Efficacy and Safety of Decitabine as Epigenetic Priming With Induction Chemotherapy in Pediatric Acute Myelogenous Leukemia (AML) Subjects

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

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.

Study Overview

• Status: Terminated
• Conditions: Pediatric Acute Myelogenous Leukemia (AML)
• Intervention / Treatment: Drug: Decitabine; Drug: Decitabine

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • New Lambton Heights, New South Wales, Australia
    • Westmead, New South Wales, Australia
  • Victoria
    • Parkville, Victoria, Australia
  • Western Australia
    • Subiaco, Western Australia, Australia
• Canada
  • Alberta
    • Calgary, Alberta, Canada
• United States
  • Arizona
    • Phoenix, Arizona, United States
  • California
    • Madera, California, United States
  • Colorado
    • Aurora, Colorado, United States
  • Florida
    • Miami, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Boston, Massachusetts, United States
    • Worcester, Massachusetts, United States
  • Minnesota
    • Rochester, Minnesota, United States
  • New York
    • New Hyde Park, New York, United States
    • New York, New York, United States
  • North Carolina
    • Charlotte, North Carolina, United States
  • Ohio
    • Columbus, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Texas
    • Dallas, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Washington
    • Seattle, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Males and females, age 1 to 16 years, inclusive
2. 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)
3. 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)
4. Diagnosis of acute myelogenous leukemia ( AML) (bone marrow or peripheral blood blasts greater than or equal to 20%)
5. Adequate cardiac function as defined by an echocardiogram or multiple gated acquisition (MUGA) scan demonstrating an ejection fraction greater than 50%
6. Are willing and able to comply with all aspects of the protocol
7. Provide written informed consent from subject's guardian or legally authorized representative and child assent (if applicable).

Exclusion Criteria

1. Females who are pregnant (positive B-hCG test) or lactating
2. History of chronic myelogenous leukemia (CML) [t(9;22)]
3. Acute promyelocytic leukemia (M3 subtype in French-American-British [FAB] classification)
4. Known central nervous system (CNS) leukemia
5. AML associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome, or Diamond-Blackfan anemia
6. White blood cell (WBC) count greater than 100,000/mm3
7. Serum creatinine greater than 2.5 mg/dL
8. Alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN) and/or total bilirubin greater than 3 x ULN
9. Prior chemotherapy (other than hydroxyurea) or radiation therapy for AML
10. Known to be human immunodeficiency virus (HIV) positive
11. 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
12. The Investigator believes the subject to be medically unfit to receive the study drug or unsuitable for any other reason
13. Subject with hypersensitivity to decitabine, daunorubicin, cytarabine, or etoposide
14. Has participated in a drug trial in the last 4 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A	Drug: Decitabine; 5 day priming with decitabine followed by Induction Chemotherapy of ADE (daunorubicin, cytarabine, etoposide).; Drug: Decitabine; Induction Chemotherapy of ADE (daunorubicin, cytarabine, etoposide) only
Experimental: Arm B	Drug: Decitabine; 5 day priming with decitabine followed by Induction Chemotherapy of ADE (daunorubicin, cytarabine, etoposide).; Drug: Decitabine; Induction Chemotherapy of ADE (daunorubicin, cytarabine, etoposide) only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 50

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Baseline up to completion of induction therapy (Day 15)
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.	Baseline to recurrence of Leukemia or Death (up to 2 years 5 months)
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.	Baseline to Date of Death (up to 2 years 5 months)
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.	Baseline and Day 50
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.	Randomization to Day 50
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.	Baseline up to Day 50
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.	Baseline up to Day 38

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Investigators: Study Director: Eisai Medical Services, Eisai Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2011
• Primary Completion (Actual): July 19, 2013
• Study Completion (Actual): July 19, 2013

Study Registration Dates

• First Submitted: August 5, 2010
• First Submitted That Met QC Criteria: August 5, 2010
• First Posted (Estimate): August 9, 2010

Study Record Updates

• Last Update Posted (Actual): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 24, 2022
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: E7373-G000-202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No