Back to resultsA Study of Decitabine (DACOGEN) in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia
Primary Purpose
Acute Myeloid Leukemia
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Phase1 and Phase 2: decitabine
Phase 1: cytarabine
Phase 2: cytarabine
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Acute myeloid leukemia, Relapsed or refractory acute myeloid leukemia, Children, Decitabine, DACOGEN, Cytarabine
Eligibility Criteria
Inclusion Criteria:
- Histological diagnosis of acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification
- Diagnosis of AML which has relapsed or is refractory to standard of care and no curative therapy exists
- Karnofsky or Lansky score of at least 50
- Must be recovered from acute toxicity of any prior treatment
- Must have adequate organ function according to protocol-defined criteria
- Agrees to protocol-defined use of effective contraception
- Female participants of childbearing potential must have a negative serum or urine pregnancy test at Day 1 of Cycle 1
Exclusion Criteria:
- Prior treatment with decitabine or azacitidine
- Acute promyelocytic leukemia (M3 subtype in the French-American-British [FAB] classification system)
- CNS3 disease
- acute myeloid leukemia (AML) associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome or Diamond-Blackfan anemia, or bone marrow failure associated with inherited syndromes
- White blood cell count greater than 40x10^9 cells/liter(L)
- Known allergies, hypersensitivity, or intolerance to decitabine or cytarabine or their excipients
- Contraindications to the use of cytarabine per local prescribing information or prior adverse reactions to cytarabine which would prevent further use
- Currently enrolled in the treatment phase of an interventional investigational study
- Female who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug (however, the period after which it becomes safe to become pregnant after the last dose of treatment is not known)
- Male who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
- Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments
- Any social or medical condition that in the investigator's opinion renders the participant unfit for study participation
- History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease
- History of human immunodeficiency virus (HIV) antibody positive
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Decitabine and cytarabine
Arm Description
Outcomes
Primary Outcome Measures
Phase 1: Maximum Tolerated Dose (MTD) of Cytarabine
The maximum tolerated dose (MTD) for cytarabine was based on the number of participants experiencing a dose-limiting toxicity (DLT) by the end of Cycle 1. A non-hematological DLT was defined as: any Grade >=3 toxicity that persists for greater than (>) 5 days or any Grade 2 toxicity that persists for >7 days and that is intolerable to the participant. A hematological DLT was defined as Grade 4 neutropenia or thrombocytopenia due to a hypoplastic bone marrow at Day 42, in the absence of malignant infiltration. The nominal duration of each cycle was 28 days. However, participants who had not experienced bone marrow recovery at Day 28 were followed up to Day 42. Failure of marrow recovery (improvement to Grade 3) by Day 42 was considered a DLT. The maximum duration of Cycle 1 was therefore 42 days.
Phase 1 and 2: Total Clearance of Decitabine
Total clearance of drug after intravenously administration was calculated as: dose/area under the plasma concentration-time curve.
Phase 1 and 2: Volume of Distribution at Steady-State (Vss) of Decitabine
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 1 Day 28
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter, platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 2 Day 28
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter, platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Phase 2: Percentage of Participants Who Achieved CR or CRi at End of Study Treatment
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter, platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Secondary Outcome Measures
Phase 1 and 2: Maximum Plasma Concentration (Cmax) of Decitabine
Cmax is the maximum observed plasma concentration of Decitabine.
Phase 1 and 2: Area Under the Plasma Concentration-Time Curve (AUC) of Decitabine
AUC is the area under the plasma concentration-time curve of decitabine.
Phase 2: Duration of Response
Duration of response is defined as weeks from date of first response to date of first relapse or date of death.
Phase 2: Overall Response Rate
Overall response rate is defined as percentage of participants with complete remission (CR) +complete remission with incomplete blood count recovery (CRi)+partial remission (PR) per IWG Criteria. CRi: morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment. PR: all the same hematologic values of a CR, but with a decrease of >=50% of the percentage of blasts to 5% to 25% in the bone marrow aspirate.
Phase 1 and 2: Overall Survival (OS)
OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.
Phase 1 and 2: Event-Free Survival
Event free survival is defined as the time from first dose of study drug to relapse from CR, death, or second malignancy for participants who achieved CR. CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Phase 1 and 2: Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)
TEAEs are defined as adverse events with onset or worsening on or after date of first dose of study treatment. An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Full Information
NCT ID
NCT01853228
First Posted
May 10, 2013
Last Updated
March 18, 2019
Sponsor
Janssen Research & Development, LLC
1. Study Identification
Unique Protocol Identification Number
NCT01853228
Brief Title
A Study of Decitabine (DACOGEN) in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia
Official Title
Phase 1-2 Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Terminated
Why Stopped
EMA/PDCO acknowledged that available results from this study do not support further clinical studies in relapsed/refractory AML paediatric patients.
Study Start Date
October 22, 2013 (Actual)
Primary Completion Date
August 28, 2017 (Actual)
Study Completion Date
August 28, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Janssen Research & Development, LLC
4. Oversight
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to examine the safety and efficacy of decitabine in sequential administration with cytarabine in children with relapsed or refractory acute myeloid leukemia (AML).
Detailed Description
This is an open-label (identity of assigned study drug will be known) study to evaluate safety, efficacy, and pharmacokinetics (study of what the body does to a drug) of decitabine in sequential administration with cytarabine in children with relapsed or refractory AML. The study will determine the maximum tolerated dose of cytarabine that can be given following decitabine (Phase 1) and the response rate to this combination (Phase 2). Participants may enter a continuation phase of single agent-decitabine infusions for as long as such treatment would be considered beneficial. Serial pharmacokinetic samples will be collected and safety and efficacy will be monitored throughout the study.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
Acute myeloid leukemia, Relapsed or refractory acute myeloid leukemia, Children, Decitabine, DACOGEN, Cytarabine
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Enrollment
17 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Decitabine and cytarabine
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Phase1 and Phase 2: decitabine
Intervention Description
20 mg/m2 administered by intravenous infusion over 1 hour once daily for 5 consecutive days (Day 1 to Day 5 of 28-day cycle)
Intervention Type
Drug
Intervention Name(s)
Phase 1: cytarabine
Intervention Description
1 g/m2, 2 g/m2, and 1.5 g/m2 dose levels administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) for the determination of the maximum tolerated dose
Intervention Type
Drug
Intervention Name(s)
Phase 2: cytarabine
Intervention Description
Phase 1 maximum tolerated dose administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle)
Primary Outcome Measure Information:
Title
Phase 1: Maximum Tolerated Dose (MTD) of Cytarabine
Description
The maximum tolerated dose (MTD) for cytarabine was based on the number of participants experiencing a dose-limiting toxicity (DLT) by the end of Cycle 1. A non-hematological DLT was defined as: any Grade >=3 toxicity that persists for greater than (>) 5 days or any Grade 2 toxicity that persists for >7 days and that is intolerable to the participant. A hematological DLT was defined as Grade 4 neutropenia or thrombocytopenia due to a hypoplastic bone marrow at Day 42, in the absence of malignant infiltration. The nominal duration of each cycle was 28 days. However, participants who had not experienced bone marrow recovery at Day 28 were followed up to Day 42. Failure of marrow recovery (improvement to Grade 3) by Day 42 was considered a DLT. The maximum duration of Cycle 1 was therefore 42 days.
Time Frame
Cycle 1 (42 days)
Title
Phase 1 and 2: Total Clearance of Decitabine
Description
Total clearance of drug after intravenously administration was calculated as: dose/area under the plasma concentration-time curve.
Time Frame
Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 minute (min), 0.5 hour, 1 hour, and 2 hour after end of infusion
Title
Phase 1 and 2: Volume of Distribution at Steady-State (Vss) of Decitabine
Description
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
Time Frame
Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion
Title
Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 1 Day 28
Description
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter, platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Time Frame
Cycle 1 (28 days) Day 28
Title
Phase 2: Percentage of Participants Who Achieved CR or CRi at Cycle 2 Day 28
Description
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter, platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Time Frame
Cycle 2 (28 days) Day 28
Title
Phase 2: Percentage of Participants Who Achieved CR or CRi at End of Study Treatment
Description
Response rate (percentage of participants who achieved CR or CRi) was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) or complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter, platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Time Frame
End of study treatment (approximately 3 years)
Secondary Outcome Measure Information:
Title
Phase 1 and 2: Maximum Plasma Concentration (Cmax) of Decitabine
Description
Cmax is the maximum observed plasma concentration of Decitabine.
Time Frame
Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion
Title
Phase 1 and 2: Area Under the Plasma Concentration-Time Curve (AUC) of Decitabine
Description
AUC is the area under the plasma concentration-time curve of decitabine.
Time Frame
Cycle 1 (28 days) Day 5: pre-infusion, 0.5 hour during infusion, end of infusion and at 5 min, 0.5 hour, 1 hour, and 2 hour after end of infusion
Title
Phase 2: Duration of Response
Description
Duration of response is defined as weeks from date of first response to date of first relapse or date of death.
Time Frame
From time of response to relapse, study completion/withdrawal, or death, whichever comes first, for up to approximately 3 years 10 months
Title
Phase 2: Overall Response Rate
Description
Overall response rate is defined as percentage of participants with complete remission (CR) +complete remission with incomplete blood count recovery (CRi)+partial remission (PR) per IWG Criteria. CRi: morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment. PR: all the same hematologic values of a CR, but with a decrease of >=50% of the percentage of blasts to 5% to 25% in the bone marrow aspirate.
Time Frame
Up to approximately 3 years 10 months
Title
Phase 1 and 2: Overall Survival (OS)
Description
OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.
Time Frame
From enrollment to death or withdrawal, whichever comes first, for up to approximately 3 years 10 months
Title
Phase 1 and 2: Event-Free Survival
Description
Event free survival is defined as the time from first dose of study drug to relapse from CR, death, or second malignancy for participants who achieved CR. CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter platelet count of >100,000/microliter and participant must be independent of transfusions for a minimum of 1 week before each marrow assessment.
Time Frame
From enrollment to progression/relapse, death, or withdrawal, whichever comes first, for up to approximately 3 years 10 months
Title
Phase 1 and 2: Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)
Description
TEAEs are defined as adverse events with onset or worsening on or after date of first dose of study treatment. An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Time Frame
Approximately 3 years 10 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histological diagnosis of acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification
Diagnosis of AML which has relapsed or is refractory to standard of care and no curative therapy exists
Karnofsky or Lansky score of at least 50
Must be recovered from acute toxicity of any prior treatment
Must have adequate organ function according to protocol-defined criteria
Agrees to protocol-defined use of effective contraception
Female participants of childbearing potential must have a negative serum or urine pregnancy test at Day 1 of Cycle 1
Exclusion Criteria:
Prior treatment with decitabine or azacitidine
Acute promyelocytic leukemia (M3 subtype in the French-American-British [FAB] classification system)
CNS3 disease
acute myeloid leukemia (AML) associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome or Diamond-Blackfan anemia, or bone marrow failure associated with inherited syndromes
White blood cell count greater than 40x10^9 cells/liter(L)
Known allergies, hypersensitivity, or intolerance to decitabine or cytarabine or their excipients
Contraindications to the use of cytarabine per local prescribing information or prior adverse reactions to cytarabine which would prevent further use
Currently enrolled in the treatment phase of an interventional investigational study
Female who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug (however, the period after which it becomes safe to become pregnant after the last dose of treatment is not known)
Male who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments
Any social or medical condition that in the investigator's opinion renders the participant unfit for study participation
History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease
History of human immunodeficiency virus (HIV) antibody positive
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
City
Gent
Country
Belgium
City
Copenhagen Ø
Country
Denmark
City
Paris
Country
France
City
Toulouse Cedex 9
Country
France
City
Vandoeuvre-Lès-Nancy
Country
France
City
Essen
Country
Germany
City
Hamburg
Country
Germany
City
Hannover
Country
Germany
City
Stuttgart
Country
Germany
City
Rotterdam
Country
Netherlands
City
Barcelona
Country
Spain
City
Madrid
Country
Spain
City
Valencia
Country
Spain
City
Birmingham
Country
United Kingdom
City
Cambridge
Country
United Kingdom
City
Glasgow
Country
United Kingdom
City
Sutton
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
A Study of Decitabine (DACOGEN) in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia
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