Acute Meyloid Leukemia and High Risk Myelodysplastic syndromes MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
HOVON Foundation
Eligibility
Sex/Gender
All
Inclusion criteria
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 AML-related • 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 170
Exclusion criteria
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - 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.;Secondary Objective: - 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 (pre-treatment) 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. ;Primary end point(s): • Cumulative CR/CRi rate after 3 cycles;Timepoint(s) of evaluation of this end point: These endpoints will be evaluated when relevant data for all patients are available | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 (pre-treatment) 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. ;Timepoint(s) of evaluation of this end point: These endpoints will be evaluated when relevant data for all patients are available | — |
Countries
Belgium, Germany, Lithuania, Netherlands, Norway, Sweden, Switzerland
Contacts
Public ContactHOVON Data Center
HOVON
Outcome results
None listed