E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adults with acute myelogenous leukaemia (AML) in first complete remission (CR1) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000881 |
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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 |
To target the upper range of the busulfan therapeutic window (AUC from 4400 to 6000 μM.min) from a once daily myeloablative regimen in adult patients with AML in CR1 receiving the IV BuCy2 regimen. A daily PK guided dose adjustment from Day-7 (Dose 2) to Day-5 (Dose 4) of Bu treatment is expected to enable the same targeting performance (≥ 70 to 80% of patients within the therapeutic window) as that achieved for the larger therapeutic window (i.e.: 3600 6000 μM.min) without dose adjustment. |
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E.2.2 | Secondary objectives of the trial |
Pharmacokinetic objectives -To confirm the narrow intra-patient variability of once daily busulfan pharmacokinetics already demonstrated on a q.i.d. dosing regimen. -To explore the relationships between the pharmacokinetics and the safety and/or efficacy parameters. Clinical objectives -To determine the safety profile by assessing the toxicity of IV Bu when used in once-daily infusion in combination with cyclophosphamide. -To determine the efficacy profile of the once daily IV BuCy2 by determining the kinetic of myeloablation, the kinetic of neutrophils and platelets engraftment and chimerism. -To determine relapse rate and overall survival at 1 and 2 years. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult patients with acute myelogenous leukaemia are eligible to enter the study if: They are in first complete remission, CR1 (CR is defined as percentage of leukemic blasts < o = 5% in BM, recovery of normal neutrophils and normal platelets, no extramedullary disease). They are planned to receive allogeneic HSCT according to center criteria from either HLA matched sibling donor or unrelated donor with HLA compatibility ≥ 9/10 on HLA A, B, C, DRB1, DQB1. Age ≥ 18 years old and ≤ 55 years. Karnofsky s performance status > o = 70%. Comorbidity score: Sorror HCT-CI < 3 (see appendix III). Life s expectancy > 3 months. Adequate organ system function: Cardiac: no uncontrolled arrhythmias (untreated atrial fibrillation or flutter or ventricular arrhythmia) or symptomatic cardiac diseases (coronary artery disease, congestive heart failure or myocardial infarction). Left Ventricular Ejection Fraction (LVEF) by echocardiogram must be > o = 50% or shortening fraction > o = 30%. Pulmonary: no symptomatic pulmonary disease. Adequate pulmonary function tests : Forced Expiratory Volume in 1 sec (FEV1) / Forced Vital Capacity (FVC) ratio > o = 60 % of expected (corrected for haemoglobin), or diffusing capacity of lung for carbon monoxide (DLCO) > o = 50% of predicted. Hepatic function: transaminases (ALT, AST) each < o = 2 upper normal limit (UNL). Total bilirubin < o = 1.5 x UNL. Renal function: serum creatine < o = 1.5 x UNL or creatinine clearance measured by EDTA or calculated > o = 75 % of normal. Viral serology: negative serology for Hepatitis B (Ag), C and HIV. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial. The patient must give written (personally signed and dated) informed consent before completing any study-related procedure which means assessment or evaluation that would not form part of the normal medical care of the patient. Central venous access secured through an indwelling catheter. Women of childbearing potential must be using a medically accepted method of contraception (i.e. oral contraceptives, intrauterine devices) to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and for up to 6 months after the last dose of study treatment in such a manner that the risk of pregnancy is minimised. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study treatment. Fertile men must be using an effective method of birth control if their partners are women of childbearing potential. |
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E.4 | Principal exclusion criteria |
Patient with at least one of the following criteria will not be included: Serious concomitant illness or medical condition: clinical or microbiological evidence of infection. Chronic or active hepatitis or cirrhosis. Unstable concomitant disease. Second transplant requiring dose modification of busulfan. Prior history of hepatic disease. Patient being treated with voriconazole. Patient with hepatic iron overload. Known hypersensitivity to drugs of similar chemical structures to study medication. A female is not eligible to enter the study if she is pregnant or lactating or has a positive pregnancy test at inclusion. Male or female of childbearing potential who is unwilling or unable to use a medically accepted method to avoid pregnancy during the 2 months preceding the start of study treatment, throughout the study period and at least 6 months following the last dose of study treatment. Patient not available for follow-up assessments. Treatment with any investigational drug within the 30 days prior to registration, and up to thirty days after the study treatment administration. Clinically relevant cardiovascular, neurological or other systemic disease making implementation of the protocol difficult. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is to target the upper range of Busulfan therapeutic window (AUC from 4400 to 6000microM.min) from once daily mieloablative regimen in adult patients with AML in CR1 receiving the iv BuCy2 regimen. |
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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 | 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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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 | No |
E.8.1.2 | Open | No |
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.8.3 |
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 | 2 |
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 | Information not present in EudraCT |
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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Lo studio terminera` alla fine del periodo di follow-up dell`ultimo paziente arruolato (ultimo follow-up tra il giorno+366 e il giorno+730 dal trapianto) |
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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 | 1 |
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 | 1 |
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 |