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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT03306264

Studienbeginn:
Februar 2018

Letztes Update:
07.01.2021

Wirkstoff:
ASTX727, Dacogen

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, Preleukemia, Leukemia, Myelomonocytic, Acute, Leukemia, Myelomonocytic, Chronic, Leukemia, Myelomonocytic, Juvenile, Myelodysplastic Syndromes, Syndrome

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Astex Pharmaceuticals, Inc.

Collaborator:
-

Studienleiter

Harold Keer, MD, PhD
Study Director
Astex Pharmaceuticals, Inc.

Kontakt

Studienlocations
(3 von 82)

Universitaetsklinikum Freiburg
79106 Freiburg im Breisgau
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Michael Luebbert
Phone: 0761 270 36190
E-Mail: michael.luebbert@uniklinik-freiburg.de
» Ansprechpartner anzeigen
Philipps-Universität Marburg, Klinik für Innere medizin, Hämatologie, Onkologie und Immunologie
35033 Marburg
(Hessen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Stephan Metzelder, MD
Phone: (49) 64 21 5860
E-Mail: metzelde@med.uni-marburg.de
» Ansprechpartner anzeigen
UNIVERSITTSKLINIKUM Schleswig-Holstein
23538 Lubeck
(Schleswig-Holstein)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Friederike Wortmann, MD
Phone: 0049 451 50044151
E-Mail: Friederike.Wortmann@uksh.de
» Ansprechpartner anzeigen
Staedtisches Klinikum Braunschweig
38114 Braunschweig
(Niedersachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Juergen Krauter, MD
Phone: (49) 0 531 595-3700
E-Mail: j.krauter@klinikum-braunschweig.de
» Ansprechpartner anzeigen
Oberärztin für Innere Medizin, Hämato-/Onkologie und Palliativmedizin
40479 Düsseldorf
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Aristoteles Giagounidis, MD
E-Mail: aristoteles.giagounidis@vkkd-kliniken.de
» Ansprechpartner anzeigen
Pinnacle Research Group
36207 Anniston
United StatesAktiv, nicht rekrutierend» Google-Maps
Arizona Clinical Research Center
85715 Tucson
United StatesAktiv, nicht rekrutierend» Google-Maps
Compassionate Cancer Care Research Group
92708 Fountain Valley
United StatesAktiv, nicht rekrutierend» Google-Maps
University of Southern California
90007 Los Angeles
United StatesAktiv, nicht rekrutierend» Google-Maps
Georgetown University
20007 Washington
United StatesAbgeschlossen» Google-Maps
Boca Raton Clinical Research
33322 Boca Raton
United StatesAktiv, nicht rekrutierend» Google-Maps
Holy Cross Hospital
33308 Fort Lauderdale
United StatesAktiv, nicht rekrutierend» Google-Maps
Rush University Medical Center
60612 Chicago
United StatesAktiv, nicht rekrutierend» Google-Maps
University of Chicago
60637 Chicago
United StatesAktiv, nicht rekrutierend» Google-Maps
Quincy Medical Group
62301 Quincy
United StatesAktiv, nicht rekrutierend» Google-Maps
Indiana Blood and Marrow Transplantation
46237 Indianapolis
United StatesAbgeschlossen» Google-Maps
Norton Cancer Institute
40207 Louisville
United StatesAktiv, nicht rekrutierend» Google-Maps
Johns Hopkins
21287 Baltimore
United StatesAktiv, nicht rekrutierend» Google-Maps
Regional Cancer Care Associates
20817 Bethesda
United StatesAbgeschlossen» Google-Maps
Michigan Center of Medical Research
48334 Farmington Hills
United StatesAbgeschlossen» Google-Maps
Cancer & Hematology Centers of Western Michigan
49503 Grand Rapids
United StatesAktiv, nicht rekrutierend» Google-Maps
Mayo Clinic Rochester
55905 Rochester
United StatesAktiv, nicht rekrutierend» Google-Maps
Hackensack
07601 Hackensack
United StatesAktiv, nicht rekrutierend» Google-Maps
Roswell Park
14263 Buffalo
United StatesAktiv, nicht rekrutierend» Google-Maps
Monter Cancer Center
11042 Lake Success
United StatesAktiv, nicht rekrutierend» Google-Maps
Weill Cornell Medicine
10065 New York
United StatesAktiv, nicht rekrutierend» Google-Maps
Gabrail Cancer Center
44718 Canton
United StatesAktiv, nicht rekrutierend» Google-Maps
Ohio State University
43210 Columbus
United StatesAktiv, nicht rekrutierend» Google-Maps
Oregon Health & Sciences University
20817 Portland
United StatesAktiv, nicht rekrutierend» Google-Maps
West Penn Allegheny Cancer Institute
15224 Pittsburgh
United StatesAktiv, nicht rekrutierend» Google-Maps
University of Pittsburgh Hillman Cancer Center
15232 Pittsburgh
United StatesAbgeschlossen» Google-Maps
Charleston Hematology Oncology Associates
29414 Charleston
United StatesAktiv, nicht rekrutierend» Google-Maps
Vanderbilt
37232 Nashville
United StatesAktiv, nicht rekrutierend» Google-Maps
Baylor Scott & White University Medical Center
75246 Dallas
United StatesAktiv, nicht rekrutierend» Google-Maps
University of Texas Southwestern Medical Center
75390-9179 Dallas
United StatesAktiv, nicht rekrutierend» Google-Maps
Houston Methodist Cancer Center
77030 Houston
United StatesAktiv, nicht rekrutierend» Google-Maps
MD Anderson Cancer Center
77030 Houston
United StatesAktiv, nicht rekrutierend» Google-Maps
Utah Cancer Specialists
84124 Salt Lake City
United StatesAbgeschlossen» Google-Maps
Kadlec Clinic Hematology and Oncology
99336 Kennewick
United StatesAktiv, nicht rekrutierend» Google-Maps
Fred Hutchinson Cancer Research Center
98109 Seattle
United StatesAktiv, nicht rekrutierend» Google-Maps
University of Alberta Hospital
T6G 2B7 Edmonton
CanadaAktiv, nicht rekrutierend» Google-Maps
Queen Elizabeth II (QEII) Health Sciences Center
B3H 2Y9 Halifax
CanadaRekrutierend» Google-Maps
Ansprechpartner:
Mary-Margaret Keating, MD
Phone: 902-473-7006
E-Mail: mary-margaret.keating@nshealth.ca
» Ansprechpartner anzeigen
Juravinski Hospital & Cancer Center
L8V 1C3 Hamilton
CanadaAktiv, nicht rekrutierend» Google-Maps
Ottawa Hospital - General Campus
K1H8L6 Ottawa
CanadaRekrutierend» Google-Maps
Ansprechpartner:
Mitchell Sabloff, MD
Phone: 613-737-8899
Phone (ext.): 71284
E-Mail: msabloff@toh.ca

Jessica Milloy, BSc
Phone: 613-737-8899
Phone (ext.): 79848
E-Mail: jmilloy@ohri.ca
» Ansprechpartner anzeigen
Sunnybrook Health Sciences Centre
M4N 3M5 Toronto
CanadaAktiv, nicht rekrutierend» Google-Maps
Princess Margaret Cancer Center - University Health Network
M5G 2M9 Toronto
CanadaRekrutierend» Google-Maps
Ansprechpartner:
Karen Yee, MD
Phone: 416-946-4495
Phone (ext.): 4495
E-Mail: karen.yee@uhn.ca

Stephanie Sankar
Phone: 416-946-4501
Phone (ext.): 2445
E-Mail: Stephanie.Sankar@uhn.ca
» Ansprechpartner anzeigen
Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Est-de-l'Ile-de-Montréal - Hôpital Maisonneuve Rosemont
H1T 2M4 Montréal
CanadaAktiv, nicht rekrutierend» Google-Maps
Somogy Megyei KAposi Mor Oktato Korhaz
7400 Kaposvár
HungaryRekrutierend» Google-Maps
Ansprechpartner:
Miklos Egyed
Phone: (36) 82501341
Phone (ext.): 36309021067
E-Mail: dregyedmiklos@yahoo.com
» Ansprechpartner anzeigen
Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo
15121 Alessandria
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Lorella Depaoli, MD
Phone: (39) 0131 206133
E-Mail: ldepaoli@ospedale.al.it
» Ansprechpartner anzeigen
Fondazione IRCCS C Granda OM Policlinico
20122 Milan
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Nicola Stefano Fracchiolla, MD
Phone: (39) 0255032696
E-Mail: nicola.fracchiolla@policlinico.mi.it
» Ansprechpartner anzeigen
Azienda Ospedaliero-Universitaria Maggiore della Carità Novara
28100 Novara
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Monia Lunghi, MD
Phone: (39) 0321 3733092
E-Mail: monia.lunghi@med.uniupo.it
» Ansprechpartner anzeigen
Hospital Universitario Central de Asturias
33011 Oviedo
SpainRekrutierend» Google-Maps
Ansprechpartner:
Teresa Bernal del Castillo, MD
Phone: (34) 985108000
Phone (ext.): 37613
E-Mail: teresa.bernal@sespa.es
» Ansprechpartner anzeigen
Hospital Universitario Virgen de las Nieves
18012 Granada
SpainRekrutierend» Google-Maps
Ansprechpartner:
Antonio Romero Aguilar, MD
Phone: (34) 9580 20000
E-Mail: antonio.romero.aguilar.sspa@juntadeandalucia.es
» Ansprechpartner anzeigen
Hospital General Universitario Gregorio Marañón
28007 Madrid
SpainRekrutierend» Google-Maps
Ansprechpartner:
Gabriela Rodriguez Macias, MD
Phone: (34) 915 868394
E-Mail: mgabrielarm@yahoo.com
» Ansprechpartner anzeigen
Hospital Universitario de Salamanca
37007 Salamanca
SpainRekrutierend» Google-Maps
Ansprechpartner:
Maria Belen Vidriales, MD
Phone: (34) 92 32 91100
Phone (ext.): 55375
E-Mail: mbvidri@usal.es
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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.)

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Total 5-day Area Under the Curve (AUC) exposures of decitabine (Time Frame - 18 months):
Primary Endpoint



Secondary outcome:

1. Number of participants with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03. (Time Frame - 18 months):
Safety assessment

2. Long Interspersed Nucleotide Elements (LINE)-1 demethylation (Time Frame - 18 months):
Pharmacodynamics assessment

3. Maximum plasma concentration (Cmax) (Time Frame - 2 months):
Secondary pharmacokinetics parameter

4. Time to reach maximum concentration (Tmax) (Time Frame - 2 months):
Secondary pharmacokinetics parameter

5. Elimination rate constant (Time Frame - 2 months):
Secondary pharmacokinetics parameter

6. Apparent total systemic clearance (Time Frame - 2 months):
Secondary pharmacokinetics parameter

7. Apparent elimination half life (Time Frame - 2 months):
Secondary pharmacokinetics parameter

8. Apparent volume of distribution (Time Frame - 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. (Time Frame - 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 (Time Frame - 18 months):
Efficacy analysis - Clinical response

11. Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days. (Time Frame - 18 months):
Efficacy analysis - RBC transfusion independence

12. Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks. (Time Frame - 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. (Time Frame - 18 months):
Efficacy analysis - Leukemia-free survival

14. Overall survival: number of days from date subject was randomized to date of death. (Time Frame - 18 months):
Efficacy analysis - Overall survival

Studien-Arme

  • Experimental: ASTX727
    ASTX727 (cedazuridine + decitabine) - Cycle 1 or Cycle 2 (crossover)
  • Active Comparator: IV decitabine
    Dacogen (decitabine for injection) - Cycle 1 or Cycle 2 (crossover)

Geprüfte Regime

  • ASTX727 (cedazuridine + decitabine):
    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).
  • Dacogen (decitabine for injection):
    Decitabine 20 mg/m^2 one-hour IV infusion Dailyx5 (in one 28-day cycle: either Cycle 1 or Cycle 2).

Quelle: ClinicalTrials.gov


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