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PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

Azacitidine for injection (AZA) (Vidaza, Celgene Corp., Summit, NJ), represents a well-established and registered agent in Myelodysplastic Syndromes (MDS) and in acute myeloid leukemia (AML) [1]. A...

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors. Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486. Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days. Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.

CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS The safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.)

CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

Background Azacitidine safety and efficacy were established in studies of mainly Caucasian patients. Differences in drug metabolism enzymes between Caucasian and East Asian populations prevent extrapolation of drug effects between these groups. This phase 2 study evaluated azacitidine safety, efficacy and pharmacokinetics in patients with higher-risk myelodysplastic syndromes (HR-MDS) in mainland China. Methods Patients aged ≥18 years with HR-MDS were to receive subcutaneous azacitidine 75 mg/m2 /day for 7 days per 28-day cycle, for ≥6 cycles. Pharmacokinetic blood samples were collected in cycle 1 predose on days 5-7, and postdose on day 7. Pharmacokinetic outcomes are descriptively compared with those of a historical North American cohort. Results Of 72 participants, 46 (64%) completed ≥6 cycles. Response rate was 96%, driven primarily by stable disease (94%); one patient achieved complete remission. Hematologic improvement was attained by 53% of patients. Azacitidine mean plasma concentration versus time profiles were similar in shape for Chinese (n = 12) and North American (n = 45) patients. Maximum plasma concentration (Cmax ) was higher in Chinese patients; however, mean azacitidine exposure (1190 ng·h/mL) was similar to the North American cohort (1021 ng·h/mL). Most common grade 3-4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (69%) and neutropenia (67%). Conclusions Azacitidine was safe and effective in Chinese patients with HR-MDS. Clinical outcomes were comparable to those for primarily Caucasian patients in the phase 3 AZA-001 study. Cmax differences between Chinese and North American patients were not associated with differences in TEAE frequency or severity. No initial azacitidine dose adjustment is required for Chinese patients with HR-MDS.

Azacitidine is a cytidine analog used in the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia. The pharmacological effect of azacitidine arises after incorporation into the DNA and RNA. To this end, the drug first has to be converted into its triphosphate forms. This paper describes the development of an assay for quantitative determination of azacitidine triphosphate (aza-CTP) in peripheral blood mononuclear cells (PBMCs). To quantify aza-CTP, separation from the endogenous nucleotides cytidine triphosphate (CTP) and uridine triphosphate (UTP) is required. This was a challenge as the structures of these nucleotides are highly similar and the monoisotopic molecular masses of aza-CTP, UTP and the naturally occurring [(13)C]- and [(15)N]-isotopes of CTP differ less than 0.02 Da. Efforts to select a specific MS(2)-fragment for aza-CTP using a triple quadrupole mass spectrometer remained without success. Therefore, we investigated the feasibility to separate these highly resembling nucleotides based on accurate mass spectrometry using a linear trap quadrupole (LTQ) coupled with an Orbitrap. The LTQ-Orbitrap was able to differentiate between aza-CTP and the endogenous nucleotides UTP and [(13)C]-CTP. There was no baseline resolution between aza-CTP and [(15)N]-CTP, but the [(15)N]-CTP interference was low. For quantification, extracted ion chromatograms were obtained for the accurate m/z window of the aza-CTP product ion. The assay was able to determine aza-CTP concentrations in PBMC lysate from 40.7 to 281 nM. Assuming that an average cell suspension extracted from 16 mL blood contains 10 to 42 million PBMCs per mL, this range corresponds with 2.58/10.9-17.8/74.9 pmol aza-CTP per million PBMCs. Intra-assay accuracies were between -1.1 and 9.5% deviation and coefficient of variation values were ≤13.2%. The assay was successfully applied to quantify aza-CTP in samples from two patients treated with azacitidine. Aza-CTP concentrations up to 19.0 pmol per million PBMCs were measured. This is the first time that aza-CTP concentrations were quantified in PBMCs from patients treated with azacitidine.

Parenteral azacitidine improves overall survival in higher-risk myelodysplastic syndromes. An oral azacitidine formulation would allow extended dosing schedules, potentially improving safety and/or efficacy. Two Phase 1 studies evaluated the pharmacokinetics (PK) of oral azacitidine in subjects with hematologic malignancies. Study 1 evaluated different oral formulations (immediate release tablet [IRT], enteric-coated tablet, and capsule; N = 16). Study 2 assessed the effect of food (Part 1; N = 17) and gastric pH modulation with omeprazole (Part 2; N = 14) on oral azacitidine PK. Azacitidine plasma concentration-time profiles for IRT and capsule formulations were similar, with more rapid time to maximum plasma concentration (Tmax ) than the enteric-coated tablet. Study 2 evaluated only IRT formulations of oral azacitidine. Under fed condition, Tmax was delayed ∼1.5 hours but area under the concentration-time curve (AUC∞ ) and maximum plasma concentrations (Cmax ) were comparable under fed and fasted conditions. Mean azacitidine AUC∞ and Cmax increased upon omeprazole co-administration (18.3% and 13.2%, respectively, vs. oral azacitidine alone), but not to a clinically meaningful extent. High inter-subject variability in AUC∞ and Cmax (%CV range 46.4-68.9%) was observed. Oral azacitidine is rapidly absorbed with little or no effect of food on PK parameters, and does not require dose adjustments when taking a proton-pump inhibitor.

Study Objective To assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of 25–100 mg/m2, and determine the effect of renal impairment on PK after single and multiple 75 mg/m2 SC azacitidine doses. Design Multicenter, phase I, open-label, parallel group study. Setting Community clinics and major academic centers. Patients Twenty-seven patients with solid or hematologic malignancies. Interventions Part 1 evaluated azacitidine dose proportionality in patients with normal renal function randomized to single 25, 50, 75, or 100 mg/m2 SC doses. The 75 mg/m2 dosing group received 4 additional days of SC azacitidine. In Part 2, patients with severe renal impairment (creatinine clearance

Aim Clinical and pharmacokinetic effects of azacitidine in higher-risk myelodysplastic syndromes were established in mainly Caucasian populations. Because of inter-ethnic genotype variability of drug-metabolizing enzymes, it is important to evaluate azacitidine in populations expected to use the drug. Methods In this single-arm study, Taiwanese patients with higher-risk myelodysplastic syndromes received azacitidine 75 mg/m2/day for 7 days/28-day cycle for up to six cycles. Response-evaluable patients had baseline and cycle 6 marrow assessments. Clinical outcomes are compared descriptively with those from a phase 3 study comprising mainly Caucasian patients (N = 179). Pharmacokinetics in a subgroup of Taiwanese patients are descriptively compared with a historical control of North American patients (N = 45). Results Median age of Taiwanese patients (N = 44) was 64 years (range 36–90), and 46% had poor cytogenetics. Median number of azacitidine cycles was six (1–6). No response-evaluable patient (n = 33) achieved complete or partial remission; however, 22 patients (50%) achieved hematologic improvement, 12 of 32 patients attained RBC transfusion independence and 7 of 18 attained platelet transfusion independence. Most common grade 3–4 treatment-emergent adverse events were neutropenia (52%) and leukopenia (39%). Pharmacokinetic profiles were similar for Taiwanese (N = 12) and North American (N = 45) patients. Maximum plasma concentration was higher in Taiwanese patients; however, mean azacitidine exposure was within the range for North American patients. Conclusion These data confirm the safety and efficacy of azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Clinical outcomes were generally comparable with those for Caucasian patients. No meaningful differences in azacitidine pharmacokinetics were observed for Taiwanese patients, and no initial dose adjustment is necessary.

Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

Purpose To assess the potential inhibitory and inductive effects of azacitidine on cytochrome P450 isozymes in vitro. Methods The inhibitory effects of azacitidine on various CYP isozymes were determined in human liver microsomes. In addition, the ability of azacitidine to induce CYP enzymes in cultured human hepatocytes was evaluated. Results Azacitidine did not inhibit CYP2B6-, CYP2C8-, CYP2C9-, CYP2C19-, CYP2D6-, and CYP3A4-mediated activities in human liver microsomes up to a concentration of 100 μM, while weak inhibition (

CC-486 (oral azacitidine) is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML) from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05) reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle), with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle. Trial Registration ClinicalTrials.gov NCT00528983

Parenteral azacitidine improves overall survival in higher-risk myelodysplastic syndromes. An oral azacitidine formulation would allow extended dosing schedules, potentially improving safety and/or efficacy. Two Phase 1 studies evaluated the pharmacokinetics (PK) of oral azacitidine in subjects with hematologic malignancies. Study 1 evaluated different oral formulations (immediate release tablet [IRT], enteric-coated tablet, and capsule; N = 16). Study 2 assessed the effect of food (Part 1; N = 17) and gastric pH modulation with omeprazole (Part 2; N = 14) on oral azacitidine PK. Azacitidine plasma concentration-time profiles for IRT and capsule formulations were similar, with more rapid time to maximum plasma concentration (Tmax ) than the enteric-coated tablet. Study 2 evaluated only IRT formulations of oral azacitidine. Under fed condition, Tmax was delayed ∼1.5 hours but area under the concentration-time curve (AUC∞ ) and maximum plasma concentrations (Cmax ) were comparable under fed and fasted conditions. Mean azacitidine AUC∞ and Cmax increased upon omeprazole co-administration (18.3% and 13.2%, respectively, vs. oral azacitidine alone), but not to a clinically meaningful extent. High inter-subject variability in AUC∞ and Cmax (%CV range 46.4-68.9%) was observed. Oral azacitidine is rapidly absorbed with little or no effect of food on PK parameters, and does not require dose adjustments when taking a proton-pump inhibitor.

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.

Background: CC-486 is an orally bioavailable formulation of azacitidine that has demonstrated clinical activity in subjects with Myelodysplastic Syndromes (MDS) and Acute Myleoid Leukemia (AML). In these patient populations, CC-486 in extended dosing regimens, 200 mg and 300 mg given daily on a 14 or 21 out of 28-day schedule, induces sustained global genomic hypomethylation. Methods: This Phase I, multicenter, open-label study was conducted in subjects with solid tumors to evaluate: 1) the effect of carboplatin or ABI-007 on the PK of CC-486; 2) the effect of CC-486 on the PK of carboplatin or ABI-007; and 3) the PD (DNA methylation) effects of CC[[Unable to Display Character: ‑]]486 as a single agent and in combination with carboplatin or ABI-007. Safety and efficacy information of this trial are presented in a separate abstract submission. Subjects received CC-486 on Days 1-14 with carboplatin AUC 4 on Day 8 of a 21-day cycle (Arm A), CC-486 on Days 1-14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of a 21-day cycle (Arm B), or CC-486 on Days 1-21 of a 21-day cycle (Arm C). Results: High inter-subject variability was observed in PK concentrations and parameters. In subjects from Arms A and B, following administration of CC-486 alone or in combination with carboplatin or ABI-007, CC-486 was rapidly absorbed and reached Tmax within approximately 1.0 hour post-dose (median); azacitidine PK parameters (AUC, Cmax, half-life elimination, apparent clearance, and volume of distribution) were comparable following administration of CC-486 alone or in combination. Similarly, carboplatin and ABI-007 PK parameters were similar following administration of carboplatin or ABI-007 alone or in combination with CC-486. In subjects from the 3 Arms, global genomic hypomethylation was observed in PBMCs, with maximum effect on Day 15. A PK/PD (AUC/hypomethylation change on Day 15) correlation was noted (r>0.5; p Conclusion: Carboplatin and ABI-007 had minimal to no effect on CC-486 PK parameters, and vice-versa. Following administration of CC-486, global genomic hypomethylation was correlated with plasma AUC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B217. Citation Format: Eric Laille*, Aaron N. Nguyen*, Gengxi Chen, Drew Rasco, Patricia LoRusso, Daniel D. Von Hoff, Johanna Bendell, Pamela Munster, William J. Edenfield, Ramesh Ramanathan, Michael B. Gonzalez, Anne Blackwood-Chirchir, Jorge DiMartino. A Phase I study of CC-486 (oral azacitidine) to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of azacitidine administered alone and in combination with carboplatin or ABI-007 (NAB-paclitaxel) in subjects with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B217.

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 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.

7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (inf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA. [Table: see text]