2022 EHA: PHARMACOKINETIC EXPOSURE EQUIVALENCE AND PRELIMINARY EFFICACY AND SAFETY FROM A RANDOMIZED CROSSOVER PHASE 3 STUDY OF AN ORAL HYPOMETHYLATING AGENT, ASTX727 (DEC-C), COMPARED TO IV DECITABINE IN AML PATIENTS

View poster: 

PHARMACOKINETIC EXPOSURE EQUIVALENCE AND PRELIMINARY EFFICACY AND SAFETY FROM A RANDOMIZED CROSSOVER PHASE 3 STUDY OF AN ORAL HYPOMETHYLATING AGENT, ASTX727 (DEC-C), COMPARED TO IV DECITABINE IN AML PATIENTS

Abstract:

Background: Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. ASTX727 (DEC-C) is a fixed dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, a novel cytidine deaminase inhibitor (CDAi). In clinical trials with myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) patients, DEC-C provides DEC exposures that are equivalent to IV DEC at the approved dose of 20 mg/m2 daily×5 and is approved as INQOVI® in the US, Canada, and Australia.

Aims: To demonstrate DEC exposure bioequivalence of oral DEC-C and IV-DEC and generate clinical data using DEC-C in AML patients.

Methods: The ASCERTAIN study was a randomized cross over design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare PK [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 onwards until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria.

Results: 89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%) and intermediate-risk in 45 (51.7%) patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV DEC and DEC-C cycles, and the DEC AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, anemia, febrile neutropenia, neutropenia, and pneumonia). As of the data cutoff date (10 SEP 2021), median follow up was 7.95 months (IQR 6.11-11.86). Of the 77 patients who had ≥6 months of follow up or discontinued treatment, the best response was complete response (CR) in 17 (22.1%, 95% CI: 13.4, 33.0%). In addition, 4 patients (5.2%) had CR with incomplete blood cell count recovery (CRi), with 1 patient (1.3%) who had CR with incomplete platelet recovery (CRp), resulting in composite response rate [CR + CRp] of 23.4% [18/77 patients, 95% CI: 14.5, 34.4%]. These results obtained with DEC-C are consistent with those observed for IV DEC. Based on preliminary and limited study follow-up with ~46% censored observations, the median survival was approximately 7.9 months (95% CI: 5.9, 13.0).

Summary/Conclusion: This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that the oral FDC of DEC-C (35mg/100 mg) resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m2 over 5 days. In addition, safety findings and preliminary clinical activity is also consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV decitabine Daily×5 regimen.

2021 ASH: Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subgroup from ASCERTAIN Phase 3 Study

View Poster:

Efficacy of Oral Decitabine/Cedazuridine (ASTX727) in the CMML Subgroup from the ASCERTAIN Phase 3 Study

Abstract:

Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%; 90% CI 93% to 106%) to IV decitabine 20 mg/m in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML.

Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows:  median age 71.5 years, 69%Male/31%Female, median weight 87kg (range 65-124), 25%ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 109/L, platelets 84 x 109/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI); Overall response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT).

Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g. Zeidan, et al 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients.

References:
Garcia-Manero, et al ASH 2019
Savona, et al, Int. MDS Symposium, 2021
Zeidan, et al, Cancer 2017: 3754-3762.

2021 ASH: Oral decitabine/cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: a Longer-Term Follow-Up of from the ASCERTAIN Study

View Poster
Oral decitabine/cedazuridine in Patients with Lower Risk Myelodysplastic Syndrome: a Longer-Term Follow-Up of from the ASCERTAIN Study

Abstract:
Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study.
Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety.
Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 109/L (range 0.11-7.1), platelets (plt) 86 x 109/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant.
Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population.
References:
Garcia-Manero, et al, ASH 2019
Savona, et al, Int. MDS Symp. 2021
Garcia-Manero, et al,. J. Clin. Onc. 2021 39:13, 1426-1436

ASH 2021: A Phase 1 Study Evaluating ASTX727 (decitabine and cedazuridine) and Venetoclax in Combination Therapy in Newly Diagnosed AML Patients Unfit for Intensive Induction Chemotherapy

View Poster:

A Phase 1 Study Evaluating ASTX727 (decitabine and cedazuridine) and Venetoclax in Combination Therapy in Newly Diagnosed AML Patients Unfit for Intensive Induction Chemotherapy

Abstract:

Introduction: The combination of a DNA methyltransferase inhibitor (DNMTi; parenteral azacitidine or decitabine) with the BCL2 inhibitor venetoclax is a newly established standard-of-care regimen for patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive induction chemotherapy (DiNardo et al, 2020). Replacing the parenteral DNMTi with an oral DNMTi with equivalent exposure may provide the benefit of reducing patient and caregiver burden of chronic parenteral therapy, and may help responding patients stay on treatment longer. ASTX727 (a fixed-dose combination of decitabine 35 mg and cedazuridine 100 mg) is an oral DNMTi that provides equivalent exposure to its parenteral DNMTi at standard dosing (Savona et al, 2020) and is under evaluation in combination with venetoclax as an all-oral regimen.

Methods: This is an ongoing Phase 1 study being conducted at 7 US medical centers (ClinicalTrials.gov NCT04657081). Newly diagnosed AML patients 75 years or older, or with comorbidities that preclude use of intensive induction chemotherapy are eligible. The primary objective is to evaluate the effect of ASTX727 on the PK of venetoclax. Key secondary objectives are to evaluate the effect of venetoclax on the PK of ASTX727, and to determine the safety and efficacy profile for the combination. For Cycle 2 and beyond, ASTX727 is administered orally daily on days 1-5 and venetoclax 400 mg is administered orally daily on days 1-28 of 28-day cycles. For Cycle 1, ASTX727 is given in the same dose schedule while venetoclax is given as a ramp-up on days 1 and 2 according to the venetoclax US prescribing information (USPI); therefore, the PK studies are conducted during Cycle 2. Delay of subsequent cycles and venetoclax dose modifications for hematologic toxicities and anti-fungal concomitant medications follow the venetoclax USPI. Response assessments are evaluated using the 2017 ELN criteria (Döhner et al, 2017) and the CRh criterion (complete response [CR] with partial hematologic recovery) defined as those patients achieving marrow CR criteria but not peripheral blood count criteria and demonstrating an absolute neutrophil count >500/μL and platelet >50,000/μL (Kantarjian et al, 2017).

Results: At the data cut-off date of August 1, 2021, 15 AML patients have enrolled and received study treatment. Median age is 78 years (range 66 – 84) and 9 (60%) are males. Of the 12 patients with data, 2 (17%), 6 (50%), and 4 (33%) patients are in the favorable, intermediate, and adverse risk ELN categories, respectively. Of the 15 dosed patients, 6 (40%) are diagnosed with AML with myelodysplasia-related changes. The median duration of exposure is 2 cycles (range 1-5) and 1.7 months (range 0.8-5.6). The most common adverse events (AEs) of Grade 2 or higher occurring in ≥10% of patients include neutropenia (5, 33%), febrile neutropenia (2, 13%), anemia (2, 13%), thrombocytopenia (2, 13%), vomiting (2, 13%), pneumonia (2, 13%), peripheral edema (2, 13%), hypertension (2, 13%) and vascular access complication (2, 13%). There are 17 serious AEs experienced in 7 patients; a grade 3 pneumonia and a grade 3 dysphagia are the only serious AEs assessed as related to ASTX727 and/or venetoclax and both events occurred in the same patient. Both AEs were part of the patient’s medical history. Two deaths have occurred to date: one patient due to rapidly progressive disease during Cycle 2 and one patient who achieved a best response of CRh transitioned to hospice due to progressive multiple myeloma. Of 9 patients with response assessments and evaluable data, 3 (33%) achieved CR and 4 (44%) achieved CRh as the best response for a composite CR+CRh rate of 78%. Preliminary PK data available from 9 patients show venetoclax exposures are not affected by coadministration of ASTX727and are similar to historical data. Exposures of decitabine and cedazuridine are consistent with the range seen in previous studies. Updated PK, safety, and efficacy data will be provided in December 2021.

Conclusions: A preliminary analysis of ASTX727 and venetoclax combination therapy in patients with newly diagnosed AML unfit for intensive induction chemotherapy demonstrate expected PK data, and a similar safety and efficacy profile to the approved combination therapy of a DNMTi and venetoclax. These preliminary data suggest that an all-oral regimen of a DNMTi in combination with venetoclax is feasible and should be investigated further.

2021 Virtual 16th MDS Conference: Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine

View Poster
Prolonged survival observed in 133 MDS patients treated with oral decitabine/cedazuridine

Abstract: 

Background and aims

DNMTi are active in MDS treatment, however chronic parenteral therapy constitutes a burden for these patients, often elderly with co-morbid conditions. Oral decitabine(35 mg)/cedazuridine(100mg) given Days 1-5 every 28 days produces equivalent pharmacokinetic exposure (AUV) to 20 mg/m2 IV decitabine dosing (Garcia-Manero, ASH 2019).

Methods

This randomized, cross-over study enrolled MDS/CMML subjects appropriate to receive IV decitabine per the US label. Subjects either received IV decitabine or oral decitabine/cedazuridine, followed by the converse in C2, allowing intrapatient PK comparison. All subjects received oral decitabine/cedazuridine for subsequent cycles providing longer term safety and efficacy data.

Results

133 patients (IPSS HR: 16%, Int-1: 48%, Int-2: 20%, LR:4%, CMML:12%) were enrolled (US and Canada). The median age was 71y; 65% Male; 41% RBC and 9% platelet transfusion dependent, respectively. Subjects received a median of 9 cycles of treatment and 26% proceeded to HCT, typically after 4-6 cycles. The most common adverse events of thrombocytopenia, neutropenia, and anemia were consistent with expected AEs with parenteral DNMTi. Complete Response(CR) was achieved in 22%(95% CI 15.1,29.8), and overall response (CR + Partial Response + marrow CR + Hematologic Improvement) of 62% (95% CI 52.8, 69.9) was similar to seen with parenteral DNMTi.  K-M estimated mOS was 31.7 months.

Conclusion

Oral decitabine/cedazuridine is the only DNMTi demonstrating equivalent pharmacokinetic exposure to its IV form, and led to expected equivalent responses, with mOS of 31.7mo in this study. Additional studies using oral decitabine/cedazuridine in combination with new oral agents for hematological disease are warranted.

2021 Blood Virtual Congress: Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

View Poster:
Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Abstract:

Aim: Confirm fixed dose combination (FDC) of oral decitabine/cedazuridine produces similar clinical activity vs. IV decitabine. Background: An oral FDC of 35 mg decitabine and 100 mg of CDA inhibitor cedazuridine has shown 99% (90% CI 93% to 106%) equivalent exposure to 20 mg/m2 IV decitabine in a randomized cross-over study(1). If oral decitabine/cedazuridine treatment produces similar clinical results its use may decrease the burden associated with chronic parenteral hypomethylating agent (HMA) therapy in MDS and CMML.

Methods: Randomized cross over design: 133 subjects treated in US or Canada.
Primary PK endpoint: decitabine AUC equivalence over 5 days of dosing. Efficacy endpoints: best response per IWG 2006, transfusion independence, OS, and safety. AEs were graded by CTCAE v 4.03.

Results:  Patient Characteristics: median age 71.0 years; 65% male; 88%MDS/12%CMML; 43% either RBC or platelet baseline transfusion-dependent; 25% poor-risk cytogenetics, and 42% baseline BM blasts >5%. Best Response: CR in 29/133 patients (22%), mCR with HI:17% (without HI 16%), and HI: 7.5%, for an overall objective response (CR+mCR+HI) of 62%; 26% proceeded to transplant. With median follow up of 24.7 months, median OS had not been reached. Treatment-Emergent AEs (Grade ≥3 regardless of causality): thrombocytopenia (61%), neutropenia (58%), anemia (51%), febrile neutropenia (32%), leukopenia (25%), and pneumonia (18%), of patients treated with oral decitabine/cedazuridine (excluding IV decitabine cycle).

Conclusion: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with historical clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway.

References:  Garcia-Manero, et al, Blood 2019; 134 (Supplement_1): 846. doi: https://doi.org/10.1182/blood-2019-122980

ASH 2020: Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

View Poster:
Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Abstract:

Introduction:
Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study).

 Methods:
We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Results:

138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle).

Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway.

 

Garcia-Manero et al., Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML

View further details:

Garcia-Manero et al, “Oral cedazuridine/decitabine: a phase 2, pharmacokinetic/pharmacodynamic, randomized, crossover study in MDS and CMML”. Blood. 2020 Apr 13. pii: blood.2019004143. doi: 10.1182/blood.2019004143. [Epub ahead of print]

Abstract:

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

2019 ASH – Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine

View Presentation
Abstract # 846 – Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine

Authors: Guillermo Garcia-Manero, MD1, James McCloskey, MD2, Elizabeth A. Griffiths, MD3, Karen W.L. Yee, MD4, Amer M. Zeidan, MBBS, MHS5, Aref Al-Kali, MD6, Kim-Hien Dao, DO, PhD7, H. Joachim Deeg, MD8, Prapti A. Patel, MD9, Mitchell Sabloff, MSc, MD, FRCPC10, Mary-Margaret Keating, MD11, Nancy Zhu, MD12*, Nashat Y. Gabrail, MD13*, Salman Fazal, MD14, Joseph Maly, MD15, Olatoyosi Odenike, MD16, Aditi Shastri, MD17, Amy E. DeZern, MD18, Casey L. O’Connell, MD19, Gail J. Roboz, MD20, Aram Oganesian, PhD21*, Yong Hao, MD, PhD21*, Harold N. Keer, MD, PhD21, Mohammad Azab, MD21 and Michael R. Savona, MD22

1The University of Texas MD Anderson Cancer Center, Houston, TX; 2John Thuerer Cancer Center, Hackensack Medical Center, NJ; 3Roswell Park Comprehensive Cancer Center, Buffalo, NY; 4Princess Margaret Cancer Centre, Toronto, ON, CAN; 5Yale University and Yale Cancer Center, New Haven, CT; 6Mayo Clinic, Rochester, MN; 7Oregon Health & Science University, Portland, OR; 8Fred Hutchinson Cancer Research Center, Seattle, WA; 9University of Texas Southwestern Medical Center, Dallas, TX; 10Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada; 11Hematology/Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; 12University of Alberta, Edmonton, AB, Canada; 13Gabrail Cancer Center, Canton, OH; 14West Penn Hospital, Allegheny Health Network, Pittsburgh, PA; 15Norton Cancer Institute, Louisville, KY; 16University of Chicago, Chicago, IL; 17Department of Hematology and Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; 18Johns Hopkins University Hospital, Baltimore, MD; 19USC Keck School of Medicine, University of Southern California, Los Angeles, CA; 20Weill Cornell Medicine, The New York Presbyterian Hospital, New York, NY; 21Astex Pharmaceuticals, Inc., Pleasanton, CA; 22Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN

 Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int’l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study).

 Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

 Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of <1% and the 95% CI of the difference included zero. Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 5% were thrombocytopenia, neutropenia, anemia, febrile neutropenia, and leukopenia). As of the data cutoff, median follow up was 5.2 months ( IQR 3.5-8.0) with 101 patients evaluable for response . Preliminary response analysis of all evaluable patients showed best responses of complete response (CR) in 12 patients (11.9%), marrow (m)CR in 46 (45.5%) including 14 patients (13.9%) with mCR + hematological improvement (HI), hematologic improvement (HI) in 7 (6.9%) resulting in an objective response rate (CR+mCR+ HI) in 65 patients (64%). In addition, of all 133 treated patients, 16 patients (12%) underwent hematopoietic cell transplant. Updated response data will be presented at the meeting.

Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned.

2019 ACOP: A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

View Poster
A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes

Abstract

Objectives:
Cytidine deaminase (CDA) rapidly degrades decitabine (DAC), an approved treatment for myelodysplastic syndromes, resulting in poor and variable bioavailability. Low doses of oral DAC co-administered with a novel and potent CDA inhibitor, cedazuridine (E7727), have been shown in clinic to produce exposures similar to IV DAC with acceptable inter-patient variability. The objective of this work was to further develop a semi-physiological population PK model ([1]) to characterize the PK enhancement of oral DAC when co-administered with cedazuridine and to identify potential covariates that impact the PK of DAC and/or cedazuridine.

Methods:
Model development utilized serial cedazuridine and DAC plasma concentration observations of IV DAC, oral DAC, and cedazuridine monotherapies and DAC+cedazuridine combinations. Observations from Phase 1/2 Study ASTX727-01 included dose escalation data (n=43; cohorts of 40:20, 60:20, 100:20, 100:40, and 100:30 mg cedazuridine:DAC with n=6 per cohort), dose confirmation data (n=42; 35:100 mg cedazuridine:DAC), and an FDC formulation extension (n=26). R was used for data processing, exploratory analysis, and visual predictive checks, while model development and parameter estimation utilized NONMEM. Covariate effects were explored using a full model approach.

Results:
Mono- and combination therapy data were sequentially integrated into a semi-physiological population PK model. Semi-physiological structural modeling elements included an IV DAC depot, oral DAC and cedazuridine transit compartment absorption, and portal vein, liver, central, and peripheral compartments. CDA metabolism of DAC primarily occurs in the liver compartment, with additional extra-hepatic metabolism. A maximum effect (Emax) inhibition model, dependent on local cedazuridine concentrations, described the drug effect of the oral ASTX727 combination therapy on CDA metabolism of DAC. IV DAC data were used to parameterize distribution and metabolism of DAC, while oral DAC monotherapy data was used to parameterize oral absorption. cedazuridine mono- and combination therapy data were used to parameterize cedazuridine PK parameters. Stratified individual-level random effects did not demonstrate systematic biases for any covariates, including weight-based effects.

Conclusions:
A semi-physiological population PK model was sequentially developed from mono- and combination therapy observations of plasma concentrations from the ASTX727-01 dose escalation and confirmation study. The analysis characterized the PK enhancement of oral DAC when co-administered with cedazuridine across a range of dose regimens and found no significant covariate effects, including weight-based effects. The resulting model will be used to interpret outcomes from an ongoing Phase 3 study (FDC ASTX727 of 35 mg DAC / 100 mg cedazuridine), while simulations will quantitatively inform future clinical development of ASTX727.