E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
adult patients with AML and NPM1 mutation |
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E.1.1.1 | Medical condition in easily understood language |
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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 |
Primary Efficacy Objective
• Evaluation of efficacy based on overall survival (OS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1) |
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E.2.2 | Secondary objectives of the trial |
Secondary Efficacy Objectives
• Evaluation of efficacy based on complete remission (CR) rates, event-free survival, cumulative incidences of relapse (CIR) and death (CID) in CR
Safety and QoL Objectives
• Evaluation of safety based on toxicity induced by gemtuzumab ozogamicin (GO)
• Evaluation of safety based on duration of neutropenia and leukopenia after consolidation therapy, incidence of infection, duration of hospitalization
• Assessment of quality of live
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Both female and male patients meeting the mentioned inclusion and exclusion criteria will be included in this clinical trial, because the risk to get AML does not depend on a patient’s gender. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study
• Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification
• Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories.
• Age ≥ 18 years. There is no upper age limit.
• No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 5 days during the diagnostic screening phase.
• Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration.
• Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and within one year after the last dose of chemotherapy. Women of child-bearing potential must either commit to continued 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). ). “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 preceding 24 consecutive months.
Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy.
• Signed written informed consent
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E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a patient from study enrollment:
• AML with other recurrent genetic changes (according to WHO 2008):
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
AML with t(15;17)(q22;q12); PML-RARA (or other translocations involving RARA)
AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL)
AML with t(6;9)(p23;q34); DEK-NUP214
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
• Performance status WHO >2
• Patients with ejection fraction < 50% by MUGA or ECHO scan within 14 days of day 1
• Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or ALP >2.5x upper normal serum level, not attributable to AML; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
• Uncontrolled infection
• Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients 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.
• Known positive for HIV,active HBV, HCV, or Hepatitis A infection
• Bleeding disorder independent of leukemia
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients 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.
• No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
Overall Survival (OS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Rates of complete remission after induction therapy (CR)
• Cumulative incidences of relapse (CIR) and death in CR (CID)
• Event free survival
• Days in hospital during each cycle and during the whole intervention
Safety Endpoints
• Rate of ED/HD
• Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0), timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during different treatment cycles
• Incidence of infection after induction and consolidation therapy
• Duration of neutropenia and thrombocytopenia after induction and consolidation therapy
QoL Endpoint
• Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics according to Messerer et al
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continuous assessment for safety is performed.
QOL + secondary Efficacy endpoint assessments are performed at the end of study. |
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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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indiv:Pat. can withdraw IC at any time;a physician can withdraw a patient from the study due to: conc. disease, unaccep. AE &non-compliance; In case of pregnancy during the study,a patient is withdrawn immediately from the study. Single inv. site: study is terminated prematurely in a single center in case of detected fraud.Whole study: is terminated prematurely in case of fulfilled safety endpoints &the external review board as well as the internal review board agrees to terminate the study |
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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 | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |