2023 SOHO: Randomized Phase 1-2 Study to Assess Safety and Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients: Interim Safety Analysis

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View Presentation:   Randomized Phase 1-2 Study to Assess Safety and Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients: Interim Safety Analysis

Abstract:

Background: Cedazuridine (CED), a cytidine deaminase (CDA) inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination (FDC) of 35 mg DEC/100 mg CED standard dose (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 D1-5 (Garcia-Manero et al, 2020).  Attenuated HMA regimens (e.g., 3 days IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017).

Aims: This Phase 1/2 study explores lower dose oral DEC/CED regimens in LR-MDS patients.

Methods: Phase 1/2 study in lower-risk-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1: explored 28-day regimens, dose ranges 5-20 mg DEC/100mg CED; duration ranges 5-10 days.  Primary endpoints: recommended Phase 2 dose (RP2D) based on safety and dose-limiting toxicity (DLT). Secondary endpoints: clinical activity per 2006 IWG (transfusion independence [TI], LFS, OS).  Phase 2: randomized 81 LR-MDS 1:1 to receive Phase 1 RP2D vs. 35 mg DEC/100 mg CED (SD) for 3days (SD-3Day) (reflecting attenuated HMA regimen for LR-MDS).  Similar efficacy and safety endpoints as Phase 1.

Results: Phase 1: 47 patients treated with five different DEC/CED regimens. DLT (myelosuppression-associated) increased with higher treatment doses and longer duration. Hematologic Improvement (HI) % across dosing regimens: 30% (14/47), 8-week RBC transfusion-independent rate: 33% (7/21); mOS: 31 months (95%Cl:19,NE); mLFS 23 months (95%Cl:14,32). Based on clinical efficacy and safety, 10mg DEC/100mgCED D1-5 every 28D (LD-5Day) was selected as RP2D.

Phase 2: Baseline: Int-1 (65-73%), 48% prior MDS treatment (21%ESA, 26% luspatercept), 46% RBC transfusion-dependent (TD); 14% platelet TD. At cutoff, 80 subjects had received a median of 4.5 treatment cycles, ~10 patients received subsequent transplant. PK data showed LD-5Day exposure about half SD-3Day exposure. Reported adverse event terms with LD-5Day were similar to SD-5day, with most common grade ≥3 from myelosuppression. By cycle 8, average neutrophil counts were higher in LD-5Day regimen vs. SD-3Day regimen; platelet changes were similar. Of 8 all-cause deaths at data cutoff, only 1 was within 30days (in SD-3Day group).

Conclusion: This Phase 1/2 study suggests LD-5Day regimen is tolerable (less neutropenia) and potentially an optimal regimen for LR-MDS (longer term efficacy analysis vs. SD-3Day regimen pending).

2023 SOHO: Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subpopulation from Phase 2 and ASCERTAIN Phase 3 Studies

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View Presentation:  Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subpopulation from Phase 2 and ASCERTAIN Phase 3 Studies

Abstract:

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease characterized by persistent monocytosis, splenomegaly, and both dysplastic and myeloproliferative changes in the bone marrow. Hypomethylating agents (HMAs) are approved for CMML treatment. ASTX727 (DEC/CED), an orally available fixed dose combination (FDC) of 35 mg decitabine (DEC) and 100 mg cedazuridine (CED), a cytidine deaminase inhibitor, produces comparable PK AUC exposure compared to IV DEC (Garcia-Manero, et al, 2019).

Aims: We present the  combined clinical experience of CMML patients in studies leading to FDA approval of oral DEC/CED (ClinicalTrilas.gov NCT02103478 and NCT03306264, respectively) including genetic profiles.

Methods: 33 CMML candidates for parenteral decitabine with PS 0-2 were enrolled and received standard oral decitabine/cedazuridine (DEC/CED) regimen. Clinical endpoints were best response by International Working Group (IWG) 2006, transfusion independence (TI), transformation-free survival (TFS), overall survival (OS), and safety. Molecular profiling used an NGS panel, including somatic mutations affecting CMML prognosis and response to HMA therapy. Cox-regression analysis on various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for OS.

Results: Patients:  Median age 71 years, 55% patients  ECOG PS of 1, 85% no prior anticancer therapy for CMML, one-third RBC transfusion-dependent at baseline, 70% CMML-1 (2022 WHO classification), 76% MD-CMML. Patients received a median of 10 cycles of therapy (range 2-36).

Efficacy: 7 (21.2%) Complete Responses (CR), 14 (42.4%) marrow CR (mCR), including 5 (15.2%) with hematologic improvement (HI); overall response rate (ORR) [CR + PR+ mCR + HI] 75.8%.  Of those RBC transfusion-dependent at baseline, 63.6% became TI for at least 8 weeks. mTFS was 28.3 months; mOS 35.7 months. Safety: profile was consistent with decitabine; most grade ≥3 events from myelosuppression. Given the advanced age, only 3(9%) went on to transplant. Cox regression analysis only associated post-treatment RBC TI with survival with no observed effect on OS for other baseline or response-related factors; the sensitivity of these analyses is limited by patient number.

Conclusions/Summary: DEC/CED has clinical benefit in CMML patients with a well-tolerated safety profile. TI may be associated with longer survival.

2023 EHA: EFFICACY AND SAFETY OF ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN THE CMML SUBPOPULATION FROM PHASE 2 AND ASCERTAIN PHASE 3 STUDIES

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View Presentation: EFFICACY AND SAFETY OF ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN THE CMML SUBPOPULATION FROM PHASE 2 AND ASCERTAIN PHASE 3 STUDIES

Abstract:

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease characterized by persistent monocytosis, splenomegaly, and both dysplastic and myeloproliferative changes in the bone marrow. Hypomethylating agents are approved for CMML treatment as they have historically been included in pivotal studies, however only account for ~10% of trial patients. ASTX727, an orally available fixed dose combination (FDC) of 35 mg decitabine (DEC) and 100 mg cedazuridine (CED), a cytidine deaminase inhibitor, produces comparable PK AUC exposure compared to intravenous decitabine (Garcia-Manero, et al, 2019).

 

Aims: We present the combined clinical experience of patients with CMML in the critical studies leading to FDA approval of oral DEC/CED (ClinicalTrilas.gov NCT02103478 and NCT03306264, respectively) with additional analysis of genetic profiles for the subset.

Methods: 33 CMML patients (16 from phase 2, and 17 from phase 3) who were candidates for parenteral decitabine with PS 0-2 were enrolled and received standard oral decitabine/cedazuridine FDC for 5 days. Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, leukemia free survival (LFS), overall survival (OS), and safety. Peripheral blood collected prior to treatment was used for DNA isolation from leukocytes, and molecular abnormalities identified using a NGS hematologic malignancy panel, including 8 genes frequently associated with CMML. Cox-regression analysis on the various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for OS.

 Results: Median age was 71 years, with 55% patients with ECOG PS of 1. One-third of patients were RBC transfusion-dependent at baseline. 70% of patients were subtyped as CMML-1 based on the 2022 WHO classification, and 76% patients had MD-CMML. The median number of mutations in CMML patients was 3 (range 0-5) among 8 commonly mutated genes (see Figure 1). 85% of patients had received no prior anticancer therapy for CMML. Patients received a median of 10 cycles of therapy (range 2-36).

Seven patients (21.2%) had Complete Responses (CR), 14 (42.4%) had marrow CR (mCR), including 5 (15.2%) who also had hematologic improvement (HI). Overall response rate (ORR) [CR + PR+ mCR + HI] was 75.8%. 63.6% of those dependent on red blood cell (RBC) transfusions at baseline became transfusion independent (TI) for at least 8 weeks and 45.5% for 16 weeks. Median LFS was 28.3 months and median OS was 35.7 months. Safety profile is consistent with decitabine, with most grade 3 or higher events related to myelosuppression; Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [61%], thrombocytopenia [55%], anemia [36%], febrile neutropenia [27%], and leukopenia [24%]). Given the advanced age of the CMML cohort, only 3 (9%) went on to Hematopoietic Stem Cell Transplant. Cox regression analysis suggested that post-treatment RBC TI seemed to be associated with survival; no apparent effect on OS was observed for other baseline or response-related factors, including baseline genetic variants, such as ASXL1 among others (Figure 1) though the sensitivity of such analysis is limited by the number of patients.

 Conclusions/Summary: DEC/CED has a well-tolerated safety profile with clinical benefit in CMML patients.  Preliminary analysis suggests an association between TI and longer survival.

2023 EHA: RANDOMIZED PHASE 1-2 STUDY TO ASSESS SAFETY AND EFFICACY OF LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS: INTERIM SAFETY ANALYSIS

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View Presentation: RANDOMIZED PHASE 1-2 STUDY TO ASSESS SAFETY AND EFFICACY OF LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS: INTERIM SAFETY ANALYSIS

Abstract:

Background:
Cedazuridine(CED),a cytidine deaminase(CDA) inhibitor allows oral availability of decitabine(DEC) and 5 daily doses of the fixed-dose combination of 35 mg DEC/100 mg CED standard  dose(SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 days 1-5 (Garcia-Manero etal, 2020). Attenuated HMA regimens (e.g., 3 days of IV DEC) have shown activity in LR-MDS (Jabbour, etal. 2017).

Aims:
This Phase 1/2 study explores the optimal dosing schedule of Low Dose oral DEC/CED in patients with LR-MDS.

Methods:
A two-part Phase 1/2 study is being conducted in LR-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1 explored 6 different 28-day regimens, ranging from 5-20 mg DEC with 100mg CED and treatment duration of 5-10 days (Figure 1).The primary endpoints were determination of the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLT) and safety. Secondary endpoints included clinical activity based on modified International Working Group (IWG) 2006 MDS response criteria, transfusion independence rate, leukemia-free survival (LFS), and overall survival (OS).
In Phase 2, 81 LR-MDS were randomly assigned in a 1:1 ratio to receive the RP2D from Phase 1 or 35 mg DEC/100 mg CED (SD) for 3 days, a regimen based on 3-day IV decitabine dosing in the NCCN guidelines for treatment of LR-MDS. Efficacy and safety endpoints of the Phase 2 were the same as those of the Phase 1.
Results:
In Phase 1, 47 patients were treated with five different DEC/CED regimens. DLT associated with prolonged neutropenia was seen in proportion to the dose per cycleand the number of days of treatment. Based on the clinical efficacy and safety profile, 10mg DEC/100mg CED for 5 days was selected as the RP2D.The Hematologic Improvement (HI) % for all dosing schedules was 30% (14/47),and the RBC transfusion-independent % over 8 weeks was 33% (7/21). Of the 47 patients treated, 23 (47%) had an event of death at the data cutoff, with a median
OS of 31 months (95% Cl: 19, NE); the median LFS was 23 months (95% Cl: 14, 32).

In Phase 2, IPSS INT-1 risk was 73% and 65% in the LD and SD arms, respectively. 48% were previously treated for MDS (21% and 26% were treated with ESA or luspatercept,  respectively). At baseline, RBC and platelet transfusion dependence was 46% and 14%, respectively. At the data cutoff, 80 subjects had received a median of 4.5 cycles of treatment, and approximately 10 patients had discontinued treatment to receive bone marrow transplant. In the pharmacokinetic analysis, the total cycle Area Under Curve (AUC) for decitabine in the LD 5-day was about half of the SD 3-day exposure and 1/4 of the D 5-day exposure. Reported adverse event terms were similar to those reported for SD 5-day, with the most common grade ≥ 3 treatment-emergent adverse events (TEAEs) being neutropenia (19%), anemia (20%), and febrile neutropenia (6%). Average neutrophil counts by cycle 8 in subjects receiving LD 5-day regimen were slightly higher compared to subjects receiving SD 3-day dosing (Figure 2A), while changes in platelet count were similar in both arms (Figure 2B). Of the 8 all-cause deaths at data cutoff, only 2 and 1 were within 60 and 30 days, respectively, in the SD group.

Summary/Conclusion:
This Phase 1/2 study shows that a LD 5-day treatment regimen is tolerable and safe with less neutropenia, suggesting that it may bean optimal regimen for LR-MDS provided that longer term efficacy results prove to be comparableto theSD 3-day regimen.

2023 Int. Congress on MDS: Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX27) in the CMML Subpopulation from Phase 2 and Ascertain Phase 3 Studies

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View Presentation: Efficacy and Safety of Oral Decitabine/Cedazuridine (ASTX27) in the CMML Subpopulation from Phase 2 and Ascertain Phase 3 Studies

Abstract:

Background and aims: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease characterized by persistent monocytosis with dysplastic and myeloproliferative changes in the bone marrow. Hypomethylating agents have been approved for CMML in MDS trials but typically account for only ~10% of trial patients. ASTX727, an orally available fixed dose (FDC) combination of 35 mg decitabine (DEC) and 100 mg cedazuridine (CED), a cytidine deaminase inhibitor, produces comparable PK AUC exposure compared to intravenous decitabine (Garcia-Manero, et al, 2019). Here, we present outcome data from subjects with CMML enrolled in the Phase 2 and 3 studies that led to the approval of oral DEC/CED.

Methods: The studies enrolled 33 subjects who were candidates for parenteral decitabine. Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, leukemia free survival, overall survival, and safety.

Results: Seven patients (21.2%) had Complete Responses (CR), 14 (42.4%) had marrow CR (mCR), including 5 (15.2%) with hematologic improvement (HI); Overall response rate (ORR) [CR + PR+ mCR + HI] was 75.8%. 63.6% of those dependent on red blood cell transfusions at baseline became transfusion independent for at least 8 weeks and 45.5% for 16 weeks. Median LFS was 28.3 months and median OS was 35.7 months. Safety profile is consistent with decitabine, with most grade 3 or higher events related to myelosuppression.

Conclusion: DEC/CED has a well-tolerated safety profile with clinical benefit in CMML patients.

2023 Int. Congress on MDS: Randomized Phase 2 Study to Assess Safety And Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients: Interim Safety Analysis

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View Presentation: Randomized Phase 2 Study to Assess Safety And Efficacy of Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients: Interim Safety Analysis

Abstract: 

Background and Aims: Cedazuridine (CED), a cytidine deaminase(CDA) inhibitor allows oral availability of decitabine(DEC) and 5 daily doses of the fixed-dose combination of 35 mg DEC/100 mg CED (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 days 1-5 (Garcia-Manero et al, 2020).  Attenuated HMA regimens (e.g. 3 days of IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017).  A Phase 1 study of multiple regimens tested in LR-MDS showed 10 mg DEC/100 mg CED  D1-5 every 28 days has pharmacodynamic and clinical activity while avoiding severe neutropenia. This study compares this LD regimen to dosing SD at 3 days every 28-days has pharmacodynamic and clinical activity while avoiding severe neutropenia.  This study compares this LD regimen to dosing SD at 3 days ever 28-days.

Methods: 81 LR-MDS (IPSS low risk and lnt-1) were randomized to receive 10mg DEC/100 mg CED for 5 days (LD)(n=40) or 35 mg DEC/ 100 mg CED daily for 3 days (SD)(n=41). Study endpoints include clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, leukemia-free survival (LFS), and overall survival (OS) and safety analysis.

Results: Interim safety and treatment discontinuations are presented. Several subjects in both arms discontinued treatment due to BM transplant (~10 subjects). The median duration of exposure was 4-4.5 cycles, and 45% of subjects receiving 3 cycles or less treatment (at ~ 2 months after Last Patient In). Subjects receiving LD had reduced neutropenia compared to those treated with SD.

Conclusion: Overall, Phase 2 study suggests that the LD regimen produces less neutropenia with potential impact on sequelae such as infection.

2023 Intl. Congress on MDS: PHASE 1 STUDY EVALUATING LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS

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View Presentation: Phase 1 Study Evaluating Low-Dose (LD) Oral Decitabine/Cedazuridine (ASTX727) In Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Abstract:

Introduction and Aims: Cedazuridine (CED), a cytidine deaminase inhibitor allows oral availability of decitabine (DEC); 5 daily doses of the fixed-dose combination of 35mg DEC/100mg CED provides equivalent exposure to an IV DEC regimen of 20mg/m2 D1-5 every 28 days(Garcia-Manero et al, 2020). This study explores the optimal dosing schedule of LD oral DEC/CED in LR-MDS patients.

Methods: A two-part Phase 1/2 study is being conducted in LR-MDS (IPSS low risk and lnt-1). Phase 1A, subjects were assigned to three regimens of DEC/CED (5mg/100mg, 10mg/100mg, and 15mg/100mg) for 10 days in a 28-day cycle. Phase 1B, subjects were assigned to three LD regimens with shorter durations of DEC/CED (10mg/100mg for 5 days, 10mg/100mg for 7 days, and 20mg/100mg for 5 days). The primary endpoints were dose-limiting toxicities (DLTs), safety, and the determination of the recommended phase 2 dose (RP2D). Secondary endpoints were pharmacokinetics, pharmacodynamic, and efficacy. Sub-analysis was performed based on genomic mutation profiles.

Results: 47 subjects received study treatment in various LD DEC/CED regimens. DLT associated with prolonged neutropenia were associated with higher dose and number of treatment days per cycle. The safety profile was generally consistent with decitabine treatment (myelosuppression). Neutropenia was less common with the low-dose/short-dose regimens. Clinical activity was observed in all dosing cohorts.

Conclusion: Based on the clinical efficacy and safety profile, 10mg DEC/100mg CED for 5 days was selected as the RP2D for further study. The RP2D regimen is being currently compared to 35mg DEC/100mg CED for 3 days in an ongoing Phase 2 study.

2023 Intl MDS Congress: Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

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View Presentation: Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

Abstract:
Background & Aims:
Parenteral therapy using hypomethylating agents (HMAs) requires 5-7 days each month, resulting in hospital or clinic visits on a chronic basis and represents a substantial burden for this primarily elderly population and their caregivers. Magrolimab has demonstrated encouraging preliminary data and is currently being evaluated in a randomized Phase 3 study (ENHANCE, NCT04313881), comparing the efficacy and safety of magrolimab plus azacitidine with that of azacitidine plus placebo in previously untreated patients with higher-risk MDS. This phase 2 study examines the possibility of using an oral HMA (oral decitabine/cedazuridine) in combination with magrolimab which may provide the benefits of combination therapy without the burden of significant parenteral therapy.

Methods:
ASTX727-10 is a phase 2, international, single-arm, open-label study investigating the safety and efficacy of combination oral decitabine/cedazuridine and magrolimab treatment in intermediate to very high-risk MDS, based on MDS International Prognostic Scoring System-Revised (IPSS-R). Secondary objectives include analysis for safety and efficacy assessments based on the IPSS- Molecular (IPSS-M) and p53 status. To be eligible, subjects with ECOG Performance Status ≤2 must have previously untreated MDS per WHO 2016 classification with < 20% bone marrow blasts and be willing to undergo red blood cell transfusions to achieve a hemoglobin >9 gm/dl at the start of study treatment. Key exclusion criteria include significant medical issues, creatinine clearance < 50 ml/min, immediate eligibility for hematopoietic stem cell transplant, or secondary MDS.

Results:
Approximately 100 subjects will be enrolled.

Conclusion:
The study is anticipated to open soon.

2022 ASH: Prolonged Survival in Bi-Allelic TP53-Mutated (TP53mut) MDS Subjects Treated with Oral Decitabine/Cedazuridine in the Ascertain Trial (ASTX727-02)

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View Presentation: Prolonged Survival in Bi-Allelic TP53-Mutated (TP53mut) MDS Subjects Treated with Oral Decitabine/Cedazuridine in the Ascertain Trial (ASTX727-02)

Abstract:

Introduction: TP53 mutations (TP53mut) in myelodysplastic syndrome (MDS) patients have been characterized as an independent prognostic factor for poor outcome. These patients may have similar response rates to hypomethylating agents (HMAs) but markedly diminished overall survival (05) compared to those with wild-type (WT) TP53 status (9.4 vs. 20.7 months [mo.]; Takahashi, K, et al. Oncotarget. 2016). Further analyses have defined monoallelic (MA) and bi allelic (BA)/multi-hit TP53mut populations with very different survival outcomes (8.4 vs. 30 mo.; Bernard, et al. Nat Med. 2020). Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) with pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m2 daily X 5 days on a 28-day cycle. The ASCERTAIN study enrolled MDS and chronic myelomonocytic leukemia (CMML) subjects and the primary endpoint demonstrating PK (AUC) equivalence of oral decitabine/cedazuridine compared with IV decitabine was met (Garcia-Manero, ASH 2019); median overall survival (mOS) was 31.7 mo. (Savona, et al. MDS symposium 2021). Here we present preliminary analysis of the mutation profile of subjects enrolled on ASCERTAIN and evaluate the impact on overall and leukemia-free survival based on the NCCN MDS panel with a focus on the TP53 mutant population.

Methods: 133 subjects with MDS/CMML were enrolled to ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine for all subsequent cycles until treatment discontinuation for disease progression, toxicity, patient’s decision, or hematopoietic stem cell transplantation. Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next generation sequencing (NGS) hematologic malignancy panel of 179 genes including 30 genes from the NCCN MDS panel.

Results: Of the 133 treated subjects, NGS analysis was available for 125 subjects. The percentage of subjects with mutations in the following genes were: TET2 (36.8%), TP53 (35.2%), ASXL1 (28%), DNMT3A (25.6%), SRSF2_MFSD11 (17.6%), SF381 (15.2%), STAG2 (12.8%), EZH2 (11.2%), RUNX1 (11.2%), U2AF1 (10.4%), BCOR (10.4%), CBL (8.8%). TP53, EZH2, RUNX1, CBL, DNMT3A, SF381, and ASXL1 were selected for further analysis
based on their reported negative impact on OS and leukemia-free survival (LFS). TP53 and CBL mutations were closely associated with a worse OS (Hazard Ratio[HR] and 95% Cl: 1.70 (1.00, 2.87) and 2.54 (1.19, 5.43), respectively) and LFS (HR and 95% Cl: 1.63 (0.98, 2.72) and 2.01 (0.95, 4.26), respectively) compared with WT gene status, while subjects with DNMT3A mutation showed a trending advantageous relationship with OS and LFS over WT gene status. The TP53mut population (N=44) was characterized by median age 70.5 years, 63.6% M: 36.4% F, 91% MDS: 9% CMML, IPSS categories: 20% HR, 30% lnt-2, 39% lnt-1, 2% LR, 9% N/A, Cytogenetics: 27% Better-risk, 18% Intermediate risk, 48%
Poor risk, 5% N/A, ECOG 0: 39%, 1: 61%, MA 68%, BA/multi-hit 32%. The median OS and LFS of the TP53mut population were 25.5 and 22.1 mo., respectively, compared to the TP53 WT group with mOS and LFS estimates 33.7 and 31.7 months, respectively (Figure 1). The TP53mut population was further characterized by allelic status and found to have 14 subjects with BA mutations and 30 subjects with MA TP53 mutations without other chromosomal deletions. The respective estimated mOS and 95% Cl in the BA vs MA were 13.0 (5.3, 29.1) months vs. 29.2 (19.8, NE) mo. (Figure 2).

Conclusion: The NGS mutational profile of MDS and CMML subjects in the ASCERTAIN trial included 35% with TP53mut and this group had a worse survival than those with WT TP53 apparently driven by the poor outcome of those with BA TP53mut. Further LOH studies will help refine this analysis, but in this conservative estimate, treatment with oral decitabine/cedazuridine in the ASCERTAIN study resulted in an estimated survival of 13 months for BA TP53mut which compares favorably with historical results.

2022 ASH: ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

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View Presentation: ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients

Abstract:

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS.

Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS).

Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 – 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34).

In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%).

Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934).

Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy

with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day

cycle in the ongoing Phase 2 study.