E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
previously untreated acute myeloid leukemia (AML) or high risk myelodysplasie (MDS) |
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E.1.1.1 | Medical condition in easily understood language |
previously untreated acute myeloid leukemia (AML) or high risk myelodysplasie (MDS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028532 |
E.1.2 | Term | Myelodysplasia |
E.1.2 | System Organ Class | 100000004864 |
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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 |
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
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E.2.2 | Secondary objectives of the trial |
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) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) > 60mL/min/1.73 m^2
• Total bilirubin ≤ 2.5 x ULN
• AST ≤ 2.5 x ULN
• ALT ≤ 2.5 x ULN
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E.4 | Principal 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:
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
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E.5 End points |
E.5.1 | 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 of the distinct predefined dose levels
Primary endpoint Part A: Induction - Efficacy
• EFS after induction treatment with or without lenalidomide (i.e., time from registration to induction failure, death from any cause or relapse whichever occurs first)
Primary endpoint Part B: Maintenance - Efficacy
• Cumulative incidence of relapse (CIR) after second randomization (maintenance treatment with lenalidomide or observation only)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of the trial. After last patient has completed maintenance treatment. |
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E.5.2 | 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
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the end of the trial. After last patient has completed maintenance treatment. |
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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 | Yes |
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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
compared to standard therapy |
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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 |
Austria |
Belgium |
Estonia |
Finland |
Germany |
Lithuania |
Luxembourg |
Netherlands |
Norway |
Sweden |
Switzerland |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 14 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 14 |