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

NCT ID: NCT03306264

Last Updated: 2024-08-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 227 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-02-15
• Study Completion Date: 2023-05-25

Brief Summary

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.

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.)

Conditions

Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

ASTX727

Intervention Type: DRUG

ASTX727 oral tablet

Dacogen

Intervention Type: DRUG

Decitabine 20 mg/m\^2 one-hour IV infusion

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.

Group Type: EXPERIMENTAL

ASTX727

Intervention Type: DRUG

ASTX727 oral tablet

Dacogen

Intervention Type: DRUG

Decitabine 20 mg/m\^2 one-hour IV infusion

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.

Group Type: EXPERIMENTAL

ASTX727

Intervention Type: DRUG

ASTX727 oral tablet

Dacogen

Intervention Type: DRUG

Decitabine 20 mg/m\^2 one-hour IV infusion

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.

Group Type: EXPERIMENTAL

ASTX727

Intervention Type: DRUG

ASTX727 oral tablet

Dacogen

Intervention Type: DRUG

Decitabine 20 mg/m\^2 one-hour IV infusion

Interventions

ASTX727

ASTX727 oral tablet

Intervention Type: DRUG

Dacogen

Decitabine 20 mg/m\^2 one-hour IV infusion

Intervention Type: DRUG

Other Intervention Names

decitabine 35 mg + cedazuridine 100 mg; decitabine

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Astex Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Pinnacle Research Group

Anniston, Alabama, United States

Mayo Clinic Arizona

Phoenix, Arizona, United States

Arizona Clinical Research Center

Tucson, Arizona, United States

Compassionate Cancer Care Research Group

Fountain Valley, California, United States

University of Southern California

Los Angeles, California, United States

Yale

New Haven, Connecticut, United States

Georgetown University

Washington D.C., District of Columbia, United States

Boca Raton Clinical Research

Boca Raton, Florida, United States

Holy Cross Hospital

Fort Lauderdale, Florida, United States

Mount Sinai

Miami Beach, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Chicago

Chicago, Illinois, United States

Quincy Medical Group

Quincy, Illinois, United States

Indiana Blood and Marrow Transplantation

Indianapolis, Indiana, United States

Norton Cancer Institute

Louisville, Kentucky, United States

Johns Hopkins

Baltimore, Maryland, United States

Regional Cancer Care Associates

Bethesda, Maryland, United States

Michigan Center of Medical Research

Farmington Hills, Michigan, United States

Cancer & Hematology Centers of Western Michigan

Grand Rapids, Michigan, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Hackensack

Hackensack, New Jersey, United States

Roswell Park

Buffalo, New York, United States

Monter Cancer Center

Lake Success, New York, United States

Weill Cornell Medicine

New York, New York, United States

Montefiore

The Bronx, New York, United States

Gabrail Cancer Center

Canton, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Oregon Health & Sciences University

Portland, Oregon, United States

West Penn Allegheny Cancer Institute

Pittsburgh, Pennsylvania, United States

University of Pittsburgh Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Charleston Hematology Oncology Associates

Charleston, South Carolina, United States

Vanderbilt

Nashville, Tennessee, United States

Baylor Scott & White University Medical Center

Dallas, Texas, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Houston Methodist Cancer Center

Houston, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Utah Cancer Specialists

Salt Lake City, Utah, United States

Kadlec Clinic Hematology and Oncology

Kennewick, Washington, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Uniklinikum Salzburg

Salzburg, , Austria

General Hospital Hietzing

Vienna, , Austria

Klinikum Wels-Grieskirchen

Wels, , Austria

University of Alberta Hospital

Edmonton, Alberta, Canada

Queen Elizabeth II (QEII) Health Sciences Center

Halifax, Nova Scotia, Canada

Juravinski Hospital & Cancer Center

Hamilton, Ontario, Canada

Ottawa Hospital - General Campus

Ottawa, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Princess Margaret Cancer Center - University Health Network

Toronto, Ontario, Canada

Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Est-de-l'Ile-de-Montréal - Hôpital Maisonneuve Rosemont

Montreal, Quebec, Canada

FN Ostrava

Ostrava, Poruba, Czechia

University Hospital Brno

Brno, , Czechia

Fakultni Nemocnice Kralovske Vinohrady FNKV

Prague, Česká Republika, Czechia

Centre de lutte contre le Cancer Leon Berard

Lyon, Rhone, France

Hospital Emile Muller

Mulhouse, , France

Universitaetsklinikum Freiburg

Freiburg im Breisgau, Baden, Germany

Philipps-Universität Marburg, Klinik für Innere medizin, Hämatologie, Onkologie und Immunologie

Marburg, Hesse, Germany

UNIVERSITTSKLINIKUM Schleswig-Holstein

Lübeck, Schleswig-Holstein, Germany

Staedtisches Klinikum Braunschweig

Braunschweig, , Germany

Oberärztin für Innere Medizin, Hämato-/Onkologie und Palliativmedizin

Düsseldorf, , Germany

University Hospital Halle

Halle, , Germany

University of Leipzig

Leisnig, , Germany

Debreceni Egyetem Klinikai Kozpont

Debrecen, , Hungary

Somogy Megyei KAposi Mor Oktato Korhaz

Kaposvár, , Hungary

University of Pecs, 1st Department of Internal Medicine

Pécs, , Hungary

University of Szeged

Szeged, , Hungary

Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo

Alessandria, , Italy

AOUC Azienda Ospedaliero-Universitaria Careggi

Florence, , Italy

Fondazione IRCCS C Granda OM Policlinico

Milan, , Italy

Azienda Ospedaliero-Universitaria Maggiore della Carità Novara

Novara, , Italy

Ospedale S. Eugenio

Rome, , Italy

ULSS 8 Vicenza - Ospedale San Bortolo di Vicenza

Vicenza, , Italy

Hospital U. Marqués de Valdecilla

Santander, Cantabria, Spain

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, Spain

Hospital San Pedro de Alcantara

Cáceres, , Spain

Hospital Universitario Virgen de las Nieves

Granada, , Spain

Hospital Duran i Reynals

L'Hospitalet de Llobregat, , Spain

Hospital General Universitario Gregorio Marañón

Madrid, , Spain

Clinica Universitaria Navarra

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Clinica Universitaria Navarra

Pamplona, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Hospital Universitari I Politècnic La Fe

Valencia, , Spain

Oxford University Hopsitals NHS Trust

Oxford, Oxfordshire, United Kingdom

The Christie NHS Fundation Trust

Manchester, , United Kingdom

Countries

United States; Austria; Canada; Czechia; France; Germany; Hungary; Italy; Spain; United Kingdom

References

Garcia-Manero G, McCloskey J, Griffiths EA, Yee KWL, Zeidan AM, Al-Kali A, Deeg HJ, Patel PA, Sabloff M, Keating MM, Zhu N, Gabrail NY, Fazal S, Maly J, Odenike O, Kantarjian H, DeZern AE, O'Connell CL, Roboz GJ, Busque L, Buckstein R, Amin H, Randhawa J, Leber B, Shastri A, Dao KH, Oganesian A, Hao Y, Keer HN, Azab M, Savona MR. Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study. Lancet Haematol. 2024 Jan;11(1):e15-e26. doi: 10.1016/S2352-3026(23)00338-1.

Reference Type: DERIVED

PMID: 38135371 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan: Statistical Analysis Plan (for MDS and CMML)

View Document

Document Type: Statistical Analysis Plan: Statistical Analysis Plan (for AML)

View Document

Other Identifiers

2018-003395-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ASTX727-02

Identifier Type: -

Identifier Source: org_study_id