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

Study Overview
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Brief Summary
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This randomized clinical trial studies liposomal cytarabine-daunorubicin CPX-351 in treating patients with untreated myelodysplastic syndrome or acute myeloid leukemia. Drugs used in chemotherapy, such as liposomal cytarabine-daunorubicin CPX-351, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed Description
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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.

Official Title
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Liposomal Cytarabine and Daunorubicin (CPX-351) for Adults With Untreated High-Risk MDS and Non-APL AML at High Risk of Treatment-Related Mortality

Conditions
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Acute Biphenotypic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Liposomal Cytarabine-Daunorubicin CPX-351


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (lower-dose liposomal cytarabine-daunorubicin CPX-351)<br>INDUCTION/RE-INDUCTION: Patients receive lower-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 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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposomal Cytarabine-Daunorubicin CPX-351<br>* Given IV<br>* Other names: Liposomal AraC-Daunorubicin CPX-351;|
| Experimental: Arm II (closed to accrual effective 4/21/14)<br>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. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposomal Cytarabine-Daunorubicin CPX-351<br>* Given IV<br>* Other names: Liposomal AraC-Daunorubicin CPX-351;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related Mortality Rate. (TRM) | Estimate whether the 32 units/m2 or the 64 units/m2 or both dose levels of CPX-351 are likely to improve treatment-related mortality (TRM) rate while keeping the CR rate constant in patients with untreated high-risk MDS or non-APL AML at high risk of TRM. | Up to 1 month after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Remission Rate (CR+CRp) | Overall Remission Rate for the CR/CR with incomplete platelet count recovery (CRp) rate after up to 4 cycles of induction/re-induction therapy. | Up to day 28 |