previously untreated acute myeloid leukemia (AML) or high risk myelodysplasie (MDS) MedDRA version: 18.1 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864 MedDRA version: 18.1 Level: LLT Classification code 10028532 Term: Myelodysplasia System Organ Class: 100000004864
Conditions
Sponsors
HOVON Foundation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Age 18-65 years, inclusive - 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 score > 4.5 - WHO performance status 0, 1 or 2 - Sampled bone marrow and/ blood cells for centralized molecular analysis and MRD evaluation, unless in case of a dry marrow tap with no possibility to collect marrow cells. In cases of marrow tap failure only blood cells will be sampled. - Adequate renal and hepatic functions as indicated by the following laboratory values: - Serum creatinine =1.0 mg/dL (=88.7 µmol/L); if serum creatinine >1.0 mg/dL (>88.7 µmol/L), then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m^2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m^2) = 186 x (Serum Creatinine in mg/dL)^-1.154 x (age in years)^-0.203 x (0.742 if patient is female) x (1.212 if patient is black) NOTE: if serum creatinine is measured in umol/L, recalculate it in mg/dL according to the equation: 1 mg/dL = 88.7 umol/L) and use above mentioned formula. - Serum bilirubin =2.5 x upper limit of normal (ULN) - Aspartate transaminase (AST) = 2.5 x ULN - Alanine transaminase (ALT) = 2.5 x ULN - Alkaline phosphatase = 2.5 x ULN - Written informed consent - Ability to adhere to the lenalidomide Pregnancy Prevention Program Part B: - CR or CRi - Absolute neutrophil count (ANC) = 1.5 x 10^9/L - Platelet count = 75 x 10^9/L - Serum creatinine clearance = 30 ml/min or estimated glomerular filtration rate (GFR) > 60mL/min/1.73 m^2 - Total bilirubin = 2.5 x ULN - AST = 2.5 x ULN - ALT = 2.5 x ULN Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 871 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 56
Exclusion criteria
Exclusion criteria: - Previous therapy with lenalidomide - Acute promyelocytic leukemia - Myeloproliferative neoplasia - Previous treatment for AML or high risk MDS (IPSS-R > 4.5), except hydroxyurea - Concurrent history of active malignancy in two past years prior to diagnosis except for: - basal and squamous cell carcinoma of the skin - in situ carcinoma of the cervix - Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera) - Cardiac dysfunction as defined by: - Myocardial infarction within the last 6 months of study entry, or - Reduced left ventricular function with an ejection fraction < 50% as measured by MUG scan or echocardiogram or - Unstable angina, or - Unstable cardiac arrhythmias - Hypersensitivity to the active substance or to any of the excipients of the drug product - Pregnant or lactating females - Unwilling or not capable to use effective means of birth control - Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule Part B: - Severe cardiac dysfunction (NYHA classification II-IV, see appendix G) - Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix F) - Severe neurological or psychiatric disease - Serious active infections - Previous serious toxicities related to the use of lenalidomide - CMV reactivation, which is not responsive to first line valganciclovir
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A run-in: - To select in a randomized approach the feasible dose level of lenalidomide when given orally at three variable dose levels (at 20 mg/day 1-21; 15 mg/day 1-21 or at 10 mg/day 1-21 ) in combination with standard induction cycles I and II in patients with AML/ MDS with IPSS-R> 4.5 Part A: - To evaluate the effect of lenalidomide on EFS at the selected (during Part A run-in) feasible dose level when combined with remission induction chemotherapy cycles I and II in a randomized comparison to remission induction cycles I and II without addition of lenalidomide in a phase III study Part B: - To evaluate the effect of 6 cycles of maintenance therapy with lenalidomide treatment (10 mg/day for 21 days followed by 14 days rest) after post remission chemotherapy cycle III or autoHSCT versus observation only ;Secondary Objective: Part A : - To investigate the efficacy of lenalidomide in combination with remission induction chemotherapy cycles I and II (compared to the same treatment without lenalidomide) in all patients with regard to complete remission rate (CR/CRi), DFS, CIR and OS - To investigate the clinical efficacy of lenalidomide in combination with cycles I and II in molecularly and cytogenetically distinguishable subsets with regard to CR/CRi, DFS, CIR and OS - To evaluate the treatment effects according to MRD measurements following therapy by standardized sampling of marrow/blood following remission induction treatment Part B: - To investigate the clinical efficacy of lenalidomide with regard to DFS and OS measured from 2nd randomization - To assess post remission and post transplant adverse events and need for transfusions when lenalidomide is applied after post remission chemotherapy/autoHSCT see protocol for full seconday objectives (1700 characters);Primary end point(s): Primary endpoint Part A-run-in: Lenalidomide dose level selection - DLT and duration of myelosuppression of induction treatment with or without lenalidomid | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints Part A Run-in : Lenalidomide dose level selection - Response (CR and CRi) after induction therapy cycles I and II Secondary endpoints Part A: Induction- Efficacy - EFS in the distinct prognostic subsets (AML good-risk vs. AML intermediate-risk vs. AML poor-risk vs. AML-very poor-risk) and cytogenetically and molecularly defined subgroups of AML - Response (CR and CRi) after induction therapy cycles I and II - Disease-free survival (DFS, measured from time of CR/CRi to day of relapse or death from any cause, whichever occurs first) - OS measured from the time of registration - Outcome of induction treatments in relation to MRD measurements - Evaluation of molecular prognostic markers and gene expression profiles for and overexpression of defined genes (e.g. EVI1, cereblon) for outcome in relation to induction and post induction treatments - Toxicities - Evaluation of MRD after induction and post-induction treatments - Time to hematopoietic recovery (ANC 0.5 and 1.0 x 10^9/L; platelets 50 and 100 x 10^9/L) after each treatment cycle - Number of platelet transfusions and last day of platelet transfusion after each cycle - Impact of the use of lenalidomide on the effectiveness of stem cell mobilization Secondary endpoints Part B: Maintenance - efficacy - OS and DFS measured from 2nd randomization, and also in the distinct prognostic subsets (AML good-risk vs. AML intermediate-risk vs. AML poor-risk vs. AML very poor-risk) and cytogenetically and molecularly defined subgroups of AML - Toxicities - Number of platelet transfusions and last day of platelet transfusion after each cycle - Number of RBC transfusions in relation to maintenance or no maintenance treatment - Evaluation of MRD after 2nd randomization - Time to hematopoietic recovery (ANC 0.5 and 1.0x10^9/L; platelets 50 and 100x10^9/L) after each treatment cycle ;Timepoint(s) of evaluation of this end point: At the end of the trial. After last pat | — |
Countries
Austria, Belgium, Estonia, Finland, Germany, Lithuania, Luxembourg, Netherlands, Norway, Sweden, Switzerland
Contacts
Public ContactHDC
HOVON Data Center
Outcome results
None listed