Back to resultsEfficacy and Safety of Decitabine as Epigenetic Priming With Induction Chemotherapy in Pediatric Acute Myelogenous Leukemia (AML) Subjects
Primary Purpose
Pediatric Acute Myelogenous Leukemia (AML)
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Decitabine
Decitabine
Sponsored by
About this trial
This is an interventional treatment trial for Pediatric Acute Myelogenous Leukemia (AML)
Eligibility Criteria
Inclusion Criteria
- Males and females, age 1 to 16 years, inclusive
- Females of childbearing potential must have a negative serum beta human chorionic gonadotropin ( B-hCG) at Visit 1 (Screening) and a negative urine pregnancy test prior to starting study drugs (Visit 2). Female subjects of childbearing potential must agree to be abstinent or to use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, intrauterine devise (IUD), or have a vasectomised partner) for at least one menstrual cycle prior to starting study drug(s) and throughout the Randomization Phase or 30 days after the last dose of study drug. Those females using hormonal contraceptives must also be using an additional approved method of contraception (as described previously)
- Sexually mature male patients who are not abstinent or have not undergone a successful vasectomy, who are partners of women of childbearing potential must use, or their partners must use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, IUD) starting for at least one menstrual cycle prior to starting study drug(s) and throughout the Randomization Phase and for 30 days (longer if appropriate) after the last dose of study drug. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception (as described previously)
- Diagnosis of acute myelogenous leukemia ( AML) (bone marrow or peripheral blood blasts greater than or equal to 20%)
- Adequate cardiac function as defined by an echocardiogram or multiple gated acquisition (MUGA) scan demonstrating an ejection fraction greater than 50%
- Are willing and able to comply with all aspects of the protocol
- Provide written informed consent from subject's guardian or legally authorized representative and child assent (if applicable).
Exclusion Criteria
- Females who are pregnant (positive B-hCG test) or lactating
- History of chronic myelogenous leukemia (CML) [t(9;22)]
- Acute promyelocytic leukemia (M3 subtype in French-American-British [FAB] classification)
- Known central nervous system (CNS) leukemia
- AML associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome, or Diamond-Blackfan anemia
- White blood cell (WBC) count greater than 100,000/mm3
- Serum creatinine greater than 2.5 mg/dL
- Alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN) and/or total bilirubin greater than 3 x ULN
- Prior chemotherapy (other than hydroxyurea) or radiation therapy for AML
- Known to be human immunodeficiency virus (HIV) positive
- Any history of or concomitant medical condition that, in the opinion of the Investigator, would compromise the subject's ability to safely complete the study
- The Investigator believes the subject to be medically unfit to receive the study drug or unsuitable for any other reason
- Subject with hypersensitivity to decitabine, daunorubicin, cytarabine, or etoposide
- Has participated in a drug trial in the last 4 weeks.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm A
Arm B
Arm Description
Outcomes
Primary Outcome Measures
Percentage of Participants With Morphologic Complete Remission (CR)
Disease response measurements were based on bone marrow evaluations (biopsies, aspirates, or both) performed by local pathology laboratories and assessed by study investigators. A designation of CR required that the participant achieve a morphologic leukemia-free state and have an absolute neutrophil count (ANC) greater than 1000 per microliter (/mcL) and a platelet count greater than 100,000/mcL.
Secondary Outcome Measures
DNA Methylation
Bone marrow samples were obtained at baseline and completion of induction therapy. DNA was extracted, and global DNA methylation was evaluated using the Infinium® Human Methylation450® BeadChip Array according to the manufacturer's protocol (Illumina, San Diego, California). Paired differential methylation analysis of end-induction marrows to participant matched screening marrows was performed to identify differentially methylated cytosines followed by guanine residue (CpG) loci (DML). A paired Wilcoxon rank test was conducted to compare end-induction marrows with diagnostic marrows within each arm to identify loci considered statistically significant and differentially methylated. Three different behaviors were defined: 'hypermethylation' (increased intensity in the tumor), 'hypomethylation' (decreased intensity in the tumor) and 'no change' (no substantial differences of intensity).
Leukemia-free Survival (LFS)
LFS was defined as time from CR until the recurrence of leukemia (greater than or equal to [>=] 5% bone marrow blasts, reappearance of peripheral blasts or the appearance of new dysplastic changes, or death, whichever occurred first). For participants who did not achieve a CR, LFS is set to zero days. For participants with CR who do not have leukemic recurrence or death, data for LFS was censored on the date of the last follow-up bone marrow or hematology examination, whichever is later. LFS was analyzed using Kaplan-Meier method.
Overall Survival (OS)
OS was defined as the time from the date of the first dose of study treatment to the date of death from any cause. OS was analyzed using Kaplan-Meier method.
Percentage of Participants With Minimal Residual Disease (MRD) at Baseline and Day 50
After induction chemotherapy, based on bone marrow biopsies. No formal statistical analyses of MRD were performed for this study.
Time to CR
Disease response measurements were based on bone marrow evaluations (biopsies, aspirates, or both) performed by local pathology laboratories an assessed by study investigators. CR: requires that the participant achieved a morphologic leukemia-free state and had an ANC >1000/mcL and platelets >100,000/mcL. Hemoglobin concentration or hematocrit had no bearing on remission status, although the participant had to be independent of transfusions. Kaplan-Meier curves were used to describe time to CR.
Time to Neutrophil Recovery
Blood sampling was used to determine recovery, and is defined as less than or equal to 1000 per cubic millimeter (/mm^3) for absolute neutrophil count (ANC). Summarized using Kaplan-Meier product limit estimators.
Time to Platelet Recovery
Blood sampling was used to determine recovery and is defined as less than or equal to 100,000/mm^3 for platelet count. Summarized using Kaplan-Meier product limit estimators.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01177540
Brief Title
Efficacy and Safety of Decitabine as Epigenetic Priming With Induction Chemotherapy in Pediatric Acute Myelogenous Leukemia (AML) Subjects
Official Title
A Randomized, Open Label, Multicenter Study to Evaluate the Efficacy and Safety of Decitabine as Epigenetic Priming With Induction Chemotherapy in Pediatric Acute Myelogenous Leukemia (AML) Subjects
Study Type
Interventional
2. Study Status
Record Verification Date
October 2013
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated early due to enrollment difficulties and the futility of observing differences in remission rate between treatment arms.
Study Start Date
March 3, 2011 (Actual)
Primary Completion Date
July 19, 2013 (Actual)
Study Completion Date
July 19, 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eisai Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
The purpose of this study is to provide data on the activity of a standard daunorubicin, cytarabine, and etoposide (ADE) induction plus epigenetic priming with decitabine as assessed by standard measures of complete remission (CR), leukemia free survival (LFS) and overall survival (OS), as well as, on minimal residual disease (MRD). It will also provide necessary data on the safety and Pharmacokinetics (PK) of decitabine in pediatric patients that is currently unavailable.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pediatric Acute Myelogenous Leukemia (AML)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
25 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A
Arm Type
Experimental
Arm Title
Arm B
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Decitabine
Intervention Description
5 day priming with decitabine followed by Induction Chemotherapy of ADE (daunorubicin, cytarabine, etoposide).
Intervention Type
Drug
Intervention Name(s)
Decitabine
Intervention Description
Induction Chemotherapy of ADE (daunorubicin, cytarabine, etoposide) only
Primary Outcome Measure Information:
Title
Percentage of Participants With Morphologic Complete Remission (CR)
Description
Disease response measurements were based on bone marrow evaluations (biopsies, aspirates, or both) performed by local pathology laboratories and assessed by study investigators. A designation of CR required that the participant achieve a morphologic leukemia-free state and have an absolute neutrophil count (ANC) greater than 1000 per microliter (/mcL) and a platelet count greater than 100,000/mcL.
Time Frame
Day 50
Secondary Outcome Measure Information:
Title
DNA Methylation
Description
Bone marrow samples were obtained at baseline and completion of induction therapy. DNA was extracted, and global DNA methylation was evaluated using the Infinium® Human Methylation450® BeadChip Array according to the manufacturer's protocol (Illumina, San Diego, California). Paired differential methylation analysis of end-induction marrows to participant matched screening marrows was performed to identify differentially methylated cytosines followed by guanine residue (CpG) loci (DML). A paired Wilcoxon rank test was conducted to compare end-induction marrows with diagnostic marrows within each arm to identify loci considered statistically significant and differentially methylated. Three different behaviors were defined: 'hypermethylation' (increased intensity in the tumor), 'hypomethylation' (decreased intensity in the tumor) and 'no change' (no substantial differences of intensity).
Time Frame
Baseline up to completion of induction therapy (Day 15)
Title
Leukemia-free Survival (LFS)
Description
LFS was defined as time from CR until the recurrence of leukemia (greater than or equal to [>=] 5% bone marrow blasts, reappearance of peripheral blasts or the appearance of new dysplastic changes, or death, whichever occurred first). For participants who did not achieve a CR, LFS is set to zero days. For participants with CR who do not have leukemic recurrence or death, data for LFS was censored on the date of the last follow-up bone marrow or hematology examination, whichever is later. LFS was analyzed using Kaplan-Meier method.
Time Frame
Baseline to recurrence of Leukemia or Death (up to 2 years 5 months)
Title
Overall Survival (OS)
Description
OS was defined as the time from the date of the first dose of study treatment to the date of death from any cause. OS was analyzed using Kaplan-Meier method.
Time Frame
Baseline to Date of Death (up to 2 years 5 months)
Title
Percentage of Participants With Minimal Residual Disease (MRD) at Baseline and Day 50
Description
After induction chemotherapy, based on bone marrow biopsies. No formal statistical analyses of MRD were performed for this study.
Time Frame
Baseline and Day 50
Title
Time to CR
Description
Disease response measurements were based on bone marrow evaluations (biopsies, aspirates, or both) performed by local pathology laboratories an assessed by study investigators. CR: requires that the participant achieved a morphologic leukemia-free state and had an ANC >1000/mcL and platelets >100,000/mcL. Hemoglobin concentration or hematocrit had no bearing on remission status, although the participant had to be independent of transfusions. Kaplan-Meier curves were used to describe time to CR.
Time Frame
Randomization to Day 50
Title
Time to Neutrophil Recovery
Description
Blood sampling was used to determine recovery, and is defined as less than or equal to 1000 per cubic millimeter (/mm^3) for absolute neutrophil count (ANC). Summarized using Kaplan-Meier product limit estimators.
Time Frame
Baseline up to Day 50
Title
Time to Platelet Recovery
Description
Blood sampling was used to determine recovery and is defined as less than or equal to 100,000/mm^3 for platelet count. Summarized using Kaplan-Meier product limit estimators.
Time Frame
Baseline up to Day 38
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria
Males and females, age 1 to 16 years, inclusive
Females of childbearing potential must have a negative serum beta human chorionic gonadotropin ( B-hCG) at Visit 1 (Screening) and a negative urine pregnancy test prior to starting study drugs (Visit 2). Female subjects of childbearing potential must agree to be abstinent or to use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, intrauterine devise (IUD), or have a vasectomised partner) for at least one menstrual cycle prior to starting study drug(s) and throughout the Randomization Phase or 30 days after the last dose of study drug. Those females using hormonal contraceptives must also be using an additional approved method of contraception (as described previously)
Sexually mature male patients who are not abstinent or have not undergone a successful vasectomy, who are partners of women of childbearing potential must use, or their partners must use a highly effective method of contraception (eg, condom + spermicide, condom + diaphragm with spermicide, IUD) starting for at least one menstrual cycle prior to starting study drug(s) and throughout the Randomization Phase and for 30 days (longer if appropriate) after the last dose of study drug. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception (as described previously)
Diagnosis of acute myelogenous leukemia ( AML) (bone marrow or peripheral blood blasts greater than or equal to 20%)
Adequate cardiac function as defined by an echocardiogram or multiple gated acquisition (MUGA) scan demonstrating an ejection fraction greater than 50%
Are willing and able to comply with all aspects of the protocol
Provide written informed consent from subject's guardian or legally authorized representative and child assent (if applicable).
Exclusion Criteria
Females who are pregnant (positive B-hCG test) or lactating
History of chronic myelogenous leukemia (CML) [t(9;22)]
Acute promyelocytic leukemia (M3 subtype in French-American-British [FAB] classification)
Known central nervous system (CNS) leukemia
AML associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome, or Diamond-Blackfan anemia
White blood cell (WBC) count greater than 100,000/mm3
Serum creatinine greater than 2.5 mg/dL
Alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN) and/or total bilirubin greater than 3 x ULN
Prior chemotherapy (other than hydroxyurea) or radiation therapy for AML
Known to be human immunodeficiency virus (HIV) positive
Any history of or concomitant medical condition that, in the opinion of the Investigator, would compromise the subject's ability to safely complete the study
The Investigator believes the subject to be medically unfit to receive the study drug or unsuitable for any other reason
Subject with hypersensitivity to decitabine, daunorubicin, cytarabine, or etoposide
Has participated in a drug trial in the last 4 weeks.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eisai Medical Services
Organizational Affiliation
Eisai Inc.
Official's Role
Study Director
Facility Information:
City
Phoenix
State/Province
Arizona
Country
United States
City
Madera
State/Province
California
Country
United States
City
Aurora
State/Province
Colorado
Country
United States
City
Miami
State/Province
Florida
Country
United States
City
Atlanta
State/Province
Georgia
Country
United States
City
Baltimore
State/Province
Maryland
Country
United States
City
Boston
State/Province
Massachusetts
Country
United States
City
Worcester
State/Province
Massachusetts
Country
United States
City
Rochester
State/Province
Minnesota
Country
United States
City
New Hyde Park
State/Province
New York
Country
United States
City
New York
State/Province
New York
Country
United States
City
Charlotte
State/Province
North Carolina
Country
United States
City
Columbus
State/Province
Ohio
Country
United States
City
Portland
State/Province
Oregon
Country
United States
City
Dallas
State/Province
Texas
Country
United States
City
Salt Lake City
State/Province
Utah
Country
United States
City
Seattle
State/Province
Washington
Country
United States
City
New Lambton Heights
State/Province
New South Wales
Country
Australia
City
Westmead
State/Province
New South Wales
Country
Australia
City
Parkville
State/Province
Victoria
Country
Australia
City
Subiaco
State/Province
Western Australia
Country
Australia
City
Calgary
State/Province
Alberta
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
29034009
Citation
Gore L, Triche TJ Jr, Farrar JE, Wai D, Legendre C, Gooden GC, Liang WS, Carpten J, Lee D, Alvaro F, Macy ME, Arndt C, Barnette P, Cooper T, Martin L, Narendran A, Pollard J, Meshinchi S, Boklan J, Arceci RJ, Salhia B. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. Clin Epigenetics. 2017 Oct 5;9:108. doi: 10.1186/s13148-017-0411-x. eCollection 2017.
Results Reference
derived
Learn more about this trial
Efficacy and Safety of Decitabine as Epigenetic Priming With Induction Chemotherapy in Pediatric Acute Myelogenous Leukemia (AML) Subjects
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