Phase 3 Randomized, Open-Label Study of Guadecitabine vs Treatment Choice in Previously Treated Acute Myeloid Leukemia

NCT ID: NCT02920008

Last Updated: 2024-08-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 302 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-03-16
• Study Completion Date: 2020-06-01

Brief Summary

Multicenter, randomized, open-label, parallel-group study of guadecitabine vs treatment choice (TC). Participants will be randomly assigned in a 1:1 ratio to either guadecitabine or TC. TC options include the 8 high or low intensity, locally available regimens below; or Best supportive Care (BSC) alone:

• High intensity (intermediate or high dose cytarabine [HiDAC]; mitoxantrone, etoposide, and cytarabine [MEC]; or fludarabine, cytarabine, granulocyte colony stimulating factor [G-CSF], +/- idarubicin [FLAG/FLAG-Ida]).
• Low intensity (low dose cytarabine [LDAC], decitabine, or azacitidine).
• BSC.

Detailed Description

This Phase 3, randomized, open-label, parallel-group multicenter study of the efficacy and safety of guadecitabine in adults with previously treated acute myeloid leukemia (AML) will be conducted in approximately 20 countries. There will be a 14-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last approximately 2 years. Duration of individual participant participation will vary, and participants may continue to receive treatment for as long as they continue to benefit.

Approximately 404 participants from approximately 100 study centers will be randomly assigned to either guadecitabine or treatment choice (TC) in a 1:1 ratio (approximately 202 participants per group). TC is as follows:

• High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).
• Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.
• Best Supportive Care (BSC).

Guadecitabine will be given subcutaneous (SC) at a dose of 60 microgram per meter square (mg/m^2) in 28-day cycles. In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. Cycle 2 will be either the 5-day regimen (Days 1-5) or 10-day regimen (Days 1-5 and 8-12) based on assessment of disease response and hematologic recovery at the end of Cycle 1. In subsequent cycles, guadecitabine treatment will be for 5 days only (Days 1-5).

Conditions

Acute Myeloid Leukemia

Study Design

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

Study Groups

guadecitabine

Guadecitabine will be given SC at a dose of 60 mg/m\^2 in 28-day cycles (delayed as necessary to allow blood count recovery).

Group Type: EXPERIMENTAL

guadecitabine

Intervention Type: DRUG

In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. In Cycle 2, the guadecitabine dose will be 60 mg/m\^2 for either 10 days (Days 1-5 and 8-12) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by Day ≥28.

Treatment Choice (TC)

1. High intensity

2. Low intensity

3. Best supportive care (BSC).

Group Type: ACTIVE_COMPARATOR

Treatment Choice (TC)

Intervention Type: DRUG

• High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).
• Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.
• Best Supportive Care (BSC).

Interventions

guadecitabine

In Cycle 1, guadecitabine will be given for 10 days on Days 1-5 and Days 8-12. In Cycle 2, the guadecitabine dose will be 60 mg/m\^2 for either 10 days (Days 1-5 and 8-12) or 5 days (Days 1-5 only) based on assessment of disease response, and hematological recovery by Day ≥28.

Intervention Type: DRUG

Treatment Choice (TC)

• High intensity: intermediate or high dose cytarabine (HiDAC); mitoxantrone, etoposide, and cytarabine (MEC); or fludarabine, cytarabine, G-CSF, +/- idarubicin (FLAG/FLAG-Ida).
• Low intensity: low dose cytarabine (LDAC), decitabine, or azacitidine.
• Best Supportive Care (BSC).

Intervention Type: DRUG

Other Intervention Names

SGI-110

Eligibility Criteria

Inclusion Criteria

1. Adult participants ≥18 years of age who are able to understand study procedures, comply with them, and provide written informed consent before any study-specific procedure.

2. History of cytologically or histologically confirmed diagnosis of AML (except acute promyelocytic leukemia) according to the 2008 World Health Organization (WHO) classification (bone marrow [BM] or peripheral blood [PB] blast counts ≥20%).

3. Performance status (Eastern Cooperative Oncology Group; ECOG) of 0-2.

4. Participants with AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and who are refractory to initial induction (primary refractory) or in relapse after such initial induction with or without prior HCT.

5. Participants must have either PB or BM blasts ≥5% at time of randomization.

6. Creatinine clearance or glomerular filtration rate ≥30 mL/min as estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas, such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration).

7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child (a) while receiving treatment of guadecitabine, decitabine, or azacitidine and for at least 3 months after completing treatment and (b) while receiving treatment with high-intensity TC or LDAC and for at least 6 months after completing treatment.

Exclusion Criteria

1. Known clinically active central nervous system (CNS) or extramedullary AML, except leukemia cutis.

2. Participants who are in first relapse after initial induction, if they had a response duration of >12 months from date when first response first documented or if they are good candidates for HCT.

3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

4. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.

5. Grade 3 or higher Graft Versus Host Disease (GVHD), or GVHD on either a calcineurin inhibitor or prednisone more than 5 mg/day.

6. Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior decitabine or azacitidine.

7. Hypersensitivity to decitabine, guadecitabine, or any of their excipients.

8. Treated with any investigational therapy within 2 weeks of the first dose of study treatment.

9. Total serum bilirubin >2.5 × upper limit of normal (ULN; except for participants with Gilbert's Syndrome for whom direct bilirubin is <2.5 × ULN), or liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.

10. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.

11. 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 participant to high risk of noncompliance with the protocol.

12. Refractory congestive heart failure unresponsive to medical treatment; active infection resistant to all antibiotics; or non-AML-associated pulmonary disease requiring >2 liters per minute (LPM) oxygen, or any other condition that puts the participant at an imminent risk of death.

13. Participants with high PB blasts >50% AND poor ECOG PS of 2.

• 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

Principal Investigators

Harold N Keer, MD, PhD

Role: STUDY_DIRECTOR

Astex Pharmaceuticals, Inc.

Locations

University of Southern California

Los Angeles, California, United States

The University of Chicago Medical Center

Chicago, Illinois, United States

Franciscan Research Center

Indianapolis, Indiana, United States

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States

University of New Mexico School of Medicine

Albuquerque, New Mexico, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Weill Cornell Medical College

New York, New York, United States

Duke Cancer Institute

Durham, North Carolina, United States

University of Oklahoma Medical Center

Oklahoma City, Oklahoma, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Temple University Hospital

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Baylor Research Institute

Dallas, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

West Virginia University Hospitals, Inc.

Morgantown, West Virginia, United States

AZ Sint-Jan Brugge-Oostende AV

Bruges, , Belgium

Cliniques Universitaires Saint-Luc

Brussels, , Belgium

Universitair Ziekenhuis Gent

Ghent, , Belgium

Tom Baker Cancer Centre

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

McGill University Health Centre

Montreal, Quebec, Canada

Hopital Maisonneuve Rosemont

Montreal, , Canada

Aarhus University Hospital

Aarhus C, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Centre Hospitalier de la Côte Basque

Bayonne, , France

Hôpital de la Conception

Marseille, , France

CHRU Montpellier - Saint Eloi

Montpellier, , France

Groupe Hospitalier de la Région de Mulhouse et Sud Alsace

Mulhouse, , France

Hôpital Saint-Louis

Paris, , France

CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque

Pessac, , France

Centre Hospitalier Lyon-Sud

Pierre-Bénite, , France

Centre Henri Becquerel

Rouen, , France

Institut Universitaire du Cancer de Toulouse - Oncopole

Toulouse, , France

Universitätsklinikum Leipzig

Leipzig, Saxony, Germany

Städtisches Klinikum Braunschweig gGmbH

Braunschweig, , Germany

Marien Hospital Düsseldorf GmbH

Düsseldorf, , Germany

Universitätsklinikum Halle (Saale)

Halle, , Germany

Universitätsklinikum Schleswig-Holstein

Kiel, , Germany

Medizinischen Fakultät Mannheim der Universität Heidelberg

Mannheim, , Germany

Klinikum der Universität München

München, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

SE ÁOK I. sz. Belgyógyászati Klinika

Budapest, , Hungary

Debreceni Egyetem Klinikai Központ

Debrecen, , Hungary

Somogy Megyei Kaposi Mór Oktató Kórház

Kaposvár, , Hungary

Pecsi Tudomanyegyetem Klinikai Központ

Pécs, , Hungary

Szegedi Tudományegyetem

Szeged, , Hungary

IRCCS AOU San Martino - IST

Genova, , Italy

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, , Italy

Ospedale San Raffaele - Milano

Milan, , Italy

A.O.R.N. "A. Cardarelli"

Napoli, , Italy

A.S.U Integrata di Udine - Presidio Ospedaliero Santa Maria della Misericordia

Udine, , Italy

Akita University Hospital

Akita, , Japan

Chugoku Central Hospital

Fukuyama-Shi, , Japan

Tokai University Hospital

Isehara-shi, , Japan

Saitama Medical Center

Kawagoe-Shi, , Japan

Kobe City Medical Center General Hospital

Kobe, , Japan

Japanese Red Cross Kyoto Daini Hospital

Kyoto, , Japan

University Hospital, Kyoto Prefectural University of Medicine

Kyoto, , Japan

Gunmaken Saiseikai Maebashi Hospital

Maebashi, , Japan

Nagasaki University Hospital

Nagasaki, , Japan

The Japanese Red Cross Nagasaki Genbaku Hospital

Nagasaki, , Japan

Kindai University Hospital

Osakasayama-Shi, , Japan

Saga University Hospital

Saga, , Japan

NTT Medical Center Tokyo

Shinagawa-Ku, , Japan

Shizuoka Cancer Center

Shizuoka, , Japan

National Hospital Organization Disaster Medical Center

Tachikawa-Shi, , Japan

Yamagata University Hospital

Yamagata, , Japan

University of Fukui Hospital

Yoshida-Gun, , Japan

Instytut Hematologii i Transfuzjologi

Warsaw, , Poland

Pusan National University Hospital

Busan, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, , South Korea

Ulsan University Hospital (UUH)

Ulsan, , South Korea

Hospital Clínic de Barcelona

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Duran i Reynals

Barcelona, , Spain

Vall d'Hebron Institut d'Oncologia

Barcelona, , Spain

Hospital San Pedro de Alcántara

Cáceres, , Spain

Hospital Universitario Reina Sofía

Córdoba, , Spain

Hospital General Universitario Gregorio Marañón

Madrid, , Spain

Hospital Universitario Central de Asturias

Oviedo, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

Hospital Universitario Dr. Peset

Valencia, , Spain

Hospital Universitari i Politècnic La Fe

Valencia, , Spain

Sahlgrenska University Hospital

Gothenburg, , Sweden

Khmelnytskyi Regional Hospital

Khmelnytskyi, , Ukraine

Poltava Regional Clinical Hospital named after M. V. Sklifosovskoho

Poltava, , Ukraine

Heart of England NHS Foundation Trust - Heartlands Hospital

Birmingham, , United Kingdom

University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre

Bristol, , United Kingdom

East Kent Hospitals University NHS Foundation Trust - Kent and Canterbury Hospital

Canterbury, , United Kingdom

St. James's University Hospital

Leeds, , United Kingdom

Countries

United States; Belgium; Canada; Denmark; France; Germany; Hungary; Italy; Japan; Poland; South Korea; Spain; Sweden; Ukraine; United Kingdom

References

Roboz GJ, Sanz G, Griffiths EA, Yee K, Kantarjian H, Recher C, Byrne MT, Patkowska E, Kim HJ, Thomas X, Moors I, Stock W, Illes A, Fenaux P, Miyazaki Y, Yamauchi T, O'Connell CL, Hao Y, Keer HN, Azab M, Dohner H. Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial. Blood Adv. 2024 Apr 23;8(8):2020-2029. doi: 10.1182/bloodadvances.2023012062.

Reference Type: DERIVED

PMID: 38231126 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

SGI-110-06

Identifier Type: -

Identifier Source: org_study_id