E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Meyloid Leukemia and High Risk Myelodysplastic syndromes |
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E.1.1.1 | Medical condition in easily understood language |
Acute Meyloid Leukemia and High Risk Myelodysplastic syndromes |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
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 | 19.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To assess in a randomized comparison the effect of ibrutinib added to 10-day decitabine treatment on the cumulative CR/CRi rate after 3 cycles. |
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E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of Ibrutinib added to 10-day decitabine treatment for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards the selected dose level of the study. - To determine the efficacy profile: response rate (CR, CRi, PR), event free survival (EFS) and overall survival (OS) associated with the two therapy regimens. - To determine the impact of 3 days ibrutinib monotherapy (pretreatment) on WBC count, circulating blast count, and translational endpoints. - To measure MRD by immunophenotyping and PCR in relation to clinical response parameters. - To identify potential biomarkers predictive of response, EFS and OS by exploratory analysis (gene mutations, kinome, methylome). - To evaluate the prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery and activities of daily living (ADL) on treatment outcome. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Patients with: -a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy-related AML, or -acute leukemia's of ambiguous lineage according to WHO 2008 or -a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R > 4.5 • Patients 66 years and older. • Patients NOT eligible for standard chemotherapy, defined as HCT-CI ≥ 3. or Patient NOT eligible for standard chemotherapy for other reasons (wish of patient). • WBC ≤ 30 x109/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment) • Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: - Serum creatinine ≤ 2.5 mg/dL (≤ 221.7 μmol/L), unless considered AML-related - Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert's syndrome - Alanine transaminase (ALT) ≤ 2.5 x ULN, unless considered AMLrelated • WHO performance status 0, 1 or 2 (see Appendix D). • Male patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment. • Written informed consent. • Patient is capable of giving informed consent. |
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E.4 | Principal exclusion criteria |
• Acute promyelocytic leukemia. • Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period ( ≤ 5 days) with Hydroxyurea is allowed • Diagnosis of any previous or concomitant malignancy is an exclusion criterion: except when the patient completed successfully treatment (chemotherapy and/or surgery and/or radiotherapy) with curative intent for this malignancy at least 6 months prior to randomization. • Blast crisis of chronic myeloid leukemia. • Inability to discontinue anti-coagulants • Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.) • Cardiac dysfunction as defined by: - Myocardial infarction within the last 3 months of study entry, or - Reduced left ventricular function with an ejection fraction < 40% as measured by MUGA scan or echocardiogram or - Unstable angina or - New York Heart Association (NYHA) grade IV congestive heart failure or - Unstable cardiac arrhythmias • Patient has had major surgery within the past 4 weeks or a major wound that has not fully healed. • Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization. • History of stroke or intracranial hemorrhage within 6 months prior to randomization. • Patient has a history of human immunodeficiency virus (HIV) or active XML File Identifier: SXmsnkJS62Kp3K7o0KPX0ptFWus= Page 16/31 infection with Hepatitis C or B. • Patient has symptomatic central nervous system (CNS) leukemia (NO routinely lumbar puncture required to investigate CNS involvement) • Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance. • Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study. • Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent. • Current concomitant chemotherapy, radiation therapy, or immunotherapy; other than hydroxyurea • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cumulative CR/CRi rate after 3 cycles |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
These endpoints will be evaluated when relevant data for all patients are available |
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E.5.2 | Secondary end point(s) |
• Safety and tolerability (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia). • Efficacy profile (response rate (CR, CRi, PR), event free survival (EFS) and overall survival (OS)). • Days of staying in hospital and transfusion needs. • Prognostic value of MRD (by flowcytometry or PCR). • Gene mutations predictive of response, EFS and OS by exploratory analysis. • Prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL) on treatment outcome. Translational endpoints: • To determine the impact of 3 days ibrutinib monotherapy (pretreatment) on WBC count, circulating blast count, and kinome (using mass cytometry kinome). • To identify potential biomarkers (using mass cytometry kinome; methylome) in bone marrow and peripheral blood which are of prognostic importance in both arms, and whether they are of predictive importance for response. • To identify methylome profiles in CD34+ bone marrow blasts and stroma cells which are of prognostic importance in both arms, and whether they are of predictive importance for response. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These endpoints will be evaluated when relevant data for all patients are available |
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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) | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Decitabine treatment without inbrutinib (standard treatment) |
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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
| 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 | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Germany |
Lithuania |
Netherlands |
Norway |
Sweden |
Switzerland |
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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 | 7 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |