E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or Refractory Acute Myeloid Leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of White Blood Cells |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of the Phase 1 portion of Study DACOGENAML2004 are:
•to determine the maximum tolerable dose (MTD) of cytarabine (up to 2 g/m2 per day x 5) that can be administered on Days 8-12 following treatment with DACOGEN 20 mg/m2 per day on Days 1-5 of a 28-day cycle.
•to determine PK parameters including maximum plasma concentration (Cmax), Area under the concentration x time curve (AUC), time to maximum plasma concentration (tmax), and clearance (Cl) of decitabine on Day 5 of Cycle 1.
The primary objective of the Phase 2 portion of Study DACOGENAML2004 is to determine the response rate (CR + CRi) in children with relapsed or refractory AML when treated with DACOGEN 20 mg/m2 per day on Days 1-5 followed by cytarabine at the determined MTD on Days 8-12 for up to 4 cycles of treatment. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the safety profile of DACOGEN 20 mg/m2 per day administered on Days 1 to 5 followed by cytarabine on Days 8 to 12 for up to 4 cycles of therapy and to describe the duration of CR + CRi and evaluate the overall response (CR + CRi + PR) to treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal exclusion criteria |
- Prior treatment with decitabine or azacitidine
- Acute promyelocytic leukemia (M3 subtype in the French-American-British [FAB] classification system)
- CNS3 Disease
- 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 40 x 10^9 cells/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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1:
For the Phase 1 portion of the study the primary endpoint will be DLT in the determination of the MTD (up to 2 g/m2 per day) of cytarabine given on Days 8 to 12 following the administration of DACOGEN at 20 mg/m2 on Days 1 to 5. DLTs are defined as the following
• Hematological DLT will be defined as failure to recover to an absolute neutrophil count (ANC) of 0.5 x 109/L (common terminology criteria for adverse events [CTCAE] Grade
3) and non-transfusion dependent platelet count of 25 x 109/L (CTCAE Grade 3) due to documented bone marrow aplasia/hypoplasia (malignant infiltration or other cause excluded), by Day 42. Bone marrow aplasia/hypoplasia is defined as overall marrow cellularity less than 25%.
•Non-hematological DLT is defined as: any Grade ≥3 toxicity possibly, probably or definitely related to study drug that persists for >5 days; any Grade 2 toxicity that persists for >7 days and that is intolerable to the patient.
Phase 2:
In the Phase 2 portion of this study the primary end point will be the CR +CRi rate as determined using IWG criteria. The response status of each patient will be determined prior to each cycle of DACOGEN + cytarabine after the first cycle. The best response up to 4 cycles of DACOGEN + cytarabine for each subject will be used to determine the rate of CR + CRi.
Please refer to Page 40 & 41 of Protocol. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 4 cycles of treatment. |
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E.5.2 | Secondary end point(s) |
• Safety profile of DACOGEN 20 mg/m2 per day on Days 1-5 followed by cytarabine Days 8-12 for up to 4 cycles of therapy.
• Duration of CR + CRi
• Overall response (CR + CRi + PR)
• Event-free survival (EFS), defined as the time from first dose of study drug to relapse from CR, death, or second malignancy for subjects who achieve CR; subjects who do not achieve CR will be considered to have an event on the day of the first dose of study drug. Other alternative EFS definitions may be considered.
•Overall survival
•To determine the PK profile of DACOGEN in children with AML
Other Secondary Endpoints:
•To explore pharmacodynamic effects of DACOGEN with respect to DNA
hypomethylation status and gene expression
•To explore predictive markers for response to DACOGEN.
• Levels of DACOGEN in the CSF if samples are collected as part of other required medical care. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time of progression/relapse, withdrawal, or death, for up to 3 years after last participant enrolment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase 1-2 Safety and Efficacy Study |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |