E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly Diagnosed Core-Binding Factor
Acute Myeloid Leukemia (CBF-AML)
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E.1.1.1 | Medical condition in easily understood language |
Newly Diagnosed Core-Binding Factor
Acute Myeloid Leukemia (CBF-AML)
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 assess event-free survival (EFS) after intensive induction (daunorubicin and cytarabine) and consolidation (high-dose cytarabine) chemotherapy with or without dasatinib in patients with CBF-AML |
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E.2.2 | Secondary objectives of the trial |
• To assess the interaction between type of CBF-AML [t(8;21) versus inv(16)] and randomization accordingly on all survival endpoints
• To assess cumulative incidence of relapse (CIR) and death (CID)
• To assess relapse-free (RFS) and overall survival (OS)
• To assess outcome according to KIT mutational status
• To assess pharmacodynamic inhibition of KIT
• To assess toxicity
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion transcript resulting from t(8;21)(q22;q22) (or a variant form) or of CBFB-MYH11 fusion transcript resulting from inv(16)(p13.1q22)/t(16;16)(p13.1;q22) as assessed in one of the central AMLSG reference la-boratories (Ulm, Hannover)
• Age ≥ 18; there is no upper age limit
• No prior chemotherapy for leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase
• • Non-pregnant and non-nursing. Due to the unknown teratogenic potential of dasatinib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL with-in 72 hours prior to registration. Women of child-bearing potential must either commit to contin-ued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner’s vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least four weeks before she begins dasatinib therapy until at least 3 months after last dasatinib administration. “Women of childbearing potential” is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preced-ing 24 consecutive months.
• Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking dasatinib and for 3 months after therapy is stopped, even if they have undergone a successful vasectomy.
• Signed written informed consent.
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E.4 | Principal exclusion criteria |
• Performance status WHO >2
• Pulmonary edema and/or pleural/pericardial effusion within 14 days of day 1. If edema/effusion resolves to CTC Grade ≤1, patients can be treated with dasatinib.
• Patients with ejection fraction <50% by echocardiography or MUGA within 14 days of day 1
• Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or AP >2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
• Uncontrolled infection
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Pa-tients are not considered to have a “currently active” malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
• Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
• Known positive for HIV, active HBV, HCV, or Hepatitis A infection
• Bleeding disorder independent of leukemia
• No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.
• No consent for biobanking.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Event-free survival (EFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint of the study, EFS rate, will be evaluated
after 4 years |
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E.5.2 | Secondary end point(s) |
• Cumulative incidence of relapse (CIR) and death CID)
• Relapse-free (RFS) and overall survival (OS)
• Outcome of patients according to KIT mutational status
• Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA)
Safety endpoints:
• Rate of early (ED)/ hypoplastic (HD) deaths
• Type, frequency, severity (graded using the National Cancer Institute Common Terminology Crite-ria for Adverse Events [NCI CTCAE] version 4.03), timing and relatedness of non-hematologic toxicity observed during different treatment cycles.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be analyzed at the same time point as the
primary endpoint in an exploratory manner. |
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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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 50 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 | Yes |
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 | 9 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 7 |