CPX-351 in Treating Patients With Newly Diagnosed, High-Risk Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial studies the best dose and how well liposomal cytarabine-daunorubicin CPX-351 (CPX-351) works in treating patients with newly diagnosed acute myeloid leukemia and who are at risk for not responding well to treatment. Liposomal cytarabine-daunorubicin CPX-351 combines two chemotherapy drugs that are known to help each other work better, and may work to stop the growth of cancer cells by blocking the cells from dividing.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess preliminary efficacy (as determined by the rate of complete response [CR] or CR with incomplete blood count recovery [CRi]) of two or three dose levels of CPX-351 in patients with newly diagnosed acute myeloid leukemia (AML) at high risk for induction mortality, defined as 30-50% predicted risk of death by day 60, and to select the most promising dose level for further efficacy testing. SECONDARY OBJECTIVE: I. To confirm the rate of dose limiting toxicities, including induction mortality (at day 60) for two different sub-maximum tolerated dose (MTD) dose levels (50 and 75 U/m^2). EXPLORATORY OBJECTIVES: I. To investigate the effect of CPX-351 on immune response, as determined by the effect on recovery of functional pathogen-specific and leukemia-specific immune responses and the recovery and function of natural killer (NK) cells. II. To investigate the role of troponin-T as an early marker for CPX-351-induced cardiotoxicity. III. To investigate ex vivo the cytotoxicity of combination of Pim-1 proto-oncogene, serine/threonine kinase (Pim) kinase inhibitor(s) and CPX-351 on circulating leukemia cells. OUTLINE: INDUCTION: Patients are randomized to 1 of 2 arms. After safety is established for both dose levels, and escalation is deemed feasible, an additional arm will be studied at the standard dose level. ARM I: Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5 of a 28-day course. Patients with persistent disease may receive a second course with treatment on days 1 and 3. ARM II: Patients receive intermediate-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3. ARM III: Patients receive standard-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3. CONSOLIDATION THERAPY: Patients achieving CR receive liposomal cytarabine-daunorubicin CPX-351 on days 1 and 3. Treatment may repeat every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up monthly for as long as the study doctor thinks it is needed, every 2-3 months for up to 1 year, and every 3-4 months for up to 1 year.

Official Title
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Phase II Study of CPX-351 (Cytarabine:Daunorubicin) Liposome Injection in Patients With Newly Diagnosed AML at High Risk for Induction Mortality

Conditions
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Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Liposome-encapsulated Daunorubicin-Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and voluntarily sign an informed consent form Pathological diagnosis of AML according to World Health Organization (WHO) criteria (with at least 20% blasts in the peripheral blood or bone marrow): newly diagnosed de novo AML; except for acute promyelocytic leukemia (APL); newly diagnosed secondary AML, defined as having a history of an antecedent hematologic disorder (myelodysplastic syndromes [MDS], myeloproliferative disease [MPD] or history of cytotoxic treatment for non-hematologic malignancy) or apparent de novo AML with MDS-associated karyotype Eastern Cooperative Oncology Group (ECOG) performance status 0-3 Serum creatinine =< 2.0 mg/dL Serum total bilirubin =< 2.0 mg/dL Serum alanine aminotransferase < 3 times the upper limit of normal (ULN); Note: If elevated liver enzymes are related to disease alanine aminotransferase (ALT) should be < 5 times ULN To be considered at high risk for induction mortality patients must have 1 or 2 of the following risk factors (patients >= 60 must have at least 1 risk factor, patients < 60 must have at least 2 risk factors) present; at least one risk factor in every patient must be an AML-related factor: AML-related factors include: Antecedent hematologic disorder (AHD) (MDS, chronic myelomonocytic leukemia [CMML], or MPD) or history of exposure to cytotoxic chemotherapy [therapy-related (t)-AML]), or WHO-defined AML with MDS-related changes or apparent de novo AML with MDS-associated karyotype Unfavorable cytogenetics as defined by the European Leukemia Net Patient-related factors: Age >= 70 ECOG performance status (PS) >= 2 Co-morbidities: Serum creatinine > 1.3 g/dL Cardiac ejection fraction >= 50% by echocardiography or multi gated acquisition (MUGA) (when left ventricular ejection fraction [LVEF] expressed as a range, at least the upper limit should include 50%) Able to adhere to the study visit schedule and other protocol requirements All men and women must agree to practice effective contraception during the study period if not otherwise documented to be infertile Exclusion Criteria: Patients with history of second malignancy are eligible if they have documentation of disease stability, off therapy, based on computed tomography (CT) scan or other measures for the 6 months prior to entry in core Any serious medical condition or psychiatric illness that would prevent the patient from providing informed consent Chemotherapy or other investigational anticancer therapeutic drugs in the two weeks prior to study entry; in the event of rapidly proliferative disease, however, the use of hydroxyurea is permitted up to 24 hours before study entry in core Evidence of active central nervous system (CNS) leukemia Pregnant or lactating women Uncontrolled infection; to be eligible, patients receiving treatment for an infection (antibiotic, antifungal or antiviral treatment) must be afebrile (< 38.3 degrees Celsius [C]) and without hemodynamic instability or dyspnea from pneumonia for > 48 hours (hrs) prior to the start of induction therapy Hypersensitivity to cytarabine, daunorubicin or liposomal products History of Wilson's disease or other copper-metabolism disorder

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 (50 units/m^2) CPX-351)<br>Patients receive lower-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5 of a 28-day course. Patients with persistent disease may receive a second course with treatment on days 1 and 3. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;|
| Experimental: Arm II (intermediate-dose (75 units/m^2) CPX-351)<br>Patients receive intermediate-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;|
| Experimental: Arm III (standard-dose (100 units/m^2) CPX-351)<br>Patients receive standard-dose liposomal cytarabine-daunorubicin CPX-351 IV over 90 minutes on days 1, 3, and 5. Patients with persistent disease may receive a second course with treatment on days 1 and 3. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Response | Response is defined as Complete response (CR) or CR with incomplete blood count recovery (CRi) rate: Complete Remission (CR) is Bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 10^9/L (1000/μL); platelet count >100 x 10^9/L (100,000/μL). Complete Response with incomplete blood count recovery (CRi) is All CR criteria except for residual neutropenia (<1.0 x 10^9/L [1000/μL]) and/or thrombocytopenia (<100 x 10^9/L [100,000/μL]). | Up to 8 weeks (after induction therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose-limiting Toxicity (DLT) | Defined as induction mortality (death occurring on or before day 60), grade 3 or 4 non-hematologic toxicity, or dose limiting hematologic toxicity at least possibly related to the study drug occurring during the first 28 days from the start of therapy. Estimated for each arm with 95% confidence intervals. Fisher's exact test will be used to compare the toxicity rate between the two dose levels. | Up to day 60 |