Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML

A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) Versus IV Decitabine in Subjects With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and Acute Myeloid Leukemia (AML)

Multicenter PK study of ASTX727 versus IV decitabine. Adult participants who were candidates to receive IV decitabine were randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, participants continued to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the participants discontinued treatment or withdrew from the study.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia
• Intervention / Treatment: Drug: ASTX727; Drug: Dacogen

Detailed Description

This Phase 3 study established PK equivalence of ASTX727 to IV decitabine in approximately 227 evaluable participants. Eligible participants were randomized to receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: participants were randomly assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other therapy in Cycle 2.

In the ASTX727 cycle, participants received the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) were done on Days 1, 2, and 5, along with pre-dose PK assessments on Days 1-5 and an assessment at 3 hours post-dose on Day 3. Participants were required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours before and 2 hours after dosing.

In the IV decitabine cycle, participants received a 1-hour infusion of IV decitabine 20 mg/m^2 Daily×5. Serial PK measurements were done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3.

In Cycles ≥3, participants received the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments were done from Cycle 3 onward.)

• Study Type: Interventional
• Enrollment (Actual): 227
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, 05020
    • Uniklinikum Salzburg
  • Vienna, Austria, 01130
    • General Hospital Hietzing
  • Wels, Austria, 4600
    • Klinikum Wels-Grieskirchen
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Queen Elizabeth II (QEII) Health Sciences Center
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Juravinski Hospital & Cancer Center
    • Ottawa, Ontario, Canada, K1H8L6
      • Ottawa Hospital - General Campus
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Center - University Health Network
  • Quebec
    • Montréal, Quebec, Canada, H1T 2M4
      • Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Est-de-l'Ile-de-Montréal - Hôpital Maisonneuve Rosemont
• Czechia
  • Brno, Czechia, 62500
    • University Hospital Brno
  • Poruba
    • Ostrava, Poruba, Czechia, 708 00
      • FN Ostrava
  • Česká Republika
    • Praha 10, Česká Republika, Czechia, 10034
      • Fakultni Nemocnice Kralovske Vinohrady FNKV
• France
  • Mulhouse, France, 68100
    • Hospital Emile Muller
  • Rhone
    • Lyon, Rhone, France, 69008
      • Centre de lutte contre le Cancer Leon Berard
• Germany
  • Braunschweig, Germany, 38114
    • Staedtisches Klinikum Braunschweig
  • Düsseldorf, Germany, 40479
    • Oberärztin für Innere Medizin, Hämato-/Onkologie und Palliativmedizin
  • Halle, Germany, 06120
    • University Hospital Halle
  • Leisnig, Germany, 04103
    • University of Leipzig
  • Baden
    • Freiburg im Breisgau, Baden, Germany, 79106
      • Universitaetsklinikum Freiburg
  • Hesse
    • Marburg, Hesse, Germany, 35033
      • Philipps-Universität Marburg, Klinik für Innere medizin, Hämatologie, Onkologie und Immunologie
  • Schleswig-Holstein
    • Lubeck, Schleswig-Holstein, Germany, 23538
      • UNIVERSITTSKLINIKUM Schleswig-Holstein
• Hungary
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Klinikai Központ
  • Kaposvár, Hungary, 7400
    • Somogy Megyei Kaposi Mor Oktato Korhaz
  • Pecs, Hungary, 7400
    • University of Pecs, 1st Department of Internal Medicine
  • Szeged, Hungary, 6725
    • University of Szeged
• Italy
  • Alessandria, Italy, 15121
    • Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo
  • Firenze, Italy, 50134
    • AOUC Azienda Ospedaliero-Universitaria Careggi
  • Milan, Italy, 20122
    • Fondazione IRCCS C Granda OM Policlinico
  • Novara, Italy, 28100
    • Azienda Ospedaliero-Universitaria Maggiore della Carità Novara
  • Rome, Italy, 00144
    • Ospedale S. Eugenio
  • Vicenza, Italy, 36100
    • ULSS 8 Vicenza - Ospedale San Bortolo di Vicenza
• Spain
  • Cáceres, Spain, 10003
    • Hospital San Pedro de Alcantara
  • Granada, Spain, 18012
    • Hospital Universitario Virgen de las Nieves
  • L'Hospitalet De Llobregat, Spain, 08909
    • Hospital Duran i Reynals
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain, 28027
    • Clínica Universitaria Navarra
  • Pamplona, Spain, 31008
    • Clínica Universitaria Navarra
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • València, Spain, 46026
    • Hospital Universitari i Politècnic La Fe
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Hospital Universitario Central de Asturias
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital U. Marques de Valdecilla
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Fundation Trust
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LE
      • Oxford University Hopsitals NHS Trust
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85715
      • Arizona Clinical Research Center
  • California
    • Fountain Valley, California, United States, 92708
      • Compassionate Cancer Care Research Group
    • Los Angeles, California, United States, 90007
      • University of Southern California
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Boca Raton, Florida, United States, 33322
      • Boca Raton Clinical Research
    • Fort Lauderdale, Florida, United States, 33308
      • Holy Cross Hospital
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Quincy, Illinois, United States, 62301
      • Quincy Medical Group
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indiana Blood and Marrow Transplantation
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Cancer Institute
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins
    • Bethesda, Maryland, United States, 20817
      • Regional Cancer Care Associates
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Michigan Center of Medical Research
    • Grand Rapids, Michigan, United States, 49503
      • Cancer & Hematology Centers of Western Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore
    • Buffalo, New York, United States, 14263
      • Roswell Park
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center
    • New York, New York, United States, 10065
      • Weill Cornell Medicine
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 20817
      • Oregon Health & Sciences University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Hillman Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • West Penn Allegheny Cancer Institute
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Charleston Hematology Oncology Associates
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75390-9179
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor Scott & White University Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • Utah Cancer Specialists
  • Washington
    • Kennewick, Washington, United States, 99336
      • Kadlec Clinic Hematology and Oncology
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure; specifically able to comply with the PK assessment schedule during the first 2 treatment cycles.

2. Men or women ≥18 years who are candidates to receive IV decitabine according to FDA or European Medicines Agency (EMA) approved indications:

   1. In North America: Participants with MDS previously treated or untreated with de novo or secondary MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia [CMML]), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS.
   2. In Europe: Participants with de novo or secondary AML, as defined by the World Health Organization (WHO) criteria, who are not candidates for standard induction chemotherapy.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

4. Adequate organ function defined as follows:

   1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 × ULN.
   2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular filtration rate >50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.
5. No major surgery within 30 days of first study treatment.
6. Life expectancy of at least 3 months.
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of non-childbearing potential are those who have had a hysterectomy or bilateral oophorectomy, or who have completed menopause, defined as no menses for at least 1 year AND either age ≥65 years or follicle-stimulating hormone levels in the menopausal range.
8. Subjects and their partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months after the last dose of study treatment. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide).

Exclusion Criteria:

1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.
2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection in the 30 days before screening.
3. Treatment with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant adverse events (AEs) from previous treatment.
4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment.
5. Concurrent MDS therapies, including lenalidomide, erythropoietin, cyclosporine/tacrolimus, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment with these agents is permitted, provided that completion is at least 1 week before the first dose of study treatment.)
6. Poor medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled infections, or comorbidities that may put the patient at risk of not being able to complete at least 2 cycles of treatment.
7. Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol.
8. Rapidly progressive or highly proliferative disease (total white blood cell count of >15 × 10^9/L) or other criteria that render the subject at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months.
9. Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive heart failure or chronic obstructive pulmonary disease, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ASTX727, or compromise completion of the study or integrity of the study outcomes.
10. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 2 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MDS or CMML: Sequence A: First ASTX727, Then IV Decitabine, Then ASTX727; Participants with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study.	Drug: ASTX727; ASTX727 oral tablet; Other Names: decitabine 35 mg + cedazuridine 100 mg; Drug: Dacogen; Decitabine 20 mg/m^2 one-hour IV infusion; Other Names: decitabine
Experimental: MDS or CMML: Sequence B: First IV Decitabine, Then ASTX727, Then ASTX727; Participants with MDS or CMML received IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days) followed by ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study.	Drug: ASTX727; ASTX727 oral tablet; Other Names: decitabine 35 mg + cedazuridine 100 mg; Drug: Dacogen; Decitabine 20 mg/m^2 one-hour IV infusion; Other Names: decitabine
Experimental: AML: Sequence A: First ASTX727, Then IV Decitabine, Then ASTX727; Participants with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study.	Drug: ASTX727; ASTX727 oral tablet; Other Names: decitabine 35 mg + cedazuridine 100 mg; Drug: Dacogen; Decitabine 20 mg/m^2 one-hour IV infusion; Other Names: decitabine
Experimental: AML: Sequence B: First IV Decitabine, Then ASTX727, Then ASTX727; Participants with AML received IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days) followed by ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 2. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all participants enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study.	Drug: ASTX727; ASTX727 oral tablet; Other Names: decitabine 35 mg + cedazuridine 100 mg; Drug: Dacogen; Decitabine 20 mg/m^2 one-hour IV infusion; Other Names: decitabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine	Total 5-day ASTX727 AUC0-24 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-24 (first ASTX727 dose) was added to (Day 2 AUC0-24+ Day 5 AUC0-24) × 2. Decitabine 5-day AUC0-24 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-24+ Day 5 AUC0-24) / 2 was multiplied by 5. If AUC0-24 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-24 on Day 5; the converse was also true.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first.	From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)
AML: Number of Participants With Treatment-emergent Adverse Events (AEs)	An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first.	From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)
MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs	TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.	From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)
AML: Number of Participants With Grade 3 or Higher TEAEs	TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using CTCAE version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.	From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)
Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation	Summarized data for Cycle 1 and Cycle 2 was reported.	Pre-dose on Day 1 of Cycles 1 and 2 (as Baseline), and Days 8, 15 and 22 of Cycles 1 and 2 (each cycle= 28 days)
Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine	Total 5-day ASTX727 AUC0-inf exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-inf (first ASTX727 dose) was added to (Day 2 AUC0-inf+ Day 5 AUC0-inf) × 2. Decitabine 5-day AUC0-inf exposures after IV decitabine were calculated as follows: (Day 1 AUC0-inf+ Day 5 AUC0-inf) / 2 was multiplied by 5. If AUC0-inf on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-inf on Day 5; the converse was also true.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine	Total 5-day ASTX727 AUC0-last exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-last (first ASTX727 dose) was added to (Day 2 AUC0-last + Day 5 AUC0-last) × 2. Decitabine 5-day AUC0-last exposures after IV decitabine were calculated as follows: (Day 1 AUC0-last + Day 5 AUC0-last) / 2 was multiplied by 5. If AUC0-last on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-last on Day 5; the converse was also true.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine	Total 5-day ASTX727 AUC0-8 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-8 (first ASTX727 dose) was added to (Day 2 AUC0-8 + Day 5 AUC0-8) × 2. Decitabine 5-day AUC0-8 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-8 + Day 5 AUC0-8) / 2 was multiplied by 5. If AUC0-8 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-8 on Day 5; the converse was also true.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine	AUC0-inf was calculated using the formula AUClast + (Clast / λZ), where Clast is the last quantifiable concentration and λZ is the elimination rate constant. AUC0-inf will be calculated using the linear up-log down method. Summarized data has been reported for cycle 1 and 2.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer	Summarized data of Cmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Cmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer	Summarized data of Tmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Tmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine	Oral CL/F for oral decitabine was measured only on Day 1 and oral CL/F for oral cedazuridine was measured on Days 1, 2 and 5. Summarized data of Oral CL/F for oral decitabine on Day 1 for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of oral CL/F for oral cedazuridine on Day 1,2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer	Summarized data of t1/2 on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of t1/2 on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.	ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine	Summarized data of Vz/F on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727.	Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria	CR: normal peripheral, persistent granulocyte count ≥1.0x10^9/liter(L), platelet ≥100x10^9/L, Hemoglobin (Hgb) ≥11g/dL, normal bone marrow with persistent marrow blasts ≤5%. mCR: reduction of bone marrow blasts to≤5%, decrease by 50% or more with/without normalization of peripheral counts.PR: normal peripheral counts, granulocyte count ≥1.0x10^9/L, platelet count ≥100x10^9/L, Hgb ≥11 g/dL, normal bone marrow, marrow blasts >5%, reduced by 50% or more for at least 4 weeks. HI: HI-E: Hb increase ≥1.5 g/dL in absence of RBC transfusions. HI-P: Absolute increase of platelet count from <20 to >20X10^9/L by at least 100%,if more than 20x10^9/L, by absolute increase of at least 30x10^9/L in absence of platelet transfusions. HI-N: granulocyte increase ≥100%, by an absolute increase ≥0.5x10^9/L for at least 8 weeks. Percentage of participants with CR, mCR, PR, and HI based on IWG 2003 MDS response criteria are reported. Response has been reported based on participants with MDS or CMML.	Up to approximately 2.7 years
AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria	CR was defined as absolute neutrophil content (ANC) ≥1000/ microliter (μL), platelets ≥100,000/μL, independence from red blood cell (RBC) and platelet transfusions over the past week, no leukemic blasts and <5% leukemic blasts. CRp was defined as CR criteria except platelets <100,000/μL.and platelet transfusion over the past week. CRi was defined as CR criteria except ANC <1000/μL or platelets <100,000/μL. Percentage of participants with CR, CRi, CRp, and CR Plus CRp based on IWG 2003 AML response criteria are reported.	Up to approximately 2.4 years
AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria	CRh was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/μL), independence from RBC and platelet transfusions within 7 days of bone marrow evaluation, and peripheral blast ≤1%. Percentage of participants with CRh based on IWG 2003 AML response criteria are reported.	Day 1 of Cycle 3 up to approximately 2.4 years (each cycle= 28 days)
AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria	Time to first response was defined as time in months from the date of first treatment to the first date when any response is achieved. Time to best response was defined in months from the date of first treatment to the first date when a subject's best response, in the order of CR, CRi (or CRp or CRh), or PR, was achieved. Time to CR was defined in months from the date of first treatment to the first date when CR is achieved. CR:ANC ≥1000/ microliter (μL),platelets ≥100,000/μL,independence from RBC and platelet transfusions over the past week, no leukemic blasts, and <5% leukemic blasts.CRp: CR criteria except ANC ≥1000/μL, platelets < 100,000/μL.and platelet transfusion over the past week. CRi:CR criteria except ANC <1000/μL or platelets <100,000/μL.CRh: <5% of blasts in the bone marrow,platelets >50,000/μL and ANC >500/μL, independence from RBC and platelet transfusions within 7 days and peripheral blast ≤1%. PR: CR criteria except decrease of ≥50% in leukemic blasts.	Up to approximately 2.4 years
AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria	Duration of CR was defined as the time interval from the first CR to time of relapse. Duration of combined CR and CRh was defined as the time interval from the first CR or CRh to time of relapse. Duration of CR and combined CR and CRh was presented using a Kaplan-Meier estimate.	Up to approximately 2.4 years
MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)	Transfusion independence was defined as no transfusion for 56 consecutive days or more (84 and 112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).	Up to approximately 2.7 years
AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)	Transfusion independence was defined as no transfusion for 56 consecutive days or more (112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).	Up to approximately 2.4 years
MDS/CMML: Leukemia-free Survival (LFS)	LFS was defined as time from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. Participants who hadn't reached AML at the time of the analysis were censored at the date of the last follow-up. Leukemia-free survival was presented using a Kaplan-Meier estimate.	From randomization up to approximately 2.7 years
MDS/CMML: Overall Survival (OS)	OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate.	From randomization up to approximately 2.7 years
AML: Overall Survival (OS)	OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate.	From randomization up to approximately 2.4 years
AML: Survival Rates at 6 Months, 1 Year, and 2 Years	One-year survival rate was defined as the survival rate at the end of the first year from the date of randomization. The survival rates at 6 months and at 2 years were calculated similarly.	At Month 6, Year 1 and 2
AML: Event-free Survival (EFS)	EFS was defined as time from the date of randomization to the date of treatment failure [disease progression/relapse (due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse), discontinue treatment due to disease progression or treatment-related AE, or alternative anti-leukemia therapy except for HCT] or death from any cause, whichever occurs first. Participants without documented treatment failure at the time of the analysis were censored at the date of the last follow-up. Event-free survival was presented using a Kaplan-Meier estimate.	From randomization up to approximately 2.4 years
AML: Progression-free Survival (PFS)	PFS was defined as time from the date of randomization to the date disease progression due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse) or death from any cause, whichever occurs first. Participants without documented disease progression/relapse or death at the time of the analysis were censored at the date of the last follow-up. Progression-free survival was presented using a Kaplan-Meier estimate.	From randomization up to approximately 2.4 years

Collaborators and Investigators

• Sponsor: Astex Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2018
• Primary Completion (Actual): September 10, 2021
• Study Completion (Actual): May 25, 2023

Study Registration Dates

• First Submitted: October 2, 2017
• First Submitted That Met QC Criteria: October 4, 2017
• First Posted (Actual): October 11, 2017

Study Record Updates

• Last Update Posted (Actual): August 27, 2024
• Last Update Submitted That Met QC Criteria: July 31, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; MDS; Myelodysplastic Syndromes; decitabine; CMML; Chronic Myelomonocytic Leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Decitabine and cedazuridine drug combination
• Other Study ID Numbers: ASTX727-02; 2018-003395-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No