Liposomal Cytarabine-Daunorubicin CPX-351 in Treating Patients With Untreated Myelodysplastic Syndrome or Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Estimate whether the 32 units/m^2 or the 64 units/m^2 or both dose levels of CPX-351
(liposomal cytarabine-daunorubicin CPX-351) are likely to improve treatment-related mortality
(TRM) rate while keeping the complete remission (CR) rate constant in patients with untreated
high-risk myelodysplastic syndrome (MDS) or non-acute promyelocytic leukemia (APL) acute
myeloid leukemia (AML) at high risk of TRM.

SECONDARY OBJECTIVES:

I. Describe the CR/CR with incomplete platelet count recovery (CRp) rate after up to 4 cycles
of induction/re-induction therapy.

II. Describe the event-free survival, disease-free survival, and overall survival of patients
who achieve CR/CRp.

III. Estimate the frequency and severity of regimen-associated toxicities.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION/RE-INDUCTION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351
intravenously (IV) over 90 minutes on days 1, 3, and 5. Treatment repeats every 40 days for 4
courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR
or CRp continue on to consolidation.

CONSOLIDATION: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over
90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of
disease progression or unacceptable toxicity.

ARM II: (closed to accrual effective 4/21/14) INDUCTION/RE-INDUCTION: Patients receive
higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5.
Treatment repeats every 40 days for 4 courses in the absence of disease progression or
unacceptable toxicity. Patients achieving CR or CRp continue on to consolidation.

CONSOLIDATION: Patients receive higher-dose liposomal cytarabine-daunorubicin CPX-351 IV over
90 minutes on days 1 and 3. Treatment repeats every 40 days for 4 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 month.

Inclusion Criteria:

- Diagnosis of untreated "high-risk" MDS (>= 10% blasts) or AML other than acute
promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008
World Health Organization (WHO) classification; patients with biphenotypic AML are
eligible; outside diagnostic material is acceptable as long as peripheral blood and/or
bone marrow slides are reviewed at the study institution and cytogenetic/molecular
information is available

- Prior hydroxyurea for AML is permitted but should be discontinued prior to start
of CPX-351 treatment

- Azacitidine, decitabine, lenalidomide, and growth factors are permitted for
low-risk MDS (< 10% blasts); all treatments for MDS should be discontinued prior
to start of CPX-351 treatment

- Treatment-related mortality (TRM) score >= 13.1 as calculated with simplified model

- Bilirubin < 2.0 mg/mL x upper limit of normal; this requirement reflects the excretion
of CPX-351 by the liver

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 4.0 x upper limit of
normal; this requirement reflects the excretion of CPX-351 by the liver

- Left ventricular ejection fraction (LVEF) >= 40%, assessed within 28 days prior to
registration, e.g. by multi gated acquisition (MUGA) scan or echocardiography, or
other appropriate diagnostic modality

- Patients with symptoms/signs of hyperleukocytosis or white blood cell (WBC) >
100,000/uL can be treated with leukapheresis prior to enrollment

- Provide signed written informed consent

Exclusion Criteria:

- Refractory/relapsing blast crisis of chronic myelogenous leukemia (CML)

- Concomitant illness associated with a likely survival of < 1 year

- Active systemic fungal, bacterial, viral, or other infection, unless under treatment
with anti-microbials and controlled/stable, as defined as being afebrile and
hemodynamically stable for 24-48 hours