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Background: Novel AML treatments (Tx) have improved the tolerability and clinical outcomes for older patients (pts) with AML, especially since standard intensive chemotherapy (IC) regimens are associated with risks of toxicity and mortality. Lower-intensity Tx options for IC-ineligible pts include low-dose cytarabine (LDAC) or hypomethylating agents (HMAs; azacitidine [AZA] and decitabine), which are generally well tolerated, but have been associated with inferior outcomes vs IC [Vey 2020]. As such, the development of less-toxic regimens with better efficacy has been a priority, and increased focus has been given to optimizing Tx regimens in the outpatient setting for convenience, independence, and quality of life (QoL). The oral formulation of AZA (Oral-AZA [CC-486]) is approved in the United States, European Union, and Canada for Tx of pts with ND AML in first remission after IC who are not able to complete curative therapy (eg, HSCT). In a pivotal phase 3 trial, Oral-AZA 300 mg QD for 14 days (d)/28d Tx cycle was well tolerated and improved overall survival (OS) vs placebo in pts with AML in CR/CRi after IC. Oral-AZA has also shown preliminary clinical efficacy in pts with active AML [Savona 2015]. Novel regimens based on LDAC or HMAs in combination with newer agents, including the BCL2 inhibitor, venetoclax (VEN), have demonstrated promising activity in older pts with AML. Although only modest clinical benefits were achieved with single-agent VEN in pts with R/R AML [Konopleva 2016], the combination of VEN + AZA in pts with ND AML shows synergistic anti-leukemic activity via AZA-mediated inhibition of MCL1 and BCL-XL, enhancing BCL2 dependence in leukemic cells. In IC-ineligible ND AML, VEN + injectable AZA significantly improved remission rates and OS vs AZA alone [DiNardo 2020]. Consequently, VEN, in combination with an HMA or LDAC, was approved in the US for Tx of pts with ND AML aged ≥ 75 years (y) or those with comorbidities precluding use of IC. Given S-phase-restricted DNA incorporation of AZA, extended Oral-AZA dosing regimens (> 7d/28d Tx cycle) increases the opportunity for cycling cells to incorporate the drug, thereby sustaining epigenetic activity [Laille 2015]. An outpatient VEN + AZA oral combination regimen may also increase the likelihood of pt adherence [Eek 2016]. Here, we describe the study design and objectives of the OMNIVERSE trial of Oral-AZA + VEN in older pts with ND AML or pts with AML R/R to prior Tx. Study Design and Methods: OMNIVERSE (NCT04887857) is a multicenter, open-label, phase 1b/2 trial conducted in 3 sequential study parts (Figure). Key objectives of the 2-part, dose-finding phase 1b portion are to evaluate safety and establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of Oral-AZA + VEN, first in pts with R/R AML (World Health Organization [WHO] 2016 criteria) ineligible to receive further IC (part 1), and subsequently in pts with ND AML (WHO 2016) aged ≥ 75 y, or those aged ≥ 18-74 y with comorbidities that preclude use of IC or HSCT (part 2). Key pt eligibility criteria include an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (ECOG 3 is allowed for pts aged ≥ 18-74 y with comorbidities), and an unfavorable cytogenetic risk profile for pts with ND AML. The starting dose of Oral-AZA is 300 mg QD × 14d cycle, which can be escalated to 300 mg × 21d or de-escalated to 200 mg × 14d/28d cycle depending on dose-limiting toxicities experienced; oral VEN is taken QD continuously (or 21d/cycle for dose level -2). A modified toxicity probability interval-2 (mTPI-2) design is used to evaluate the planned dose levels. The sample size of the phase 1b portion depends on the dose levels utilized (≤ 18 pts in each part). In phase 2, pts with ND AML (same inclusion criteria as for phase 1b-part 2) will receive Oral-AZA + VEN at the RP2D. The primary endpoint is the rate of complete remission (CR) plus CR with partial hematologic recovery (CRh). Key secondary endpoints include safety, duration of CR/CRh, overall response rate (per European Leukemia Net criteria), and longitudinal minimal residual disease (MRD) profiling for CR/CRh responders. Key exploratory objectives are to characterize DNA methylation patterns and BCL2 family member expression profiles. The phase 2 expansion will enroll ~100 pts, which is calculated based on the response rates from the M14-358 (NCT02203773) and VIALE-A (NCT02993523) studies. Enrollment is planned to begin in 2021. Figure 1 Figure 1. Disclosures Ravandi: Amgen: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Carraway: Takeda: Other: Independent review committee; Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astex: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Taningco: Bristol Myers Squibb: Current Employment. Dilley: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Laille: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lopes de Menezes: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Wei: Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Servier: Consultancy; Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding.

MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m2). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m2, with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts ≤ 5%). Pharmacokinetic analyses indicated absorption of MGCD0103 within 1 hour and an elimination half-life in plasma of 9 (± 2) hours. Exposure to MGCD0103 was proportional to dose up to 60 mg/m2. Analysis of peripheral white cells demonstrated induction of histone acetylation and dose-dependent inhibition of HDAC enzyme activity. In summary, MGCD0103 was safe and had antileukemia activity that was mechanism based in patients with advanced leukemia.

Introduction: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma associated with poor prognosis. There is no consensus on standard therapy, and options are limited for patients with relapsed/refractory (R/R) disease. Romidepsin, a potent histone deacetylase inhibitor, has US FDA approval for patients with >=1 prior treatment for PTCL based on 25%-38% overall response rates (ORR) and durable responses (Piekarz et al, Blood. 2011;117:5827; Coiffier et al, J Clin Oncol. 2012;30:631). Here we report results from the phase I/II, multicenter, open-label study of romidepsin in Japanese patients with R/R PTCL or cutaneous T-cell lymphoma (CTCL) (TCL-001; NCT01456039). Methods: Patients aged >=20 years with R/R PTCL or CTCL received romidepsin via a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle until progressive disease or unacceptable toxicity. The phase I portion of the study used a 3+3 design to identify any dose-limiting toxicity (DLT; phase I primary endpoint) with romidepsin 9 mg/m2 (cohort 1) and 14 mg/m2 (cohort 2). The phase II dose was based on the highest dose where =1 day. Assessments of the intent-to-treat (ITT) population included all patients receiving at least 1 dose of romidepsin. Results: The ITT population comprised 48 patients with PTCL and 2 with CTCL (1 each in the 9 and 14 mg/m2 cohorts). The common PTCL subtypes were angioimmunoblastic T-cell lymphoma (AITL, n=21, 44%), PTCL not otherwise specified (PTCL-NOS, n=20, 42%), and anaplastic large-cell lymphoma (ALCL ALK-1 negative, n=3, 6%). Most patients had a favorable ECOG performance status (86% 0-1) and 72% were >=65 years of age. Patients had received a median of 2 prior therapies (range, 1-9). Of 9 patients assessable in phase I (n=3 at 9 mg/m2 and n=6 at 14 mg/m2), none experienced a DLT. The recommended phase II dose was 14 mg/m2 in 40 subsequently treated patients. The overall population received a median of 10 doses (range, 1-135) for a median treatment duration of 12.9 weeks (range, 0.1-184.3; 8 patients were treated for >=36 weeks). The common all-grade adverse events (AEs) were thrombocytopenia (n=49, 98%), lymphopenia (n=44, 88%), leukopenia (n=42, 84%), neutropenia (n=40, 80%), pyrexia (n=33, 66%), dysgeusia (n=31, 62%), decreased appetite (n=28, 56%), and nausea (n=27, 54%). The common grade >=3 AEs were lymphopenia (n=37, 74%), neutropenia (n=27, 54%), leukopenia (n=23, 46%), and thrombocytopenia (n=19, 38%). Of the 39 patients whose CD4+ T-cell counts were monitored, while decreased CD4+ T-cell counts ( Among the 40 patients with PTCL (phase II), the ORR was 43% (95% CI, 27%-58%), including 10 patients (25%) with complete response (CR) or CR unconfirmed (CRu) and 7 (17%) with partial responses (PR) (Table 1). The obtained ORR was significantly higher compared with the threshold ORR of 10% (P Conclusions: Results from this phase I/II study identified a tolerable dose of romidepsin and indicated that romidepsin has an acceptable toxicity profile with clinically meaningful, efficacy in Japanese patients with R/R PTCL. The efficacy and safety data were comparable with results from other romidepsin phase II studies. Disclosures Ogura: Celltrion, Inc.: Consultancy, Honoraria; SymBio Pharmaceuticals: Consultancy, Honoraria. Maruyama:Janssen: Honoraria; Takeda: Honoraria. Tobinai:Chugai Pharma: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; HUYA Bioscience: Honoraria; Celgene: Research Funding; Kyowa Hakko Kirin: Research Funding; GlaxoSmithKline: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding. Uchida:SymBio Pharmaceuticals: Research Funding. Hatake:Chugai: Research Funding; Meiji-Seika: Consultancy; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Ishida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Ishizawa:SymBio Pharmaceuticals: Research Funding. Laille:Celgene: Employment, Equity Ownership. Ro:Celgene: Employment, Equity Ownership. Tamakoshi:Celgene: Employment, Equity Ownership. Sakurai:Celgene: Employment. Ohtsu:Celgene: Employment, Equity Ownership.

Background: CC-486 is an oral formulation of the epigenetic modifier, azacitidine, in clinical development for treatment (Tx) of hematological cancers. Part 1 of this phase I, multicenter study showed no effect on pharmacokinetics (PK) of CC-486 when taken with food or with a proton-pump inhibitor (Laille, 2014). A prospective extension phase of this study is ongoing to assess the safety and efficacy of CC-486. Objectives: To assess safety, tolerability, and hematological response associated with an extended CC-486 dosing schedule in patients (pts) with MDS, AML, or CMML. Methods: Eligible pts were age ≥18 years, had confirmed WHO-defined MDS, CMML, or AML based on bone marrow (BM) aspirate and biopsy, and an ECOG performance status score 0-2. In the PK phase, pts received 2 to 3 single CC-486 doses and in the extension phase, pts received CC-486 300 mg QD for the first 21 days of repeated 28-day cycles. Tx-emergent adverse events (TEAEs) were coded by MedDRA v15.0 and graded using NCI-CTCAE v4.0. In addition to TEAEs for all pts, because PK-phase exposure was quite limited, TEAEs of interest are reported for the subset of pts who entered the extension phase (21-day dosing). Responses (complete or partial remission [CR, PR], CR with incomplete blood count recovery [CRi], marrow CR [mCR], hematologic improvement [HI], and transfusion independence [TI]) were defined by IWG 2006 (MDS) or IWG 2003 (AML) criteria. Baseline transfusion dependence (TD) was defined as ≥4 red blood cell (RBC) units or ≥2 platelet transfusions, in the 56 days before first dose. TI was defined as no transfusion for 56 consecutive days. The safety-evaluable cohort included all pts who received ≥1 CC-486 dose. Efficacy-evaluable pts had ≥1 post-baseline efficacy measurement during the extension phase as of data cut-off (June 6, 2014). Efficacy results are reported for the combined MDS and CMML pt population and separately for pts with AML. Results: A total of 32 pts (MDS n=19 [59%], CMML n=4 [13%], and AML n=9 [28%]) received ≥1 CC-486 dose and are evaluated for safety. Median (range) age of all pts was 72 (53-93) years, with 44% of pts age ≥75 years. Most pts were male (69%) and all were Caucasian. Median number of CC-486 Tx cycles for all pts was 4 (range 1-18), and within the MDS, CMML, and AML groups was 5 (1-18), 4 (2-17), and 1 (1-9), respectively. The mean ±SD Tx cycle length was 30 ±9.0 days overall (by group: 33 ±8.3 days in MDS, 25 ±5.4 in CMML, and 27 ±10.7 in AML pts). The most frequent types of TEAE were gastrointestinal (GI) and hematological (Table 1). CC-486 dose was adjusted due to GI TEAEs for 5 pts (16%), and due to hematological TEAEs for 8 pts (25%). Of all 32 pts, 30 pts (94%) entered the 21-day dosing extension phase. Of these pts, GI TEAEs (grade ≥2) were reported for 23 pts (77%). Of these, only 4 grade 3 (vomiting and diarrhea, 2 each) and no grade 4 TEAEs were observed. Hematological TEAEs (grade ≥3) were reported for 19 pts (63%). Neutropenic grade ≥2 TEAEs occurred in 12 (40%) of 30 pts, of which 29% were grade 2, 38% grade 3, and 32% grade 4. Febrile neutropenia occurred in 3 pts and grade 4 thrombocytopenia in 3. Most TEAEs occurred during the first 2 Tx cycles: GI, 73% and hematological, 55%. The efficacy-evaluable population at data cut-off included 27 pts (84%): 20 pts with MDS or CMML, and 7 pts with AML (Table 2). One pt with MDS achieved CR, 1 pt with AML achieved CRi, and 1 pt with AML achieved PR (pt was to proceed to transplant). Of HI-evaluable pts in the MDS+CMML and AML groups, respectively, 6/18 (33%) and 2/7 (29%) attained an HI response. Few pts were TD at baseline. Of pts who were RBC TD at baseline, 1/5 pts (20%) in the MDS+CMML group and 1/5 pts (20%) in the AML group attained RBC TI. Of 3 pts who were platelet TD at baseline, 1 pt with AML attained platelet TI. Conclusions: CC-486 can provide the flexibility to adjust dose or dosing regimen to improve tolerability or efficacy as needed. The safety and tolerability of CC-486 300 mg QD taken for the first 21 days of repeated 28-day cycles were consistent with the known safety profile of injectable azacitidine in these pts with MDS, CMML, and AML. Grade 3-4 gastrointestinal TEAEs were infrequent ( Disclosures Savona: Karyopharm: Consultancy, Equity Ownership; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy. Kolibaba:Celgene: Research Funding. Conkling:Celgene: Research Funding. Rifkin:Celgene: Scientific Advisory Board Other; Millennium/Takeda: Scientific Advisory Board, Scientific Advisory Board Other; Onyx/Amgen: Scientific Advisory Board, Scientific Advisory Board Other. Laille:Celgene: Employment, Equity Ownership. Kellerman:Celgene: Employment. Ukrainskyj:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment. Skikne:Celgene: Employment, Equity Ownership.

Background: Disease relapse and graft vs host disease (GvHD) following alloHSCT are major causes of treatment (Tx) failure in patients (pts) with MDS and AML (Paietta, 2012). Studies of parenteral azacitidine, an epigenetic modifier, have shown efficacy in preventing post-transplant relapse in MDS and AML pts, and possibly reducing GvHD severity (Platzbecker, 2012; de Lima, 2010). Azacitidine maintenance after alloHSCT may enhance graft vs leukemia (GvL) effects and reduce GvHD by expansion of regulatory T cells (Goodyear, 2010, 2012). CC-486 is a novel oral formulation of azacitidine which, as well as potentially allowing easier administration over extended schedules, could increase the duration of drug exposure to residual malignant cells. We now report preliminary results from a prospective phase I/II dose-finding study of CC-486 as maintenance Tx after alloHSCT in pts with MDS or AML. Objective: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics (PK), and safety outcomes of CC-486 following alloHSCT in pts with MDS or AML. Methods: Pts with WHO-defined MDS or AML who have undergone alloHSCT with myeloablative (MAC) or reduced-intensity conditioning (RIC) regimens and who had sibling or unrelated donors with ≤1 antigen mismatch at the HLA-A, -B, -C, -DRB1 or -DQB1 locus, are enrolled. CC-486 Tx is initiated between days (d) 42 and 84 after alloHSCT. Pts receive prophylactic Tx for GvHD and infections per institutional standard. A standard 3x3 MTD design is being used to evaluate 4 dosing schedules: CC-486 200 mg or 300 mg QD, administered for 7 d (Cohorts 1 and 2) or 14 d (Cohorts 3 and 4) of repeated 28d Tx cycles. MTD determination is based on DLT that occur during the first 2 Tx cycles (pts are not evaluable if unable to complete 2 Tx cycles for reasons other than a DLT). Adverse events (AEs) are graded using NCI-CTCAE v4.0. Pts are followed for safety, incidence of acute and chronic GvHD, and relapse. PK of azacitidine after CC-486 administration, alone or with standard concomitant medications, are evaluated on d 1 of CC-486 Tx cycles 1 and 2. Results: At data cut-off (7/17/2014), outcome data were available for 7 pts enrolled in the first 2 cohorts (Table): 1 pt had IPSS Int-2 MDS and 6 had AML with high-risk features. Stem cell source was from bone marrow (n=2) or peripheral blood (n=5) from unrelated (n=5) or sibling (n=2) donors. Two pts had 1 antigen mismatch and 5 had a full match.Conditioning included MAC (n=3) and RIC (n=4) regimens. One pt in Cohort 2 was not evaluable for DLT or PK assessments due to early discontinuation (AML relapse) during the first CC-486 Tx cycle. Of the 6 evaluable pts, 4 completed ≥6 CC-486 Tx cycles and 2 ongoing pts had not reached 6 cycles on-study at data cut-off (Table). One pt who had GvHD before CC-486 Tx subsequently withdrew from the study after developing febrile neutropenia and diarrhea related to GvHD of the bowel; 1 pt withdrew for personal reasons; and 1 pt discontinued after 6 Tx cycles due to relapse. At data cut-off, 3 pts remained on-study, all with continued CR (Table). No pt in Cohort 2 developed GvHD. For all pts, most AEs were grade 1-2. Grade 3-4 AEs were reported for 2 pts: both had nausea and vomiting, which were controlled with antiemetic agents upon onset; 1 also had device-related infection and dyspnea, and 1 also had febrile neutropenia and rash. No DLT emerged with these CC-486 regimens and no pt experienced secondary graft failure. Overall azacitidine plasma concentration profiles (Figure) and PK parameters were similar following CC-486 given alone or with concomitant medications, and were within range of values observed following similar CC-486 doses in pts with MDS, CMML, and AML (Garcia-Manero, 2011). The AUC range for oral CC-486 is ~10% of that seen with subcutaneous azacitidine administered at 75 mg/m2 (Garcia-Manero, 2011). Conclusion: Preliminary data from this analysis suggest that CC-486 administered at doses of 200 or 300 mg QD for 7 days every 4 weeks is safe and well tolerated in the post-transplant setting. Overall, azacitidine plasma concentration profiles and PK parameters were not affected by use of concomitant medications. No DLT and a low rate of GvHD support the ongoing evaluation of 14d extended CC-486 dosing regimens in this ongoing study, as a preliminary to a prospective, randomized trial of this new agent post-transplant. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures de Lima: Celgene: Consultancy. Champlin:Celgene: Consultancy. Giralt:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Scott:Celgene: Consultancy, Honoraria, Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Craddock:Celgene: Honoraria, Research Funding.

Abstract 1337 Background: Oral azacitidine (CC-486) is bioavailable, biologically and clinically active, and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (Garcia-Manero, J Clin Oncol, 2011). Because DNA methyltransferase (DNMT) inhibitors require active cell cycling to effect methylation reversal, prolonged administration of lower doses of azacitidine may provide more extensive reversal of DNA methylation compared with shorter administration. Purpose: We conducted analyses 1) to determine the pharmacokinetic (PK) and pharmacodynamic (PD; ie, DNA demethylating activity) profiles following subcutaneous (SC) AZA and various dosing schedules of oral azacitidine; 2) to assess the correlation between the PK and PD profiles of oral azacitidine administered in extended dosing schedules; and 3) to compare PD effects observed at different time points in the 28-day (d) treatment cycle with SC AZA or oral azacitidine administered for 7 days vs. the PD effects of 300mg QD oral azacitidine administered in extended dosing schedules in pts with MDS. Methods: This multicenter, phase 1 study had 2 parts. In Part 1, 41 pts with MDS, CMML, or AML received SC AZA (75mg/m2 QDx7d of a 28d cycle) for 1 cycle, then oral azacitidine doses ranging from 120 to 600mg (QDx7d of a 28d cycle) in subsequent cycles. In Part 2, 86 pts received oral azacitidine in 1 of 4 extended dosing schedules: 300mg QD or 200mg BID, each for 14d or 21d of repeated 28d cycles. PK parameters were derived from plasma concentrations. The correlation between PK and PD was determined using data from pts who had received oral azacitidine 200mg BID or 300mg QD for 14d or 21d for whom PD data were available at day 15 of the first 28d cycle (C1D15). The PD endpoint was reduction in percentage of highly methylated (≥70%) loci of DNA in whole blood, assessed using Illumina's Infinium Methylation27 Bead Array. Results: SC AZA or oral azacitidine were rapidly absorbed and reached Tmax (median [min, max]) within 0.5 hr [0.2, 1.1] and 1.0 hr [0.3, 3.6] post-dose, respectively. Mean elimination half-life was 1.5 +/− 0.7 hr and 0.6 +/− 0.2 hr for SC and oral azacitidine, respectively. No drug accumulation was noted following multiple dose administration. Compared with SC AZA, 300mg oral azacitidine QDx14d and QDx21d provided mean cumulative exposures (AUC) per cycle of 38% and 56%, respectively. A PK/PD correlation (AUC C1D1 vs. change in methylation on C1D15 compared with baseline) was observed with oral azacitidine 300mg QD or 200mg BID administered for 14d or 21d (r2=0.659, p Conclusions: Methylation reversal was correlated with plasma AUC following oral azacitidine dosing. Consistent with the hypothesis that prolonged exposure to lower doses of DNMT inhibitors leads to improved methylation reversal, extended dosing schedules led to significantly more demethylation compared with the 7-day oral azacitidine schedule. Additionally, DNA hypomethylation was maintained at cycle end with extended oral azacitidine dosing. The oral azacitidine 300mg QDx21d dosing schedule provided the greatest level of sustained hypomethylation at cycle end of all tested dose regimens, including SC AZA. Extended dosing schedules provide the ability to achieve the PD and epigenetic activity of oral azacitidine over a longer period of time. Disclosures: Laille: Celgene: Employment, Equity Ownership. Shi:Celgene: Employment, Equity Ownership. Garcia-Manero:Celgene: Research Funding, Speakers Bureau. Gore:Celgene: Consultancy, Research Funding. Kumar:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership.

Abstract 3480 Background: The recommended starting dose for all patients receiving SC AZA is 75 mg/m2 daily for 7 days in 28-day cycles. If no response is observed, the dose may be increased to 100 mg/m2. Conversely, if cytopenias do not adequately resolve between dosing cycles, AZA dose may be reduced. Similarly, because AZA and its metabolites are primarily excreted by the kidneys, patients with renal impairment may require monitoring for elevations of BUN or serum creatinine (cr), in which case the next AZA treatment cycle should be delayed until values return to baseline and the next AZA dose should be reduced by 50% (Vidaza® prescribing information, 2011). Currently, the pharmacokinetics (PK) of SC AZA in reduced ( Objectives: To assess the dose proportionality of AZA PK after single SC doses ranging from 25 to 100 mg/m2, and to determine the effect of renal impairment on AZA PK after single and multiple (5 days) SC doses of 75 mg/m2. Also, the safety and tolerability of AZA in patients with severe renal impairment were determined. Methods: This 2-part multicenter, randomized, open-label study included patients with solid or hematologic malignancies. Part 1 was a 4-treatment, parallel-group evaluation of the dose proportionality of SC AZA in patients with normal renal function (cr clearance [CLcr] >80 mL/min/1.73 m2, Cockcroft-Gault equation adjusted for body surface area). Patients were randomized to receive a single dose of 25-, 50-, 75-, or 100-mg/m2 SC AZA. Blood and urine samples were collected before dosing and at various time points up to 8 hours post-dose. The 75 mg/m2 dosing group in Part 1 received an additional 4 days of AZA treatment and blood and urine were collected from these patients on the same schedule on Day 5. For Part 2, patients with severe renal impairment (CLcr Results: At the time of this analysis, 21 patients were enrolled and were included in safety evaluations, with PK data available for 18 patients. At baseline, median ages of patients with normal renal function (n=17) or severe renal impairment (n=4) were 61 years (range: 38–76) and 71 years (range: 54–90), respectively. Of patients with normal renal function, 12 (70%) had solid tumors, 4 had MDS (RAEB-t [n=2], RA, RARS), and 1 had multiple myeloma. Of patients with severe renal impairment, 2 (50%) had solid tumors, 1 had CMML, and 1 had MDS (RA). In Part 1, 14 patients were randomized to either 25 mg/m2 (n=4), 50 mg/m2 (n=4), 75 mg/m2 (n=3), or 100 mg/m2 (n=3). Mean [±SD] AUC0-∞ in the 25-, 50-, 75-, and 100 mg/m2 dose groups were 490 [146], 895 [300], 1270 [480], and 1410 [212] ng*hr/mL, respectively. Preliminary results show AZA is dose proportional across the 25–100 mg/m2dose range (Figure 1). In Part 2, on Days 1 and 5 of 5 consecutive days of SC AZA administration, AZA was rapidly absorbed by patients with severe renal impairment, reaching Cmax within 0.75 hours post-dose. AZA concentration decreased thereafter in a pseudobiphasic manner (Figure 2). Similar profiles were observed in patients with normal renal function who received the same dose. Mean [±SD] AUC0-∞ values after a 75 mg/m2 SC AZA dose on Day 1 were 1270 [480] ng*hr/mL in patients with normal renal function and 1630 [913] ng*hr/mL in patients with severely impaired renal function. On Day 5, mean AUC0-∞ values were 901 [92] and 1280 [728] ng*hr/mL, respectively. Similar observations were noted for Cmax. No accumulation of AZA was noted on Day 5 in either group. High inter-patient variability was noted in both groups (% coefficient of variation up to ∼82%). Patients with or without renal impairment did not show unusual or unexpected adverse events. Conclusions: AZA is dose-proportional over the 25–100 mg/m2 dosing range. PK parameters from patients with severe renal impairment treated with multiple doses of AZA 75 mg/m2 SC were comparable to those obtained from patients with normal renal function. Treatment with AZA 75 mg/m2 SC over multiple days was safe and well tolerated in this small group of patients with normal renal function or severe renal impairment. Disclosures: Laille: Celgene Corporation: Employment, Equity Ownership. Goel:Celgene: Research Funding. Schwarz:Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

Abstract 1546 Background: When administered subcutaneously (SC), the cytidine nucleoside analog azacitidine (AZA) has been shown to significantly improve overall survival in patients (pts) with low-blast count (20%–30%) AML compared with conventional care regimens (Fenaux, JCO, 2010). An oral AZA formulation would be more convenient for pts, increase access to treatment, allow extended dosing schedules, and may improve efficacy. An initial study of oral AZA administered once daily on a 7-day schedule demonstrated it to be bioavailable, safe, and clinically active in pts with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) (Garcia-Manero, JCO, 2011). Purpose: To present results of a multicenter phase I study of the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and preliminary hematologic response rates in pts with AML receiving varying dose regimens of oral AZA. Methods: Pts aged ≥ 18 years with AML who were not candidates for other therapies (but who may have failed prior treatment) were included. In Part 1, pts received an initial cycle of SC AZA 75 mg/m2 QD x 7 days of a 28-day cycle. Thereafter, oral AZA (120–600 mg QD) was given for 7 days of repeated 28-day cycles. In Part 2, pts received only oral AZA, in 1 of 4 extended dosing schedules: 300 mg QD or 200 mg BID, each for 14 or 21 days of 28-day cycles. Oral AZA was continued until disease progression or withdrawal for other reasons. PK was assessed during the first cycle of oral AZA treatment and DNA methylation was assessed during cycles 1 and 2 of oral AZA (Infinium Methylation27 BeadArray). Pts were monitored continuously for adverse events (AEs) and assessed for treatment response (Cheson, JCO, 2003; Cheson, JCO, 2006) at the end of every second cycle. Results: In all, 23 pts (median age 68 years [range 44–85], 13 male/10 female) with AML (13 de novo, 10 transformed from MDS) have received oral AZA on 7-day QD (n=8), 14-day QD (n=4), 21-day QD (n=4), 14-day BID (n=4), or 21-day BID (n=3) treatment schedules. At baseline, 14 (61%) and 8 (35%) pts were red blood cell (RBC) or platelet transfusion dependent, respectively; 13 pts (57%) had prior AML treatment, primarily intensive chemotherapy. Eight pts had unfavorable and 12 pts had intermediate cytogenetics (data not available, n=3). At baseline, median (range) hematologic measures were WBC = 1.5 K/μL (0.4 − 21.2), ANC = 0.2 K/μL (0 − 3.5), platelets = 34.0 K/μL (6.0 − 102), and % BM blasts = 28.0% (2.0 − 92.0). Median duration of oral AZA (any regimen) was 4 cycles (range 1–14). Seven pts (30%) received ≥ 6 cycles of oral AZA and 16 pts discontinued before completing 6 cycles (Figure). PK results were consistent with recently published data (Garcia-Manero, JCO, 2011). Following a single 300 mg dose (n=8), AUC0-∞ = 230 ± 210 ng*hr/mL, Cmax = 150 ± 114 ng/mL, t1/2 = 0.54 ± 0.21 hr, and median Tmax = 0.8 hr. There was no accumulation following multiple doses. Compared with extrapolated cumulative exposure of SC AZA administered for 7 days per the approved dosing regimen, extrapolated cumulative exposures of oral AZA with extended dosing schedules ranged from 55% for 300 mg QD × 14 days to 104% for 200 mg BID × 21 days. Overall, hematologic improvement (HI) was achieved by 5 pts (22%) (Table). One pt receiving 7-day QD oral AZA achieved a CRi. Responses were seen in 3/13 pts with de novo AML and 3/10 with secondary AML (Figure), and in 2/13 pts with prior AML treatment and 4/10 pts without prior treatment. DNA methylation levels in whole blood were reduced after oral AZA in 4/7 tested pts. The most common AEs (any severity) were gastrointestinal. Most common grade 3–4 AEs were febrile neutropenia (35%), pneumonia and syncope (17% each), nausea (13%), and thrombocytopenia, diarrhea, fatigue, dehydration, headache and mental status changes (9% each). Two pts died due to causes related to AML, and 2 pts discontinued (treatment failure, withdrew consent), within the first 60 days on-study. Conclusions: Oral AZA treatment was well tolerated in this AML population of pts who were not candidates for other therapy. The oral formulation showed biological activity by reducing DNA methylation. Oral AZA also showed clinical activity in these AML pts, many of whom had complex cytogenetics and/or had failed prior therapy before study entry. Disclosures: Gore: Celgene Corporation: Consultancy, Equity Ownership, Research Funding. Off Label Use: Oral formulation for Azacitidine in AML patients. Cogle:Celgene Corporation: Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene Corporation: Employment, Equity Ownership. Shi:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Giordano:Celgene Corporation: Employment, Equity Ownership.

Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.

Abstract 117 Background: Parenteral azacitidine significantly improves overall survival of subjects with higher-risk MDS and WHO AML (20–30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009; 10:223). An oral formulation would be a more convenient administration route for patients and allow the evaluation of extended low-dose regimens, which could in turn lead to better treatment efficacy and lower toxicity profiles. The aim of this phase 1 study is to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of increasing doses of orally-administered azacitidine in subjects with MDS or AML. Methods: Subjects aged ≥ 18 years with a diagnosis of MDS or AML (not candidates for other therapies) by WHO criteria were enrolled into this multicenter, Phase 1, dose escalation study. Prior treatment with azacitidine or other demethylating agent was permitted. To allow PD/PK analyses of oral vs. subcutaneous (SC) administration, azacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. A standard “3+3” dose escalation design was used and an expansion cohort at the MTD was planned. Subjects were evaluated for DLT during the first cycle of oral azacitidine therapy. Azacitidine levels in plasma and urine were measured. DNA methylation was assayed using Illumina's Infinium Human Methylation27 BeadArrays. Response was assessed according to International Working Group (IWG) criteria for MDS (2006) and AML (2003). Results: To date, 45 subjects have enrolled into the study. Forty subjects received both SC and oral azacitidine; 5 subjects received SC azacitidine only. Median age is 70 years (range 31–91). Thirty-four subjects had MDS, 9 AML, and 2 CMML. Median pretreatment WBC and platelet counts of MDS subjects were 2.5 × 109/L (range 0.8–39.4) and 55.0 × 109/L (range 4.0–234.0) respectively. For subjects with AML, the median pretreatment WBC and platelet counts were 1.8 × 109/L (range 0.5–3.4) and 42.8 × 109/L (range 10.0–82.0) respectively. Baseline cytogenetics for subjects with MDS were as follows: 12 complex karyotype; 10 diploid; 1 with −7; 1 with t(11q23) and 10 whose karyotype was unknown. Doses of oral azacitidine evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. The MTD of oral azacitidine on a 7-day QD treatment schedule was 480 mg. The DLT was grade 3 or 4 diarrhea in 2 of 3 subjects enrolled in the 600 mg cohort. Other grade 3 or 4 AEs reported include febrile neutropenia (6 subjects), infection (6 subjects), nausea (2 subjects), vomiting (2 subjects), fatigue (2 subjects), and thrombocytopenia (2 subjects). The bioavailability of oral azacitidine ranged from 5% to 35%. The exposure (AUCinf) of oral azacitidine was highly variable compared to SC exposure, ranging from 15% to 74% (except for one subject whose PK exposure following oral therapy was 167% of his SC exposure). Median duration of oral azacitidine was 5+ cycles (range 1–19+) for subjects with MDS and 2.5+ cycles (range 1–6+) for subjects with AML. Responses were evaluated following 6 cycles of oral therapy. To date, 14 subjects have received ≥ 6 cycles of oral azacitidine: 4 (29%) had complete response (CR), 6 (43%) had stable disease (SD), 3 (21%) had disease progression, and 1 subject (7%) was not evaluated. Among subjects with CR or SD, hematologic improvement by disease-specific IWG criteria included erythroid response (n = 5), platelet response (n = 5) and neutrophil response (n = 3). Fourteen subjects are ongoing, but have not completed 6 cycles of oral therapy; 17 subjects discontinued prior to completing 6 cycles. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral azacitidine treatment, and a set of CpG loci were identified for which these changes were associated with azacitidine AUCinf and/or Cmax.. In addition, approximately 260 hypomethylated loci were common to both SC and oral therapy. Conclusions: Results to date indicate that a 7-day dosing regimen of oral azacitidine is active and well tolerated, with a manageable side effect profile in subjects with MDS or AML. Oral azacitidine exposure was highly variable and lower than that of SC azacitidine. Changes in DNA methylation were observed in the blood of MDS and AML subjects following SC and oral therapy. Evaluation of prolonged and BID treatment schedules is planned. Disclosures: Garcia-Manero: Celgene: Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Skikne:Celgene: Employment. Cogle:Celgene: Research Funding, Speakers Bureau; Eisai: Speakers Bureau. Ning:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Laille:Celgene: Employment, Equity Ownership. Ward:Celgene: Employment, Equity Ownership.