Clofarabine in combination with a standard remission induction regimen (AraC and idarubicin) in patients 18-60 years old with previously untreated intermediate and bad risk acute myelogenous leukemia (AML) or high risk myelodysplasie (MDS): a phase I-II study of the EORTC-LG and GIMEMA (AML-14A trial)

Patients with adult acute myeloid leukemia (AML) or high risk MDS are treated
in specialized hospitals by the combination of high dose cytostatic agents such
as cytosine arabinoside and anthracyclines with the aim to induce a remission
of the disease.
A complete remission can be achieved in approximately 75% of patients under the
age of 61 years. A consolidation course and a bone marrow transplantation are
given in order to diminish the chance of relapse of the disease.
However, only 50% of the patients who reached a complete remission with survive
for a long time without a relapse of the leukemia/MDS.
New antileukemic agents and/or treatment modalities are needed to further
improve the prognosis of patients with AML.
Clofarabine is a new agent that, used as single drug in older patients, has
shown a remarkable antileukemic activity. Little is known about its
interactions with other established antileukemic agents with respect to
activitiy and toxicity.

This is a phase I/II trial of the EORTC Leukemia Group and the italian GIMEMA
Acute Leukemia Working Party. In a phase I setting we will investigate the
optimal dosage and route of administration (one hour infusion or intravenous
injection) of clofarabine in combination with cytosine arabinoside and
idarubicine. The selected dose/route of administration, based primarily on the
toxicity profile, will be used in the subsequent phase II trial.
The aim of the phase II trial is to investigate the anti-tumor activity of the
chosen dose and route of administration of clofarabine.

This is an open label, multicenter clinical trial with a sequential phase I/II
design.
The phase I part contains a dose-finding study with a classical phase I design
using the 3+3 scheme aimed at documenting the safety profile and recommended
dose of clofarabine in combination with standard AML treatment consisting of
cytosine arabinoside and idarubicine.
Two different methods of administration (one hour infusion-Arm A or iv
injection - Arm B) will be tested in parallel at a maximum of 5 different
clofarabine dose levels.
The randomized phase II trial tests in parallel the 2 schemes (one hour
infusion and intravous injection) at the maximal tolerated dose as found in the
phase I trial. The Fleming 1-stage design will be applied for each arm.

Remission induction course consisting of cytosine arabinoside, idarubicine and
clofarabine:

Arm A: Clofarabine one hour infusion
Idarubicine 10 mg/m2 on days 1, 3 and 5
Cytosine arabinoside 100 mg/m2 cont. inf. on days 1 - 10
Clofarabine, test dose, on days 2, 4, 6, 8 and 10

Arm B: Clofarabine intravenous infusion
Idarubicine 10 mg/m2 on days 1, 3 and 5
Cytosine arabinoside 100 mg/m2 cont. inf. on days 1 - 10
Clofarabine, test dose, on days 2, 4, 6, 8 and 10

Test doses of clofarabine can be: 5, 7.5, 10, 15, 20, 25 or 30 mg/m2 per day

In case of treatment failure: patient off protocol
In case of partial remission: a second identical course can be given
In case of a complete remission (after one or two courses): a standard
consolidation course (without clofarabine) followed by an autologous or
allogeneic stem cell transplantation is strongly advised (but not part of the
official protocol).

The most important activities of clofarabine are the induction of leukemic cell
kill and of a longlasting pancytopenia. The most important side effects of
clofarabine, as single agent, are transient liver and renal dysfunction and a
number of less frequently occurring symptoms. These activities and side effects
are not unique and occur frequently during and after standard treatment
(containing cytosine arabinoside and idarubicine) of patients with acute
leukemia. During this study effects and side effects will be observed very
closely, and treated if possible, by the treating hematologist, and registered
on an almost daily basis at the EORTC Datacenter in Brussels. Groups of three
patients will be evaluated by the Datacenter and the study coordinators, before
a combination course with a higher level of clofarabine will start. With these
measures we will minimize the risks for the patients as good as possible.
Phase II: Expectations on the efficacy of the new drug combination have been
carefully described in the protocol. Each acute leukemia/MDS treatment is
accompanied by a large number of severe side effects. The standard combination
treatment together with the selected dose/ route of administration of
clofarabine will be carefully evaluated by the EORTC Datacenter as well as the
local hematologist in order to avoid a higher than expected number of severe
side effects.