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)

In this phase III study the new drug Laromustine (VNP 410101M) is added to the
standard chemotherapy for remission induction therapy of adults age below 65
years, with acute myeloid leukemia (AML) or refractary anemia with excess of
blasts (RAEB) with International Prognostic Score System (IPSS) >= 1.5. The aim
of this study is to examine whether the treatment outcome improves by adding
Laromustine. Laromustine is an effective drug that, if given as single
medication to AML patients with no further treatment options, induces
remissions (600 mg/m2). In this study Laromustine is given in combination with
the standard chemotherapy consisting of cytarabine en idarubicine (cycle 1) and
cytarabine and amsacrine (cycle 2). Laromustine is given on day 2 of the cycle
per infusion as a single gift. In the first part A of the study the
feasebility of three dose levels of laromustine (200, 300, 400 mg/m2 ) will be
examined compared to the treatment without laromutine in a randomized design.
Also pharmacokinetic research will be done in a limited number of patients. In
the second part B of the study the phase III will be done with the selected
dose level. In the study a risk analyses will be performed based on
hematological, clinical, cytogenetic and molecular data on which the choice
for postremission treatment is based (additional chemotherapy, autologous stem
cell transplantation or allogeneic stem cell transplantation). Further,
genexpression profiling analyses on leukemic cells will be done and minimial
residual disease measurements at previously defined timepoints to be able to
correlate the effect of therapy on these parameters afterwards.

Primary objectives

Part A:
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 IPSS³1.5 in a prospective comparison to standard induction cycles I
and II without Laromustine

Part B:
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

Secondary objectives

Part A:
To evaluate the pharmacokinetics of Laromustine in the combination with
cytarabine-idarubicin remission induction chemotherapy in a selection of
patients at different dose levels of Laromustine as well as in a limited number
of controls
To investigate the clinical efficacy of Laromustine in combination with
remission induction chemotherapy cycles I and II with regard to complete
remission rate at different dose levels of Laromustine

Part B:
To investigate the clinical efficacy of Laromustine with regard to the complete
remission rate, disease free survival (DFS), risk of relapse and overall
survival (OS) when combined with remission induction chemotherapy cycles I and
II in all patients
To investigate the clinical efficacy of Laromustine when combined with
remission induction chemotherapy cycles I and II in molecularly and
cytogenetically distinguishable subsets with regard to the complete remission
rate, disease free survival (DFS), risk of relapse and overall survival (OS)
To investigate the tolerance and toxicity of Laromustine in combination with
remission induction chemotherapy cycles I and II
To evaluate the pharmacokinetics of Laromustine and cytarabine-idarubicine
remission induction chemotherapy in a limited number of patients in both
treatment arms
To assess the effect of Laromustine on peripheral CD34 cell numbers for
autologous peripheral blood transplantation
To determine the prognostic value of molecular markers and gene expression
profiles of the leukemia assessed at diagnosis
To evaluate the treatment effects according minimal residual disease (MRD)
measurements following therapy by standardized sampling of marrow/blood
To evaluate the outcome of allogeneic sibling or unrelated donor SCT and
autologous SCT in cytogenetically and molecularly defined and prognostic
subgroups of patients.

Part A: Comparative, randomized feasibility study of remission induction
chemotherapy combined with Laromustine at three possible dose levels 200, 300,
400 mg/m2.

Part B: 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

In de experimental arm intravenously administered Laromustine will be added to
idarubine-cytarabine in cycle I and to amsacrine-cytarabine in cycle II.

The study starts at a dose level of 200 mg/m2, and if possible escalating to
400 mg/m2. If 400 mg/m2 is not feasible we return to the intermediate dose
level of 300 mg/m2, and we return to 200 mg/m2 if 300 mg/m2 is not feasible as
well. At each dose level the decision to stop or escalate will be made on the
basis of (a) the incidence of Dose Limiting Toxicities (DLTs) in the arm
treated with Laromustine versus the incidence of DLTs in the control arm and
(b) the duration of myelosuppression in the Laromustine arm compared to the
control arm.

The addition of Laromustine can increase the possibility of toxicities.
Although Laromustine is given before and seems to be tolerated well, possibly
not all toxicities are known.
Laromustine causes nausea and alopecia. Further it reduces the production of
blood as other chemotherapy does.

Further toxicities of laromustine known from previous research are pulmonary
dysfunction and liver dysfunction. The administration of the medication can be
followed by fever and chills that disappear spontaneously within a day.

At time of the normal bone marrow punctions at start and follow up a limited
amount of extra bone marrow will be collected via the same needle. This is
abouth 10 ml.
With regards to the 35 patients that participate in the pharmacokinetic studies:
For measuring the concentration of Laromustine en Cytarabine in blood, extra
blood will be collected on day 2 van cycle 1 via a special infusion needle at
several timepoints. The total amount of blood to be collected is abouth 135 ml.