Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs

NCT ID: NCT02907359

Last Updated: 2024-08-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 417 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-13
• Study Completion Date: 2020-11-30

Brief Summary

A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the efficacy and safety of guadecitabine in participants with MDS or CMML who failed or relapsed after adequate prior treatment with azacitidine, decitabine, or both. This global study will be conducted in approximately 15 countries. Approximately 408 participants from approximately 100 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine (approximately 272 participants) or Treatment Choice (approximately 136 participants). The study consists of a 21-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last more than 2 years, and the duration of individual participant participation will vary. Participants may continue to receive treatment for as long as they continue to benefit.

Detailed Description

Multicenter, randomized, open-label, parallel-group study of guadecitabine vs Treatment Choice (TC). Approximately 408 participants will be randomly assigned 2:1 to either guadecitabine or TC.

• Guadecitabine: approximately 272 participants.
• TC: approximately 136 participants.

Before randomization, the investigator will assign each participant to one of the following TC options:

• Low dose cytarabine (LDAC).
• Standard Intensive Chemotherapy (IC) of a 7+3 regimen.
• Best Supportive Care (BSC) only. BSC will be provided to all participants as per standard and institutional practice. Participants randomized to TC will not be allowed to cross over to guadecitabine. Data will be reviewed by an independent Data Monitoring Committee at regular intervals, primarily to evaluate safety during study conduct. Randomization will be stratified by disease category (MDS vs CMML), bone marrow (BM) blasts (BM blasts >10% vs BM blasts ≤10%), TC option (LDAC vs IC vs BSC), and study center region.

Guadecitabine: 60 milligrams per square meter (mg/m^2) given subcutaneously (SC) daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as the participant continues to benefit. BSC should be given according to standard and institutional practice.

Treatment Choice (TC): Before randomization, the investigator will assign each participant to one of the following TC options:

• Low dose cytarabine (LDAC) given as 20 mg/m^2 SC or intravenously (IV) once daily for 14 days in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 4 cycles in the absence of disease progression or unacceptable toxicity.
• Standard Intensive Chemotherapy (IC) of a 7+3 regimen: given as cytarabine 100-200 mg/m^2/day given as continuous infusion for 7 days and an anthracycline given as per institutional standard practice such as daunorubicin (45-60 mg/m^2/day), or idarubicin (9-12 mg/m^2/day), or mitoxantrone (8-12 mg/m^2/day) by intravenous infusion for 3 days.
• Best Supportive Care (BSC) only: given according to standard and institutional practice. BSC includes, but is not limited to blood transfusions (Red blood cells [RBCs] or platelets), growth factors including erythropoiesis stimulating agents (ESA), granulocyte stimulating factors (GSFs), iron chelating therapy, and broad-spectrum antibiotics and/or antifungals.

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic

Study Design

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

Study Groups

Guadecitabine

Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).

Group Type: EXPERIMENTAL

Guadecitabine

Intervention Type: DRUG

Treatment Choice

Participants received one of the three treatment choice options:

1. LDAC 20 mg/m^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice.

2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m^2) by IV infusion for 3 days of each 28-day cycles.

3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals.

Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.

Group Type: ACTIVE_COMPARATOR

Treatment Choice

Intervention Type: OTHER

• BSC: according to standard/institutional practice; included RBC or platelet transfusions; growth factors, i.e. erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals.
• LDAC: 20 mg/m^2 SC or IV once daily (QD) for 14 days in 28-day cycles. Other schedules were allowed per institutional practice. Treatment for ≥4 cycles absent disease progression/toxicity. BSC per institutional/standard practice.
• Standard Intensive Chemotherapy: recommended regimen of 7+3 was given as cytarabine 100-200 mg/m^2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice included daunorubicin (45-60 mg/m^2/day) or idarubicin (9-12 mg/m^2/day) or mitoxantrone (8-12 mg/m^2/day) by IV infusion. Participants with complete or partial response after IC induction received ≥1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.

Interventions

Guadecitabine

Intervention Type: DRUG

Treatment Choice

• BSC: according to standard/institutional practice; included RBC or platelet transfusions; growth factors, i.e. erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals.
• LDAC: 20 mg/m^2 SC or IV once daily (QD) for 14 days in 28-day cycles. Other schedules were allowed per institutional practice. Treatment for ≥4 cycles absent disease progression/toxicity. BSC per institutional/standard practice.
• Standard Intensive Chemotherapy: recommended regimen of 7+3 was given as cytarabine 100-200 mg/m^2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice included daunorubicin (45-60 mg/m^2/day) or idarubicin (9-12 mg/m^2/day) or mitoxantrone (8-12 mg/m^2/day) by IV infusion. Participants with complete or partial response after IC induction received ≥1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.

Intervention Type: OTHER

Other Intervention Names

SGI-110

Eligibility Criteria

Inclusion Criteria

• Adult participants ≥18 years of age who are able to understand and comply with study procedures and provide written informed consent before any study-specific procedure.
• Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
• Performance status (ECOG) of 0-2.
• Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:

1. Participant received HMA for at least 6 cycles and was still transfusion dependent.

2. Participant received HMA for at least 2 complete cycles and had disease progression prior to Cycle 6 defined as

i. ≥50% increase in bone marrow blasts from pre-HMA-treatment levels or from nadir post-HMA-treatment levels to >5% (for participants with pretreatment or nadir blasts ≤5%) or to >10% (for participants with pretreatment or nadir blasts >5%), and/or ii. Transfusion dependent and ≥2 gram/deciliter (g/dL) reduction of Hgb from pre-HMA-treatment levels.

Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.

• Participants must have either:

1. Bone marrow blasts >5% at randomization, OR

2. Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization.

• Creatinine clearance or glomerular filtration rate ≥30 milliliter/minute (mL/min) 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).
• Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing 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 with guadecitabine and for at least 3 months after completing treatment and (b) while receiving treatment with LDAC or IC and for at least 6 months after completing treatment or for the duration specified in local prescribing information, whichever is longer.

Exclusion Criteria

• Participants who have been diagnosed as having AML with peripheral blood or bone marrow blasts of ≥20%.
• Participants who may still be sensitive to repeated treatment with decitabine or azacitidine such as participants who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
• Prior treatment with guadecitabine.
• Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
• Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
• Treated with any investigational drug within 2 weeks of the first dose of study treatment.
• 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.
• Known active HIV, HBV, or HCV infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
• 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.
• Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring >2 liters per minute oxygen.
• Life expectancy of less than one month
• Participants with TP53 mutations

• 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

Yuri Sano, MD, PhD

Role: STUDY_DIRECTOR

Astex Pharmaceuticals, Inc.

Locations

City of Hope

Duarte, California, United States

Desert Hematology Oncology Medical Group, Inc.

Rancho Mirage, California, United States

Cancer Specialists of North Florida

Fleming Island, Florida, United States

Mount Sinai Medical Center

Miami Beach, Florida, United States

Rush University Medical Center

Chicago, Illinois, United States

North Shore Medical Center

Evanston, Illinois, United States

Franciscan Health Indianapolis

Indianapolis, Indiana, United States

University of Maryland

Baltimore, Maryland, United States

University of Michigan Cancer Center

Ann Arbor, Michigan, United States

John Theurer Cancer Center

Hackensack, New Jersey, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Weill Cornell Medical College

New York, New York, United States

Stony Brook University Medical Center

Stony Brook, New York, United States

Duke Cancer Center

Durham, North Carolina, United States

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Bon Secours Saint Francis Hospital

Greenville, South Carolina, United States

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Swedish Cancer Institute

Seattle, Washington, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

West Virginia University Mary Babb Randolph Cancer Center

Morgantown, West Virginia, United States

Ziekenhuis Netwerk Antwerpen Stuivenberg

Antwerp, , Belgium

Algemeen Ziekenhuis Sint-Jan Brugge-Oostende

Bruges, , Belgium

Grand Hôpital de Charleroi - Notre Dame

Charleroi, , Belgium

Tom Baker Cancer Center

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

Royal Victoria Regional Health Centre

Barrie, Ontario, Canada

Juravinski Cancer Centre

Hamilton, Ontario, Canada

Princess Margaret Hospital

Toronto, Ontario, Canada

Burnaby Hospital

Burnaby, , Canada

Moncton Hospital

Moncton, , Canada

Maisonneuve-Rosemont Hôpital Service d'Hematologie et d'Oncologie Medicale

Montreal, , Canada

Saskatchewan Cancer Agency

Regina, , Canada

Fakultní nemocnice Brno

Brno, , Czechia

Fakultni Nemocnice Hradec Králové

Hradec Králové, , Czechia

Fakultní nemocnice Ostrava

Ostrava, , Czechia

Fakultní Nemocnice Královské Vinohrady

Prague, , Czechia

Onkologická klinika Všeobecná fakultní nemocnice v Praze a 1

Prague, , Czechia

Aalborg Universitetshospital

Aalborg, , Denmark

Aarhus Universitetshospital

Aarhus, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Odense University Hospital

Odense, , Denmark

Centre Hospitalier Universitaire

La Tronche, , France

Hôpital Dupuytren

Limoges, , France

GHR Mulhouse Sud-Alsace

Mulhouse, , France

Hôpital Hôtel-Dieu

Nantes, , France

Centre Antoine Lacassagne

Nice, , France

Hôpital Saint Louis

Paris, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

Centre Hospitalier Universitaire de Toulouse

Toulouse, , France

Städtisches Klinikum Braunschweig

Braunschweig, , Germany

Marien Hospital Düsseldorf

Düsseldorf, , Germany

Universitaetsklinikum Freiburg

Freiburg im Breisgau, , Germany

Universitätsklinikum Halle

Halle, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Azienda Ospedaliera SS. Antonio E. Biagio E. Cesare Arrigo di Alessandria

Alessandria, , Italy

Azienda Ospedaliero Universitaria Careggi

Florence, , Italy

Azienda Ospedaliera Universitaria San Martino

Genova, , Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

AORN A. Cardarelli

Napoli, , Italy

Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara

Novara, , Italy

Azienda Ospedaliera Ospedali Riuniti Marche Nord

Pesaro, , Italy

Ospedale S. Eugenio

Roma, , Italy

NHO Nagoya Medical Center

Nagoya, Aichi-ken, Japan

Narita Red Cross Hospital

Narita, Chiba, Japan

University of Fukui Hospital

Yoshida, Fukui, Japan

Chugoku Central Hospital

Fukuyama-shi, Hiroshima, Japan

Tokai University Hospital

Isehara, Kanagawa, Japan

Kitasato University Hospital

Sagamihara-shi, Kanagawa, Japan

Yokohama Municipal Citizen's Hospital

Yokohama, Kanagawa, Japan

Nagasaki University Hospital

Nagasaki, Nagasaki-shi, Japan

Kansai Medical University Hirakata

Hirakata, Osaka, Japan

Kindai University Hospital

Osakasayama-shi, Osaka, Japan

Saitama Medical Center

Kawagoe, Saitama, Japan

Nippon Medical School Hospital

Bunkyō-Ku, Tokyo, Japan

The Cancer Institute Hospital of Japanese Foundation for Cancer Research

Koto, Tokyo, Japan

NTT Medical Center Tokyo

Shinagawa, Tokyo, Japan

National Hospital Organization Disaster Medical Center

Tachikawa, Tokyo, Japan

National Hospital Organization Kyushu

Fukuoka, , Japan

Fukushima Medical University

Fukushima, , Japan

Gifu Municipal Hospital

Gifu, , Japan

National Hospital Organization Kumamoto Medical Center

Kumamoto, , Japan

Japanese Red Cross Kyoto Daini Hospital

Kyoto, , Japan

University Hospital-Kyoto Prefectural University of Medicine

Kyoto, , Japan

Yamagata University Hospital

Yamagata, , Japan

Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie

Lublin, , Poland

Instytut Hematologii i Transfuzjologii

Warsaw, , Poland

Samodzielny Publiczny Centralny Szpital Kliniczny

Warsaw, , Poland

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital, Yonsei University Health System

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Seoul Saint Mary's Hospital

Seoul, , South Korea

Ulsan University Hospital

Ulsan, , South Korea

Hospital General Universitario de Alicante

Alicante, , Spain

Hospital Universitari Germans Trias i Pujol

Badalona, , Spain

Fundació Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Universitario Vall d'Hebron

Barcelona, , Spain

Hospital San Pedro de Alcantara

Cáceres, , Spain

Hospital de León

León, , Spain

Hospital General Universitario Gregorio Marañon

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Ramón Y Cajal

Madrid, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, , Spain

Sahlgrenska Universitetssjukhuset, Östra sjukhuset

Gothenburg, , Sweden

Universitetssjukhuset Örebro

Örebro, , Sweden

Medway NHS Foundation Trust

Gillingham, , United Kingdom

The Leeds Teaching Hospitals NHS Trust

Leeds, , United Kingdom

Chelsea and Westminster Hospital NHS Foundation Trust

London, , United Kingdom

Nottingham University Hospitals NHS Trust

Nottingham, , United Kingdom

Countries

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

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2015-005257-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

SGI-110-07

Identifier Type: -

Identifier Source: org_study_id