Study of Elacytarabine Versus Investigator's Choice in Patients With Late Stage Acute Myeloid Leukaemia (AML)

The study investigates the new nucleoside analogue derivative, elacytarabine, as treatment
for patients with relapsed or refractory Acute Myeloid Leukemia (AML). To be included in the
study, patients must have failed to respond to two or three different therapies for AML, or
have obtained remission but then relapsed within a relatively short period of time. Patients
of age ≥ 65 with adverse cytogenetics can be included in the study after having received
one and up to three previous induction/re-induction therapies.

Elacytarabine is an investigational drug which is not commercially available. It is the
elaidic acid ester derivative of cytarabine. Cytarabine is routinely used in the treatment
of patients with AML. A substantial portion of AML patients have a deficient uptake of
cytarabine, often explained by lack of a transport protein (hENT1) in the leukemic cell
membrane. Due to the elaidic acid (a naturally occurring fatty acid), cellular uptake of
elacytarabine is independent of this transport protein.

Patients included in the study will be randomized to elacytarabine or control treatment.
Since there is no standard therapy for relapsed or refractory AML, there is a list of 7
control treatments and the investigator has to choose one that is locked before
randomization.

Elacytarabine is given as a continuous infusion over five days, followed by a rest period of
minimum two weeks. Investigator's choice treatment is given according to the specific
routine.

After each course response evaluation and a decision on further treatment will be made.

Repeated courses of elacytarabine and control treatment might be needed to attain and/or
maintain complete remission or clinical benefit.

After the end of study treatment, all patients will be followed for relapse and survival.

Inclusion Criteria:

- 18 years of age or older

- Confirmed diagnosis of AML according to WHO classification (excluding acute
promyelocytic leukaemia) who have received two or three previous
induction/re-induction regimens or patients of age ≥ 65 with adverse cytogenetics who
have received 1-3 previous induction/re-induction regimens. One of the (re-)induction
regimens could be stem cell transplantation (SCT) for achievement of remission.
Maintenance and consolidation (including SCT) may have been given, but are not
counted as previous regimens.

- Bone marrow aspirates and/or biopsies must contain > 5 % leukaemic blast cells or
patient must have biopsy-proven extramedullary AML, or patient's peripheral blood
shows occurrence of leukaemic blast cells

- Patients must

- have never attained CR or CRi (primary refractory), or

- have failed initial induction therapy, and have attained CR or CRi after salvage
therapy(ies), and then relapsed within < 6 months, or

- have attained CR or CRi after initial induction therapy and relapsed within <12
months, and failed to respond to salvage therapy(ies), or

- have relapsed after the latest CR or CRi within < 6 months

- Patients younger than 65 years should have received previous treatment with
cytarabine

- Patients must have recovered from previous bone marrow and/or stem cell
transplantation to a stage that the patient can tolerate the study treatment. There
is no restriction on number of regimens or type of treatment administered for
maintenance or consolidation during previous stages of the disease

- ECOG performance status (PS) of 0 - 2

- Women of child-bearing potential must have a negative serum or urine pregnancy test
within 2 weeks prior to treatment start

- Male and female patients must use acceptable contraceptive methods for the duration
of time on study, and males also for 3 months after the last elacytarabine dose

- Capable of understanding and complying with protocol requirements, and must be able
and willing to sign a written informed consent form

Exclusion Criteria:

- A history of allergic reactions to egg. A history of allergic reactions of CTCAE
grade 3 or 4 to cytarabine

- Persistent clinically significant toxicities from previous chemotherapy

- A cancer history that, according to the investigator, might confound the assessment
of the study endpoints

- Known positive status for human immunodeficiency virus (HIV)

- Pregnant and nursing patients

- Uncontrolled intercurrent illness including, but not limited to, uncontrolled
infection, or psychiatric illness/social situations that would limit compliance with
study requirements

- Impairment of hepatic or renal function to such an extent that the patient, in the
opinion of the investigator, will be exposed to an excessive risk if entered into
this clinical study

- Active heart disease including myocardial infarction within previous 3 months,
symptomatic coronary artery disease, arrhythmias not controlled by medication, or
uncontrolled congestive heart failure. Any New York Heart Association (NYHA)
functional classification grade 3 or 4

- Applicable only for patients for whom an anthracycline is part of the selected
control treatment: Left ventricular ejection fraction (LVEF) must be ≥ 45 % as
measured by MUGA scan or 2D ECHO within 14 days prior to start of therapy. Either
method is acceptable for measuring LVEF

- Applicable only for patients for whom an anthracycline is part of the selected
control treatment: The patient should tolerate minimum one course of combination
therapy

- Any anti-leukaemic agents within the last 3 weeks. Hydroxyurea,however, is allowed
for up to 12 hours prior to study treatment

- Any investigational treatment within the last 14 days

- Any medical condition which in the opinion of the investigator places the patient at
an unacceptably high risk for toxicities