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

Sponsor
Astex Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT03306264
Collaborator
(none)
200
Enrollment
84
Locations
2
Arms
51.4
Actual Duration (Months)
2.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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 Design

Study Type:
Interventional
Actual Enrollment :
200 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
Multicenter, randomized, open-label, 2-period, 2-sequence crossover studyMulticenter, randomized, open-label, 2-period, 2-sequence crossover study
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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)
Actual Study Start Date :
Feb 15, 2018
Actual Primary Completion Date :
Jul 31, 2021
Actual Study Completion Date :
May 31, 2022

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Total 5-day Area Under the Curve (AUC) exposures of decitabine [18 months]

      Primary Endpoint

    Secondary Outcome Measures

    1. Number of participants with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03. [18 months]

      Safety assessment

    2. Long Interspersed Nucleotide Elements (LINE)-1 demethylation [18 months]

      Pharmacodynamics assessment

    3. Maximum plasma concentration (Cmax) [2 months]

      Secondary pharmacokinetics parameter

    4. Time to reach maximum concentration (Tmax) [2 months]

      Secondary pharmacokinetics parameter

    5. Elimination rate constant [2 months]

      Secondary pharmacokinetics parameter

    6. Apparent total systemic clearance [2 months]

      Secondary pharmacokinetics parameter

    7. Apparent elimination half life [2 months]

      Secondary pharmacokinetics parameter

    8. Apparent volume of distribution [2 months]

      Secondary pharmacokinetics parameter

    9. 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. [18 months]

      Efficacy analysis - Clinical response

    10. 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 [18 months]

      Efficacy analysis - Clinical response

    11. Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days. [18 months]

      Efficacy analysis - RBC transfusion independence

    12. Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks. [18 months]

      Efficacy analysis - Platelet transfusion independence

    13. 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. [18 months]

      Efficacy analysis - Leukemia-free survival

    14. Overall survival: number of days from date subject was randomized to date of death. [18 months]

      Efficacy analysis - Overall survival

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    5. 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.

    6. 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.

    7. No major surgery within 30 days of first study treatment.

    8. Life expectancy of at least 3 months.

    9. 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.

    10. 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.

    1. 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.

    2. 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.

    Contacts and Locations

    Locations

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

    Sponsors and Collaborators

    • Astex Pharmaceuticals, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Astex Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03306264
    Other Study ID Numbers:
    • ASTX727-02
    First Posted:
    Oct 11, 2017
    Last Update Posted:
    Aug 1, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Astex Pharmaceuticals, Inc.
    MDS
    CMML
    decitabine
    Myelodysplastic Syndromes
    Chronic Myelomonocytic Leukemia
    Acute Myeloid Leukemia
    AML
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Preleukemia
    Leukemia, Myelomonocytic, Acute
    Leukemia, Myelomonocytic, Chronic
    Leukemia, Myelomonocytic, Juvenile
    Myelodysplastic Syndromes
    Syndrome
    Decitabine

    Study Results

    No Results Posted as of Aug 1, 2022