E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/refractory acute myeloid leukemia |
acute myeloide leukemie |
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E.1.1.1 | Medical condition in easily understood language |
cancer of the bone marrow |
beenmergkanker |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066638 |
E.1.2 | Term | Acute myeloid leukemia progression |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060558 |
E.1.2 | Term | Acute myeloid leukemia recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish the recommended dose of clofarabine in combination with cytarabine and liposomal daunorubicin (DaunoXome®) in children with relapsed/refractory AML.
Note: dosages of cytarabine and liposomal daunorubicin should be comparable to those used in the current Relapsed AML 2001/01 study (i.e. in the context of the FLAG/liposomal daunorubicin regimen). |
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E.2.2 | Secondary objectives of the trial |
- To determine the safety and tolerability of this combination
- To determine (preliminary) efficacy in terms of the hematological remission rate in these patients
- To describe the durability of response, including the number of patients that undergo stem-cell transplant after re-induction with this regimen
- To describe the pharmacokinetics of clofarabine in combination with cytarabine and liposomal daunorubicin
- To preliminary assess the CSF blast disappearance, and the CSF-levels of clofarabine
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 2nd relapse of AML
• refractory AML in 1st relapse (defined as ≥ 20% blasts in the bone marrow after the 1st course of standard re-induction therapy)
• 1st early relapse (relapse within one year from initial diagnosis) of AML
• ≤ 18 years old at initial diagnosis
• Lansky play score ≥ 60; or Karnofsky performance status ≥ 60
• Life expectancy ≥6 weeks
• Calculated creatinine clearance ≥ 90 ml/min/1.73m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k*Height (cm)/serum creatinine (mg/dl). k is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys.
• Liver function:
Serum bilirubin ≤1.5 × upper limit of normal (ULN)
Aspartate transaminase (AST)/alanine transaminase (ALT) ≤2.5 × ULN
Alkaline phosphatase ≤2.5 × ULN
• Able to comply with scheduled follow-up and with management of toxicity.
• For female patients with childbearing potential, a negative test for pregnancy is to be considered before entry on study
• Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
• Written informed consent from patients or from parents or legal guardians for minor patients, according to local law and regulations
Patient group specific for dose level 5:
•Newly diagnosed 1st relapse of AML: only patients with early relapses occurring within 1 year of initial diagnosis are eligible |
|
E.4 | Principal exclusion criteria |
• Isolated extramedullary relapse, including isolated CNS-relapse
• Symptomatic CNS leukemia in case of combined relapse
• Relapsed/refractory acute promyelocytic leukemia (APL)
• Relapsed/refractory myeloid leukemia of Down Syndrome (ML DS)
• Other serious illnesses or medical conditions
• Evidence of fungal infection by:
-Evidence of pulmonary infiltrates suggestive of a fungal infection at HR-CT (within 3 weeks prior to enrollment);
-A positive Aspergillus serum test (galactomannan), according to local laboratory practice (within 3 weeks prior to enrollment)
• Evidence of cardiac dysfunction (shortening fraction below 28%)
• Pregnant or lactating patients
Prior or current history:
• Use of any anticancer therapy within 2 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy (note: hematological toxicities do not need to be considered since the patient has overt leukemia).
• History of prior veno-occlusive disease (VOD)
• Hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin
Specific for dose level 5:
• Prior stem-cell transplant in CR1 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
To identify the recommended dose of the combination of clofarabine, cytarabine and liposomal daunorubicin in relapsed/refractory AML, hence to identify dose-limiting toxicities and the MTD. |
Het vaststellen van de aanbevolen dosering van clofarabine in combinatie met cytarabine en
liposomaal daunorubicine bij kinderen met recidief/refractaire AML, en het bestuderen van
de preliminiare effectiviteit van deze combinatie. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- safety and tolerability of this combination
- (preliminary) efficacy in terms of the hematological remission rate in these patients
- durability of response, including the number of patients that undergo stem-cell transplant after re-induction with this regimen
- pharmacokinetics of clofarabine in combination with cytarabine and liposomal daunorubicin
- assess the CSF blast disappearance, and the CSF-levels of clofarabine
|
- veiligheid en verdraagzaamheid van de combinatie therapie
- voorlopige effectiviteit gedefinieerd als hematologische remissie
- duur van de response inclusief aantal patiënten die stamceltransplantatie hebben ontvangen na behandeling
- farmacokinetiek van clofarabine in cominatie met cytarabine en liposomaal daunorubicine
- evalueren van het effect op blasten in het liquor en het gehalte van clofarabine in het liquor |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 |
Develop combination therapy |
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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.8.3 |
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 | 5 |
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
|
Last visit last subject |
Laatste patiënt, laatste visite |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |