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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02920008
• Other study ID #: SGI-110-06
• Status: Completed
• Phase: Phase 3
• Start date: March 16, 2017
• Est. completion date: June 1, 2020

Study information

• Verified date: May 2023
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 302
• Est. completion date: June 1, 2020
• Est. primary completion date: January 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• 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.
• 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).

Locations

Country	Name	City	State
Belgium	AZ Sint-Jan Brugge-Oostende AV	Brugge
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Universitair Ziekenhuis Gent	Gent
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hopital Maisonneuve Rosemont	Montreal
Canada	McGill University Health Centre	Montreal	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Denmark	Aarhus University Hospital	Aarhus C
Denmark	Rigshospitalet	Copenhagen
France	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 cedex 1
France	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse
Germany	Städtisches Klinikum Braunschweig gGmbH	Braunschweig
Germany	Marien Hospital Düsseldorf GmbH	Düsseldorf
Germany	Universitätsklinikum Halle (Saale)	Halle
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Medizinischen Fakultät Mannheim der Universität Heidelberg	Mannheim
Germany	Klinikum der Universität München	Muenchen
Germany	Universitätsklinikum Ulm	Ulm
Hungary	SE ÁOK I. sz. Belgyógyászati Klinika	Budapest
Hungary	Debreceni Egyetem Klinikai Központ	Debrecen
Hungary	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvar
Hungary	Pecsi Tudomanyegyetem Klinikai Központ	Pécs
Hungary	Szegedi Tudományegyetem	Szeged
Italy	IRCCS AOU San Martino - IST	Genova
Italy	Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico	Milano
Italy	Ospedale San Raffaele - Milano	Milano
Italy	A.O.R.N. "A. Cardarelli"	Napoli
Italy	A.S.U Integrata di Udine - Presidio Ospedaliero Santa Maria della Misericordia	Udine
Japan	Akita University Hospital	Akita-shi
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-shi
Japan	Japanese Red Cross Kyoto Daini Hospital	Kyoto-shi
Japan	University Hospital, Kyoto Prefectural University of Medicine	Kyoto-shi
Japan	Gunmaken Saiseikai Maebashi Hospital	Maebashi-shi
Japan	Nagasaki University Hospital	Nagasaki-shi
Japan	The Japanese Red Cross Nagasaki Genbaku Hospital	Nagasaki-Shi
Japan	Kindai University Hospital	Osakasayama-Shi
Japan	Saga University Hospital	Saga-shi
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-Shi
Japan	University of Fukui Hospital	Yoshida-Gun
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Ulsan University Hospital (UUH)	Ulsan
Poland	Instytut Hematologii i Transfuzjologi	Warszawa
Spain	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	Sevilla
Spain	Hospital Universitari i Politècnic La Fe	Valencia
Spain	Hospital Universitario Dr. Peset	Valencia
Sweden	Sahlgrenska University Hospital	Göteborg
Ukraine	Khmelnytskyi Regional Hospital	Khmelnytskyi
Ukraine	Poltava Regional Clinical Hospital named after M. V. Sklifosovskoho	Poltava
United Kingdom	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 States	University of New Mexico School of Medicine	Albuquerque	New Mexico
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Baylor Research Institute	Dallas	Texas
United States	Duke Cancer Institute	Durham	North Carolina
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	Franciscan Research Center	Indianapolis	Indiana
United States	University of Southern California	Los Angeles	California
United States	West Virginia University Hospitals, Inc.	Morgantown	West Virginia
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Weill Cornell Medical College	New York	New York
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

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Germany,  Hungary,  Italy,  Japan,  Korea, Republic of,  Poland,  Spain,  Sweden,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Overall survival is defined as number of days from day of randomization to date of death, regardless of cause.	From the date of randomization until the date of death, or approximately 34 months
Secondary	Event-Free Survival	Event-free survival is defined as number of days from randomization to earliest date of treatment discontinuation (for reasons other than initiation of hematopoietic cell transplant [HCT]), start of alternative anti-leukemia therapy (except HCT), or death.	From the date of randomization until the date of death, or approximately 38 months
Secondary	Long-Term Survival	Survival rate at 1 year after randomization; participants were also followed to estimate 2-year survival rate.	Up to approximately 38 months
Secondary	Number of Days Alive and Out of the Hospital (NDAOH)	Number of days participants alive and out of hospital during first 6 months of the study.	6 months
Secondary	Transfusion Independence Rate	Number of participants without red blood cells (RBC) or platelet transfusion for any 8-week period after treatment divided by total number of participants in efficacy analysis.	Baseline up to approximately 38 months
Secondary	Complete Response Rate	The Complete response (CR) rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as the number of participants with a best response of CR divided by the total number of participants included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) =1000/µL, platelets =100,000/µL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells.	Baseline to end of treatment, or approximately 38 months
Secondary	Combined Complete Response and Complete Response With Partial Hematologic Recovery Rate	The combined CR and CR with partial hematologic recovery rate based on modified International Working Group (IWG) 2003 AML Response Criteria was calculated as number of participants with CR and CR with partial hematologic recovery divided by the total number of participants included in the efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is absolute neutrophil count (ANC) =1000/µL, platelets =100,000/µL, independence from red blood cells (RBC) and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells.	Baseline to end of treatment, or approximately 38 months
Secondary	Composite Complete Response Rate	Composite complete response rate based on modified IWG 2003 AML Response Criteria defined as number of participants with best response of CR, CR with incomplete platelet recovery (CRp), or CR with incomplete blood count recovery (CRi) divided by total number of participants in efficacy analysis. CR as per modified 2003 IWG AML Response Criteria is ANC =1000/µL, platelets =100,000/µL, independence from RBC and platelet transfusions over the past week, no leukemic blasts in peripheral blood and bone marrow should contain less than 5% blast cells. CRp is defined as ANC =1000/µL, Platelets <100,000/µL, independence from RBC transfusions over the past week, no leukemic blasts and bone marrow should contain less than 5% blast cells. CRi is defined as ANC <1000/µL, no leukemic blasts and bone marrow should contain less than 5% blast cells.	Baseline to end of treatment, or approximately 38 months
Secondary	Hematopoietic Cell Transplant (HCT) Rate	Number of participants who received HCT after randomization divided by total number of participants in efficacy analysis.	Baseline to long term follow-up or approximately 38 months
Secondary	Duration of Complete Response (CR) + CR With Partial Hematologic Recovery (CRh)	The time from first CR or CRh to time of relapse (the date of the earliest of the following 3 events): relapse (defined as the earliest time point whereby BM assessment or PB assessment by the investigator indicate relapse/disease progression due to confirmed reappearance of leukemic blasts in PB or =5% leukemic blasts in BM, or clinical progression determined by the investigator),; start of alternative therapy (except HCT) or; death.	Baseline to end of treatment, or approximately 38 months
Secondary	Change From Baseline in EuroQoL-5 Dimension 5 Level (EQ-5D-5L) Index Scores	Index score is calculated based on 5-level version of the EQ-5D descriptive system using the value set for England.; The range of index score is from -0.281 (for the worst health state, score of 5 for all categories) to 1 (for the best health state, score of 1 for all categories).	Baseline to 6 months
Secondary	Change in EQ-5D-5L Visual Analogue Scale (VAS) Score	VAS score is obtained using vertical 20-cm visual analogue scale with the top value of 100 labelled as 'the best health you can imagine' and the bottom value of 0 labelled as 'the worst health you can imagine'.	Baseline to 6 months
Secondary	Percentage of Participants With Adverse Events (AEs)	An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality.	From first dose until 30 days after the last dose of study drug, or approximately 38 months
Secondary	All-Cause Mortality	All-cause mortality in the first 30 days and first 60 days after the start of treatment divided by the total number of participants receiving at least one dose of study treatment.	From the first dose until 60 days after the first dose of study drug