See above
ID
Source
Brief title
Condition
- Leukaemias
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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)
Secondary outcome
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
Background summary
AML in adults continues to have a fatal prognosis in a great majority of
patients. The medical need for new therapies in this important patient group
has remained considerable. The study is a randomized Phase II in patients aged
18-65 years with newly diagnosed AML. In single arm studies the addition of
lenalidomide to chemotherapy has shown encouraging clinical response rates with
acceptable side effects in AML. Lenalidomide appears a highly active anti-AML
drug that has mainly been examined in relapsed AML and in patients of older
age, but not yet in the frontline in patients of younger age. A regimen of
lenalidomide combined with standard remission induction chemotherapy which is
potentially clinically valuable (as regards CR and CR duration, overall and in
prognostic subsets), has not yet been critically evaluated as regards
feasibility and efficacy, nor in induction nor in a combination of induction
treatment and nor in maintenance treatment. The latter questions represent the
investigational objectives of the current study.
Study objective
See above
Study design
Phase III randomized trial for remission induction as well as for the
maintenance starting with a dose selection run-in phase.
Intervention
First, we will establish in a randomized run-in study the dose level of
lenalidomide in addition to the standard induction treatment of
idarubicin/cytarabine (cycle I) and daunorubicine/cytarabine (cycle II) (part
A-run-in).
Following the dose-selection phase the study will continue as a randomized
study for induction therapy (part A).
Subsequently, we will also investigate the effect of lenalidomide maintenance
treatment (10 mg/day) by randomization to be administered in first CR.
Study burden and risks
In Part A of the study, all patients receive the standard treatment. Patients
who receive study treatment will receive by randomisation the additional drug
lenalidome in addition to standard treatment. In part B patients will receive
as happens in the current default situation, no further treatment after the
closing own stem cell transplantation or the last chemotherapy cycle. If they
draw for research arm they will be treated with six concluding cycles of
lenalidomide. The addition of this last maintenance treatment involves extra
blood controls and possible additional likelihood of side effects with respect
to the current standard.
Patients randomized for the lenalidomide arms may experience side effects.
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081HV
NL
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
Part A:
1. Age 18-65 years, inclusive
2. 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
3. WHO performance status 0, 1 or 2
4. 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
5. 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
6. Written informed consent
7. Ability and willingness to adhere to the lenalidomide Pregnancy Prevention
Program, Part B:
1. CR or CRi
2. Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
3. Platelet count >= 75 x 10^9/L
4. Serum creatinine clearance >= 30 ml/min or estimated glomerular filtration
rate (GFR) > 60mL/min/1.73^2
5. Total bilirubin <= 2.5 x ULN
6. AST <= 2.5 x ULN
7. ALT <= 2.5 x ULN
Exclusion criteria
Part A:
1. Previous therapy with lenalidomide
2. Acute promyelocytic leukemia
3. Previous treatment for AML or high risk MDS (IPSS-R > 4.5), except
hydroxyurea
4. 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
5. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled
diabetes, infection, hypertension, pulmonary disease etcetera)
6. 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 MUGA 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
7. Pregnant or lactating females
8. Unwilling or not capable to use effective means of birth control
9. Any psychological, familial, sociological and geographical condition
potentially hampering compliance with the study protocol and follow-up
schedule, Part B:
1. Severe cardiac dysfunction (NYHA classification II-IV, see appendix G)
2. Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix F)
3. Severe neurological or psychiatric disease
4. Serious active infections
5. Previous serious toxicities related to the use of lenalidomide
6. CMV reactivation, which is not responsive to first line valganciclovir
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002843-26-NL |
| CCMO | NL45528.078.13 |