Clinical trial NCT02907359: Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs
Official title: A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) Previously Treated With Hypomethylating Agents
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Lead sponsor: Astex Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2016-09-20
Enrollment: 417
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization up to death (up to approximately 38.6 months)
Secondary outcomes:
measure: Percentage of Participants With Transfusion Independence for Any 8 Consecutive Weeks
timeFrame: Up to approximately 46.6 months
measure: Percentage of Participants With Marrow Complete Response (mCR) Along With Transfusion Independence Rate
timeFrame: Up to approximately 46.6 months
measure: Survival Rate at 1 Year After Randomization
timeFrame: From randomization up to 12 months
measure: Leukemia-free Survival
timeFrame: From randomization up to 46.6 months
measure: Number of Days Alive and Out of the Hospital (NDAOH)
timeFrame: Up to 6 months
measure: Disease Response (DR) Rate
timeFrame: Up to approximately 46.6 months
measure: Duration of Complete Response (CR)
timeFrame: Up to approximately 46.6 months
measure: Time to First Response, Complete Response (CR) and Best Response
timeFrame: From study Day 1 to the earliest date that a response was first documented (up to approximately 46.6 months)
measure: Number of Red Blood Cell (RBC) and Platelet Transfusions
timeFrame: Up to 6 months
measure: Change From Baseline in Health-related Quality of Life (QOL) By EuroQol 5-level 5-dimension (EQ-5D-5L) Summary Index
timeFrame: Baseline to Month 6
measure: Change From Baseline in Health-related QOL: EuroQOL Visual Analogue Scale (EQ-VAS) Score
timeFrame: Baseline to Month 6
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose through end of study (up to approximately 46.6 months)
measure: 30-day and 60-day All-cause Mortality
timeFrame: From first dose until 60 days after study treatment initiation
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Rancho Mirage
country: United States
facility: Desert Hematology Oncology Medical Group, Inc.
state: California
city: Fleming Island
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Evanston
country: United States
facility: North Shore Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Cancer Center
state: Michigan
city: Hackensack
country: United States
facility: John Theurer Cancer Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Center
state: North Carolina
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Bon Secours Saint Francis Hospital
state: South Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Mary Babb Randolph Cancer Center
state: West Virginia
city: Antwerp
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen Stuivenberg
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende
city: Charleroi
country: Belgium
facility: Grand Hôpital de Charleroi - Notre Dame
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Barrie
country: Canada
facility: Royal Victoria Regional Health Centre
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Burnaby
country: Canada
facility: Burnaby Hospital
city: Moncton
country: Canada
facility: Moncton Hospital
city: Montréal
country: Canada
facility: Maisonneuve-Rosemont Hôpital Service d'Hematologie et d'Oncologie Medicale
city: Regina
country: Canada
facility: Saskatchewan Cancer Agency
city: Brno
country: Czechia
facility: Fakultní nemocnice Brno
city: Hradec Králové
country: Czechia
facility: Fakultni Nemocnice Hradec Králové
city: Ostrava
country: Czechia
facility: Fakultní nemocnice Ostrava
city: Praha 2
country: Czechia
facility: Onkologická klinika Všeobecná fakultní nemocnice v Praze a 1
city: Praha
country: Czechia
facility: Fakultní Nemocnice Královské Vinohrady
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Odense
country: Denmark
facility: Odense University Hospital
city: La Tronche
country: France
facility: Centre Hospitalier Universitaire
city: Limoges
country: France
facility: Hôpital Dupuytren
city: Mulhouse Cedex
country: France
facility: GHR Mulhouse Sud-Alsace
city: Nantes
country: France
facility: Hôpital Hôtel-Dieu
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Alessandria
country: Italy
facility: Azienda Ospedaliera SS. Antonio E. Biagio E. Cesare Arrigo di Alessandria
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Genova
country: Italy
facility: Azienda Ospedaliera Universitaria San Martino
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: AORN A. Cardarelli
city: Novara
country: Italy
facility: Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara
city: Pesaro
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Marche Nord
city: Roma
country: Italy
facility: Ospedale S. Eugenio
city: Nagoya-shi
country: Japan
facility: NHO Nagoya Medical Center
state: Aichi
city: Narita
country: Japan
facility: Narita Red Cross Hospital
state: Chiba
city: Yoshida
country: Japan
facility: University of Fukui Hospital
state: Fukui
city: Fukuyama-shi
country: Japan
facility: Chugoku Central Hospital
state: Hiroshima
city: Isehara
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Sagamihara-shi
country: Japan
facility: Kitasato University Hospital
state: Kanagawa
city: Yokohama
country: Japan
facility: Yokohama Municipal Citizen's Hospital
state: Kanagawa
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
state: Nagasaki-shi
city: Hirakata
country: Japan
facility: Kansai Medical University Hirakata
state: Osaka
city: Osakasayama-shi
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Bunkyō-Ku
country: Japan
facility: Nippon Medical School Hospital
state: Tokyo
city: Koto
country: Japan
facility: The Cancer Institute Hospital of Japanese Foundation for Cancer Research
state: Tokyo
city: Shinagawa
country: Japan
facility: NTT Medical Center Tokyo
state: Tokyo
city: Tachikawa
country: Japan
facility: National Hospital Organization Disaster Medical Center
state: Tokyo
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu
city: Fukushima
country: Japan
facility: Fukushima Medical University
city: Gifu
country: Japan
facility: Gifu Municipal Hospital
city: Kumamoto
country: Japan
facility: National Hospital Organization Kumamoto Medical Center
city: Kyoto
country: Japan
facility: Japanese Red Cross Kyoto Daini Hospital
city: Kyoto
country: Japan
facility: University Hospital-Kyoto Prefectural University of Medicine
city: Yamagata
country: Japan
facility: Yamagata University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul Saint Mary's Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Fundació Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: León
country: Spain
facility: Hospital de León
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Ramón Y Cajal
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Östra sjukhuset
city: Örebro
country: Sweden
facility: Universitetssjukhuset Örebro
city: Gillingham
country: United Kingdom
facility: Medway NHS Foundation Trust
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
Study officials:
affiliation: Astex Pharmaceuticals, Inc.
name: Yuri Sano, MD, PhD
role: STUDY_DIRECTOR
References: