Study of ASTX727 vs IV Decitabine in 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, randomized, open-label, crossover PK study of ASTX727 versus IV decitabine. Adult subjects who are candidates to receive IV decitabine will be 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, subjects will continue to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the subject discontinues treatment or withdraws 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 will establish PK equivalence of ASTX727 to IV decitabine in approximately 118 evaluable subjects. Eligible subjects will receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: subjects will be 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, subjects will receive the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) will be 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. Subjects will be 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, subjects will receive a 1-hour infusion of IV decitabine 20 mg/m^2 Daily×5. Serial PK measurements will be done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3.

In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments will be done from Cycle 3 onward.)

• Study Type: Interventional
• Enrollment (Actual): 200
• 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 Léon Bérard
• 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 Kozpont
  • Kaposvár, Hungary, 7400
    • Somogy Megyei Kaposi Mór Oktató Kórház
  • 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 Alcántara
  • 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 Maranon
  • 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 Politecnic 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ASTX727; ASTX727 (cedazuridine + decitabine) - Cycle 1 or Cycle 2 (crossover)	Drug: ASTX727; ASTX727 is a tablet for oral administration, containing the fixed-dose combination of 100 mg cedazuridine (a cytidine deaminase inhibitor) and 35 mg decitabine, given by mouth Dailyx5 in 28-day cycles (in Cycle 1 or Cycle 2, then in Cycle 3 and beyond).; Other Names: cedazuridine + decitabine
Active Comparator: IV decitabine; Dacogen (decitabine for injection) - Cycle 1 or Cycle 2 (crossover)	Drug: Dacogen; Decitabine 20 mg/m^2 one-hour IV infusion Dailyx5 (in one 28-day cycle: either Cycle 1 or Cycle 2).; Other Names: decitabine for injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total 5-day Area Under the Curve (AUC) exposures of decitabine	Primary Endpoint	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03.	Safety assessment	18 months
Long Interspersed Nucleotide Elements (LINE)-1 demethylation	Pharmacodynamics assessment	18 months
Maximum plasma concentration (Cmax)	Secondary pharmacokinetics parameter	2 months
Time to reach maximum concentration (Tmax)	Secondary pharmacokinetics parameter	2 months
Elimination rate constant	Secondary pharmacokinetics parameter	2 months
Apparent total systemic clearance	Secondary pharmacokinetics parameter	2 months
Apparent elimination half life	Secondary pharmacokinetics parameter	2 months
Apparent volume of distribution	Secondary pharmacokinetics parameter	2 months
MDS/CMML: Number of participants with complete response (CR), marrow CR, partial response; hematologic improvement based on International Working Group (IWG) 2006 MDS response criteria.	Efficacy analysis - Clinical response	18 months
AML: Number of participants with CR, CR with incomplete platelet recovery (CRp) and CR with incomplete blood count recovery (CRi) based on IWG 2003 AML response criteria	Efficacy analysis - Clinical response	18 months
Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days.	Efficacy analysis - RBC transfusion independence	18 months
Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks.	Efficacy analysis - Platelet transfusion independence	18 months
Leukemia-free survival in MDS/CMML participants: number of days from date of randomization to date when bone marrow or peripheral blood blasts reach ≥20%, or death.	Efficacy analysis - Leukemia-free survival	18 months
Overall survival: number of days from date subject was randomized to date of death.	Efficacy analysis - Overall survival	18 months

Collaborators and Investigators

• Sponsor: Astex Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2018
• Primary Completion (Actual): July 31, 2021
• Study Completion (Actual): March 28, 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): September 5, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

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

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