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 o 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 o acute leukemia’s of ambiguous lineage according to WHO 2008 or o 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 at diagnosis 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: o 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. o Serum bilirubin =2.5 x upper limit of normal (ULN) o Aspartate transaminase (AST) = 2.5 x ULN o Alanine transaminase (ALT) = 2.5 x ULN o 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 109/L • Platelet count = 75 x 109/L • Serum creatinine clearance = 30 ml/min or estimated glomerular filtration rate (GFR) > 60 ml/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: • 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: o basal and squamous cell carcinoma of the skin o 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: o Myocardial infarction within the last 6 months of study entry, or o Reduced left ventricular function with an ejection fraction < 50% as measured by MUG scan or echocardiogram or o Unstable angina, or o 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 (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 lenalidomide for each o | — |
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 109/L; platelets 50 and 100 x 109/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 1.0x109/L; platelets 50 and 100x109/L) after each treatment cycle ;Timepoint(s) of evaluation of this end point: At the end of the trial. After last patient | — |
Countries
Belgium, Estonia, Finland, Germany, Lithuania, Luxembourg, Netherlands, Norway, Sweden, Switzerland
Contacts
Public ContactHDC
HOVON Data Center
Outcome results
None listed