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

• Remission rate [ Time Frame: Until 300 events occur ] [ Designated as safety issue: No ]
  • Remission rate measured by overall response rate (ORR) (i.e. complete remission (CR) and complete remission with incomplete bone marrow recovery (CRi))
  • Remission rate measured by CR
  • Remission duration analysed using cumulative incidence of relapse (CIR) measured from date of CR or CRi
• Compare number of patients with adverse events (AEs) per study arm as a measure of safety and tolerability [ Time Frame: From first dose of study treatment, until 30 days after the last dose (for each patient) ] [ Designated as safety issue: Yes ]
  Summaries will include rates of occurrence of any AEs, rates of AEs by system organ classification (SOC),rates of discontinuation of study treatment due to AEs.
• Characterize exposure-response relationships for measures of effectiveness and toxicity [ Time Frame: During the first course of elacytarabine ] [ Designated as safety issue: No ]

• Remission rate [ Time Frame: Until death or 6 months follow-up is completed for all patients ] [ Designated as safety issue: No ]
  • Remission rate measured by overall response rate (ORR) (i.e. complete remission (CR) and complete remission with incomplete bone marrow recovery (CRi))
  • Remission rate measured by CR
  • Remission duration analysed using cumulative incidence of relapse (CIR) measured from date of CR or CRi (Can not be assessed for patients receving supportive / palliative care as control treatment)
• Compare number of patients with adverse events (AEs) per study arm as a measure of safety and tolerability [ Time Frame: From first dose of study treatment, until 30 days after the last dose (for each patient) ] [ Designated as safety issue: Yes ]
  Summaries will include rates of occurrence of any AEs, rates of AEs by system organ classification (SOC), rates of discontinuation of study treatment due to AE or toxicity based on clinical laboratory assessment and rates of haematological toxicity.
• Characterize exposure-response relationships for measures of effectiveness and toxicity [ Time Frame: During the first course of elacytarabine (in 50 patients) ] [ Designated as safety issue: No ]

The purpose of the study is to assess the efficacy and safety of elacytarabine versus investigator's choice treatment in patients with relapsed or refractory acute myeloid leukemia (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.

• Drug: Elacytarabine
  Elacytarabine 2000 mg/m2/d administered as a continuous intravenous infusion (CIV) in a d 1-5 q3w cycle.
• Drug: Investigator's Choice
  E.g. cytarabine single agent/combinations, hypomethylating agents, best supportive care (BSC)

• Experimental: Elacytarabine
  N/A
  Intervention: Drug: Elacytarabine
• Active Comparator: Investigator's Choice
  Intervention: Drug: Investigator's Choice

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