E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory pediatric acute myeloid leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Returning or treatment-resistant acute cancer of the myeloid line of blood cells in children |
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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 | 21.0 |
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 | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10081514 |
E.1.2 | Term | Acute myeloid leukemia refractory |
E.1.2 | System Organ Class | 100000004864 |
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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 phase 2 dose of Vyxeos®/CPX-351 in combination with clofarabine in children with relapsed/refractory AML |
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E.2.2 | Secondary objectives of the trial |
• To determine the safety and tolerability of this combination. • To determine the (preliminary) efficacy in terms of the hematological remission rate in these patients as determined by morphology with flow cytometric confirmation. • To describe the durability of response, including the number of patients that undergo stem- cell transplant after re-induction with this regimen
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age ≥1 year and <21 years • Any ≥ 2nd relapse of AML • Refractory AML (defined as ≥ 20% blasts in the bone marrow after standard induction therapy) • Early 1st relapse (defined as relapse within one year from initial diagnosis) of AML
• Complete initial work-up within 7 days prior to study entry, including bone-marrow aspiration, lumbar puncture (without intrathecal therapy) • Lansky play score ≥ 60 for patients <16 years of age; or Karnofsky performance status ≥ 60 for patients ≥ 16 years of age (see Appendix I for Performance scales). • Life expectancy > 6 weeks • The patient must have a calculated GFR ≥ 70mL/min/1.73 m2. • Liver function: total serum bilirubin ≤ 3 mg/dl or 50 µmol/L and aspartate transaminase (AST) and alanine transaminase (ALT) ≤200 U/L • Adequate cardiac function (defined as shortening fraction ≥28% or ejection fraction ≥50%)
• For female patients with childbearing potential, a negative test for pregnancy is to be performed before entry on study. • Male and female patients must use a highly effective contraceptive method during the study and for a minimum of 6 months after study treatment. • Female patients may not breastfeed during the study and for a minimum of 3 months after study treatment. • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule is required; those conditions should be discussed with the patient before registration in the trial. • Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.
Concomitant treatments: • Concomitant administration of any other experimental drug under investigation, or concurrent treatment with any other anti-cancer therapy other than specified in the protocol is not allowed. • GCSF will not be used for priming and no routine GCSF support is allowed during the 1st course, except for life-threatening infections.
Additional criteria: • At least 6 patients must be enrolled with an M3 or a WBC count >10x109/L with blasts |
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E.4 | Principal exclusion criteria |
• Evidence of a currently uncontrolled bacterial, viral or parasitic infection • Evidence of a fungal infection, defined as either: - Pulmonary infiltrates suggestive of a fungal infection at HR-CT (within 3 weeks prior to enrollment) - Positive Aspergillus serum test (galactomannan), according to local laboratory practice (within 3 weeks prior to enrollment) • Evidence of isolated extramedullary relapse, including isolated CNS-relapse • Evidence of CNS3 or symptomatic CNS leukemia • Down Syndrome • Evidence of relapsed/refractory acute promyelocytic leukemia (APL) • 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) • Known hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin |
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose-limiting toxicities (DLTs) during the first course of therapy.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLT evaluation after course 1
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E.5.2 | Secondary end point(s) |
• safety and tolerability of combination clofarabine with Vyxeos/CPX-351 • hematological remission rate • overall response rate (ORR) • number of patients that undergo HSCT
Exploratory endpoints: • serum and intracellular pharmacokinetics parameters of Vyxeos/CPX-351 • relationship ORR and intracellular Ara-CTP accumulation • correlation duration of response and MRD |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• After course 1, after each subsequent course of therapy, and at 4wks, 10wks, 3months, 6 months and 9 months, 12 months, 18 months and 24 months of FUP • end of study (EOS) |
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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 | 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 |
First administration of combination clofarabine with Vyxeos/CPX-351 in pediatric population |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 | 3 |
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 |