|- candidate number||3986|
|- NTR Number||NTR1446|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||15-sep-2008|
|- Secondary IDs||MEC-2008-216 |
|- Public Title||Randomized study to assess the added value of Laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS >= 1.5)|
|- Scientific Title||Randomized study to assess the added value of Laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS >= 1.5)|
|- ACRONYM||HOVON 92 AML|
|- hypothesis||The hypothesis to be tested is that arm B is tolerable and that the outcome in arm B is better than in arm A.|
|- Healt Condition(s) or Problem(s) studied||Acute Myeloid Leukemia (AML), Myelodysplastic syndrome (MDS), Refractory anemia with excess of blasts (RAEB-t)|
|- Inclusion criteria||1. Age 18-65 years, inclusive |
2. Subjects with
- a cytopathologically confirmed diagnosis of AML according WHO classification (excluding acute promyelocytic leukaemia) or
- a diagnosis of refractory anemia with excess of blasts (RAEB) and IPSS score >= 1.5 or
- patients with therapy-related AML/RAEB or
- patients with biphenotypic leukemia (Appendices A1 and A2).
3. WHO performance status 0, 1 or 2 (see Appendix I)
4. Written informed consent
|- Exclusion criteria||1. During part A of the study patients with a good risk AML, if already known at randomisation. These patients will be treated outside the study according to the control arm.|
2. Acute promyelocytic leukaemia
3. Previous treatment for AML or RAEB, except hydroxyurea
4. Impaired hepatic or renal function as defined by:
- ALT and/or AST > 3 x Upper Limit of Normal (ULN), or
- Bilirubin > 3 x ULN, or
- Serum creatinine> 3 x ULN (after adequate hydration), unless these are most likely caused by AML organ infiltration,
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 (another method for measuring cardiac function is acceptable), or
- Unstable angina, or
- Unstable cardiac arrhythmias
7. Pregnant or lactating females
8. Impossibility to stop Disulfiram (Antabuse) and metronidazol (Flagyl) 24 hours prior to study treatment. (Please note that this medication must be stopped 24 hours prior to study treatment.)
9. Unwilling or not capable to use effective means of birth control
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-okt-2008|
|- planned closingdate||30-sep-2012|
|- Target number of participants||800|
|- Interventions||Patients will be randomized on entry for induction between: |
Cycle I: idarubicin and conventional dose cytarabine
Cycle II: amsacrine and intermediate dose cytarabine
Cycle I: idarubicin, conventional dose cytarabine and assigned dose of Laromustine
Cycle II: amsacrine, conventional dose cytarabine and assigned dose Laromustine
All CR patients will be distinguished according to good risk, intermediate risk, and poor risk features:
- Good risk patients will receive a third cycle of chemotherapy (cycle III: mitoxantrone plus etoposide).
- Intermediate or poor risk patients with a HLA matched family donor will proceed to allogeneic stem cell transplantation.
- Poor risk patients without a HLA matched sibling donor, but with a phenotypically matched unrelated donor may proceed to marrow ablative treatment and allogeneic stem cell transplantation as soon as they have entered CR. If patients are already distinguished as poor risk following cycle I and logistically there are no impediments the patient may proceed to Allo SCT as soon as possible after cycle I.
- All other patients in CR, including patients who refuse stem cell transplantation, will undergo stem cell mobilization with G-CSF and stem cell collection.
- Patients who are not eligible for Allo SCT or auto SCT will receive cycle III as consolidation treatment.
Poor risk patients in PR after cycle II with a HLA matched family donor or with a phenotypically matched unrelated donor may proceed to allogeneic stem cell transplantation.
|- Primary outcome||Part A:|
The assessment of DLT and duration of myelosuppression of the combination of Laromustine at three selected dose levels.
Event-free survival (EFS) in relation to the induction treatment arms with and without Laromustine (i.e., time from registration to induction failure, death or relapse whichever occurs first).
|- Secondary outcome||Part A:|
The evaluation of Laromustine and cytarabine pharmacokinetics.Response and especially CR to chemotherapy cycles I and II
1) EFS in the distinct prognostic subsets (AML good-risk vs AML intermediate-risk vs AML poor-risk) and cytogenetically and molecularly defined subgroups.
2) Response and especially CR to chemotherapy cycles I and II
3) Overall survival (OS) measured from the time of registration
4) Disease-free interval (duration of the first CR) measured from the time of achievement of CR to day of relapse or death from any cause (whichever occurs first).
5) Outcome of induction treatments in relation to minimal residual disease measurements
6) Evaluation of Laromustine and cytarabine (Ara-C) pharmacokinetics
7) Evaluation of the effect of Laromustine on peripheral CD34 cell numbers collected for autologous peripheral blood transplantation
8) Evaluation of molecular prognostic markers and gene expression profiles for outcome in relation to induction and postinduction treatments
9) Evaluation of toxicities and treatment related mortality (according to Appendix H)
10) 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
11) Number of platelet transfusions and last day of platelet transfusion after each cycle.
|- Timepoints||-At entry|
-After each induction cycle
-After cycle III, autoSCT or alloSCT
-During follow up: every 6 months
|- Trial web site||http://www.hovon.nl|
|- CONTACT FOR PUBLIC QUERIES||Prof. Dr. B. L÷wenberg|
|- CONTACT for SCIENTIFIC QUERIES||Prof. Dr. B. L÷wenberg|
|- Sponsor/Initiator ||Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON)|
(Source(s) of Monetary or Material Support)
|Koningin Wilhelmina Fonds (KWF), Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON), VION pharmaceuticals, Inc.|
|- Brief summary||Study phase: |
To determine the feasibility of Laromustine when given at three possible dose levels together with standard induction cycles I and II in patients with AML/ RAEB with IPSS >= 1.5 in a prospective comparison to standard induction cycles I and II without Laromustine
To evaluate the effect of Laromustine at the selected feasible dose level when combined with remission induction chemotherapy cycles I and II as regards clinical outcome (event-free survival) in comparison to remission induction cycles I and II with no addition of Laromustine in a phase III study
Patients with previously untreated AML (except acute promyelocytic leukemia) or MDS RAEB with IPSS >= 1.5, age 18-65 years.
Comparative, randomized feasibility study of remission induction chemotherapy combined with Laromustine at three possible dose levels 200, 300, 400 mg/m2.
Multicenter, phase III study at the selected feasible dose level of Laromustine in a prospective randomized approach between Laromustine combined with two induction cycles of chemotherapy versus the same chemotherapy with no addition of Laromustine
Duration of treatment:
Expected duration of 2 induction cycles inclusive evaluation is approximately 3 months. Consolidation treatment will take an additional 1-3 months. All patients will be followed until 10 years after randomization.
|- Main changes (audit trail)|
|- RECORD||15-sep-2008 - 22-sep-2008|