Clinical trial NCT02920008: Phase 3 Randomized, Open-Label Study of Guadecitabine vs Treatment Choice in Previously Treated Acute Myeloid Leukemia
Official title: A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Previously Treated Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Keywords: AML, acute myeloid leukemia, guadecitabine, SGI-110, Phase 3
Lead sponsor: Astex Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2016-09-30
Enrollment: 302
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: 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).

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.

Primary outcomes:
measure: Overall Survival
timeFrame: From the date of randomization until the date of death, or approximately 34 months
Secondary outcomes:
measure: Event-Free Survival
timeFrame: From the date of randomization until the date of death, or approximately 38 months
measure: Long-Term Survival
timeFrame: Up to approximately 38 months
measure: Number of Days Alive and Out of the Hospital (NDAOH)
timeFrame: 6 months
measure: Transfusion Independence Rate
timeFrame: Baseline up to approximately 38 months
measure: Complete Response Rate
timeFrame: Baseline to end of treatment, or approximately 38 months
measure: Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate
timeFrame: Baseline to end of treatment, or approximately 38 months
measure: Composite Complete Response Rate
timeFrame: Baseline to end of treatment, or approximately 38 months
measure: Hematopoietic Cell Transplant (HCT) Rate
timeFrame: Baseline to long term follow-up or approximately 38 months
measure: Duration of Complete Response (CR) + CR With Partial Hematologic Recovery (CRh)
timeFrame: Baseline to end of treatment, or approximately 38 months
measure: Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores
timeFrame: Baseline to 6 months
measure: Change in EQ-5D-5L Visual Analogue Scale (VAS) Score
timeFrame: Baseline to 6 months
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: From first dose until 30 days after the last dose of study drug, or approximately 38 months
measure: All-Cause Mortality
timeFrame: From the first dose until 60 days after the first dose of study drug
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Franciscan Research Center
state: Indiana
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico School of Medicine
state: New Mexico
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: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Research Institute
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Morgantown
country: United States
facility: West Virginia University Hospitals, Inc.
state: West Virginia
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge-Oostende AV
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Hopital Maisonneuve Rosemont
city: Aarhus C
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte Basque
city: Marseille
country: France
facility: Hôpital de la Conception
city: Montpellier
country: France
facility: CHRU Montpellier - Saint Eloi
city: Mulhouse
country: France
facility: Groupe Hospitalier de la Région de Mulhouse et Sud Alsace
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Pessac
country: France
facility: CHU Hopitaux de Bordeaux - Hôpital Haut-Lévêque
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon-Sud
city: Rouen cedex 1
country: France
facility: Centre Henri Becquerel
city: Toulouse
country: France
facility: Institut Universitaire du Cancer de Toulouse - Oncopole
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbH
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf GmbH
city: Halle
country: Germany
facility: Universitätsklinikum Halle (Saale)
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Mannheim
country: Germany
facility: Medizinischen Fakultät Mannheim der Universität Heidelberg
city: Muenchen
country: Germany
facility: Klinikum der Universität München
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Budapest
country: Hungary
facility: SE ÁOK I. sz. Belgyógyászati Klinika
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Központ
city: Kaposvar
country: Hungary
facility: Somogy Megyei Kaposi Mór Oktató Kórház
city: Pécs
country: Hungary
facility: Pecsi Tudomanyegyetem Klinikai Központ
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem
city: Genova
country: Italy
facility: IRCCS AOU San Martino - IST
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: Ospedale San Raffaele - Milano
city: Napoli
country: Italy
facility: A.O.R.N. "A. Cardarelli"
city: Udine
country: Italy
facility: A.S.U Integrata di Udine - Presidio Ospedaliero Santa Maria della Misericordia
city: Akita-shi
country: Japan
facility: Akita University Hospital
city: Fukuyama-Shi
country: Japan
facility: Chugoku Central Hospital
city: Isehara-shi
country: Japan
facility: Tokai University Hospital
city: Kawagoe-Shi
country: Japan
facility: Saitama Medical Center
city: Kobe-shi
country: Japan
facility: Kobe City Medical Center General Hospital
city: Kyoto-shi
country: Japan
facility: Japanese Red Cross Kyoto Daini Hospital
city: Kyoto-shi
country: Japan
facility: University Hospital, Kyoto Prefectural University of Medicine
city: Maebashi-shi
country: Japan
facility: Gunmaken Saiseikai Maebashi Hospital
city: Nagasaki-shi
country: Japan
facility: Nagasaki University Hospital
city: Nagasaki-Shi
country: Japan
facility: The Japanese Red Cross Nagasaki Genbaku Hospital
city: Osakasayama-Shi
country: Japan
facility: Kindai University Hospital
city: Saga-shi
country: Japan
facility: Saga University Hospital
city: Shinagawa-Ku
country: Japan
facility: NTT Medical Center Tokyo
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tachikawa-Shi
country: Japan
facility: National Hospital Organization Disaster Medical Center
city: Yamagata-Shi
country: Japan
facility: Yamagata University Hospital
city: Yoshida-Gun
country: Japan
facility: University of Fukui Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
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: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital (UUH)
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologi
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals
city: Barcelona
country: Spain
facility: Vall d'Hebron Institut d'Oncologia
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcántara
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Khmelnytskyi
country: Ukraine
facility: Khmelnytskyi Regional Hospital
city: Poltava
country: Ukraine
facility: Poltava Regional Clinical Hospital named after M. V. Sklifosovskoho
city: Birmingham
country: United Kingdom
facility: Heart of England NHS Foundation Trust - Heartlands Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust - Bristol Haematology and Oncology Centre
city: Canterbury
country: United Kingdom
facility: East Kent Hospitals University NHS Foundation Trust - Kent and Canterbury Hospital
city: Leeds
country: United Kingdom
facility: St. James's University Hospital
Study officials:
affiliation: Astex Pharmaceuticals, Inc.
name: Harold N Keer, MD, PhD
role: STUDY_DIRECTOR
References: