxicities (DLTs) or Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common Grade ≥ 3 AEs regardless of relationship to the drug were thrombocytopenia (37.5%), anemia (33.3%), neutropenia (29.2%) and febrile neutropenia (16.7%). Twenty patients remain on therapy, and at least 5 so far have experienced objective clinical responses (including 1 Complete Response (CR), 1 marrow CR, 1 Partial Response and 2 Hematologic Improvement). Conclusions: ASTX727 (the combination of oral DAC and oral CDAi E7727 administered concomitantly) achieved the primary PK objective of reaching (at Day 2) or exceeding (at Day 5) IV DAC 20 mg/m2 AUC levels at the doses of 40 mg DAC and 100 mg E7727 with an excellent safety profile. Day 8 LINE-1 demethylation in Cohort 4 is consistent with that historically reported following DAC 20 mg/m2 IV for 5 days. Clinical responses have been observed. The trial will explore lower doses of oral DAC and will proceed to dose expansion followed by randomized phase 2 portion comparing IV DAC to oral ASTX727 in previously untreated Int or HR MDS and CMML patients. Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Faderl:JW Pharma: Consultancy; Karyopharm: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Astellas: Research Funding; Celator: Research Funding; Ambit: Research Funding; Onyx: Speakers Bureau; BMS: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Dua:Astex Pharmaceuticals, Inc.: Employment. Nawabi:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment.

Description: This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.

Description: Background Hypomethylating agents (HMAs) such as decitabine and azacitidine have been successfully used in the clinic to treat hematological malignancies by parenteral administration (IV or SC). Due to low oral bioavailability of these agents, relatively high doses are required to achieve therapeutic systemic exposures by the oral route. Higher oral doses can be associated with significant GI toxicities due to intestinal enterocytes being exposed to high concentrations of these agents in the lumen. One of the main factors contributing to low oral bioavailability of HMAs is the high first-pass effect due to cytidine deaminase in GI and liver. Methods In this study, E7727, a novel CDA inhibitor (CDAi) was combined with decitabine (3 mg/kg) for oral administration in cynomolgus (cyn) monkeys at E7727 doses of 0.1-10 mg/kg. Results Systemic AUC exposures for decitabine increased from 21.7 ng*hr/mL (without E7727) to as high as 1,494 ng*hr/mL at 10mg/kg E7727. At a dose combination of 1 mg/kg CDAi and 3 mg/kg decitabine (corresponding to a human equivalent dose of 36 mg/m2), AUC exposures were 301±94 ng*hr/mL, which are slightly higher than the published clinical therapeutic range after decitabine IV infusion of 20 mg/m2 (115-220 ng*hr/mL), suggesting that a combination approach for oral CDAi+decitabine is feasible to achieve required clinical exposures at a range of relatively low-dose(s). In addition, the concentration-time profile of decitabine when combined with CDAi resembled that achieved with IV decitabine over 1 hour infusion. The effect of drug-drug interaction between CDAi and decitabine was modeled based on a relationship between CDAi Ki (∼ 0.14 µM based on IC50) and Cmaxlevels and appeared to predict the observed fold-increases in decitabine AUC with high concordance. In addition, low dose oral decitabine+CDAi achieved decitabine exposures that produce potent hypomethylation as observed by LINE-1 assay. Conclusion Pronounced increase in oral decitabine exposures was achieved when combined with the novel CDA inhibitor E7727. Cyn monkeys appear to be a relevant model for human PK based on similar background of circulating serum cytidine levels reflective of similar CDA status between humans and cyn monkeys. These data support the initiation of clinical First in Human (FIH) study of ASTX727, a novel oral HMA combining oral decitabine with the CDAi E7727. Disclosures: Oganesian: Astex Pharmaceuticals: Employment. Redkar:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Joshi-Hangal:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment.

Description: 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

Description: Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved 〉10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

Description: Background: DNA methyltransferase inhibitors (DNMTi) induce remissions and improve survival for patients with MDS and those with AML unable to receive standard cytotoxic chemotherapy. Accordingly, DNMTi therapy is the backbone of SOC treatment for MDS and AML. Given the inconvenience, pain, and general detriments to QOL with SQ or IV therapy daily for 5-7 days every month with azacitidine (AZA) or decitabine (DAC), many have attempted to provide the therapy orally, but encountered difficulties with this method of administration given rapid first-pass clearance via the enzyme cytidine deaminase (CDA) which is ubiquitous in the gut and liver. Recently, DAC was combined with cedazuridine (CDZ), an oral CDA inhibitor, in a fixed-dose (35mg/100mg) combination tablet (ASTX727) to approximate the pharmacokinetics of IV DAC (Savona et al Lancet Haematology 2019). To determine if a similar strategy might be feasible with AZA, we attempted to increase the bioavailability of oral AZA with CDZ in a murine tumor model. Methods: We measured GI50 in AML cell lines treated with vehicle (DMSO), AZA, and AZA/CDZ combination. Although cancer cell lines produce CDA, total levels are negligible in comparison CDA in the gut and liver. For this reason, we then studied CDZ, AZA, and the AZA/CDZ combination in a systemic model of AML in immunocompromised mice. NSGS mice were sub-lethally irradiated and administered MOLM-13 AML cells via tail vein injection. At day seven post-transplant, engrafted mice were randomized to receive 2.5 mpk i.p. AZA(n=8), 2.5 mpk oral AZA(n=8), 3 mpk CDZ + oral AZA(n=6), or CDZ alone at 30 mpk (n=7). All oral AZA and CDZ was administered via oral gavage daily for 7 consecutive days; i.p. therapy was similarly given for 7 consecutive days. During treatment, the kinetics of MOLM-13 expansion was defined by detection of human AML in the blood as detected by flow cytometry. At approximately three weeks after transplant, CDZ-only treated mice became moribund, and all experimental groups were sacrificed for analysis of chimerism. Results: After 72 hour of treatment, no differences were noted in viability of cell lines between AZA and AZA+ CDZ in vitro. In the xenograft model, as expected, i.p. AZA-treated mice had significant decreases in leukemic expansion in the bone marrow and spleen, whereas CDZ alone did not (AZA i.p. vs CDZ, p = 0.004 and