A Study of Decitabine (DACOGEN) in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 1-2 Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Phase1 and Phase 2: decitabine
* Drug: Phase 1: cytarabine
* Drug: Phase 2: cytarabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decitabine and cytarabine<br> | Drug: Phase1 and Phase 2: decitabine<br>* 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)<br>Drug: Phase 1: cytarabine<br>* 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<br>Drug: Phase 2: cytarabine<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (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. | 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 | 
| 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. | 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 | 
| 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. | Cycle 1 (28 days) Day 28 | 
| 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. | Cycle 2 (28 days) Day 28 | 
| 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. | End of study treatment (approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 and 2: Maximum Plasma Concentration (Cmax) of Decitabine | Cmax is the maximum observed plasma concentration of Decitabine. | 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 | 
| 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. | 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 | 
| 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. | From time of response to relapse, study completion/withdrawal, or death, whichever comes first, for up to approximately 3 years 10 months | 
| 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. | Up to approximately 3 years 10 months | 
| 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. | From enrollment to death or withdrawal, whichever comes first, for up to approximately 3 years 10 months | 
| 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. | From enrollment to progression/relapse, death, or withdrawal, whichever comes first, for up to approximately 3 years 10 months | 
| 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. | Approximately 3 years 10 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, Relapsed or refractory acute myeloid leukemia, Children, Decitabine, DACOGEN, Cytarabine