Liposome-encapsulated Daunorubicin-Cytarabine, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1/2 Study of CPX-351 (NSC# 775341) Alone Followed by Fludarabine, Cytarabine, and G-CSF (FLAG) for Children With Relapsed Acute Myeloid Leukemia (AML)

This phase I/II trial studies the side effects and best dose of liposome-encapsulated daunorubicin-cytarabine when given with fludarabine phosphate, cytarabine, and filgrastim and to see how well they work in treating younger patients with acute myeloid leukemia that has come back after treatment (relapsed) or is not responding to treatment (is refractory). Liposome-encapsulated daunorubicin-cytarabine is made up of two chemotherapy drugs, cytarabine and daunorubicin hydrochloride, and works to stop cancer cell growth by blocking the cells from dividing. Drugs used in chemotherapy, such as fludarabine phosphate and cytarabine, 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. Filgrastim may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving liposome-encapsulated daunorubicin-cytarabine followed by fludarabine phosphate, cytarabine, and filgrastim may be a better treatment for patients with relapsed acute myeloid leukemia and may cause fewer side effects to the heart, a common effect of other chemotherapy treatments for acute myeloid leukemia.

Study Overview

• Status: Completed
• Conditions: Secondary Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Acute Myeloid Leukemia Post Cytotoxic Therapy
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Biological: Filgrastim; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Drug: Fludarabine Phosphate; Drug: Cytarabine

Detailed Description

PRIMARY OBJECTIVES:

I. To determine a recommended phase 2 dose (RP2D) and the toxicities associated with liposome-encapsulated daunorubicin-cytarabine (CPX-351) in pediatric and young adult patients with relapsed/refractory acute myeloid leukemia (AML).

II. To estimate the response rate (complete remission [CR] plus complete remission with partial platelet recovery [CRp]) after CPX-351 (cycle 1) followed by fludarabine phosphate, cytarabine, and filgrastim (FLAG) (cycle 2) in children with AML in first relapse.

SECONDARY OBJECTIVES:

I. To estimate the response rate (CR + CRp + complete remission with incomplete blood count recovery [CRi]) after one cycle of CPX-351.

II. To describe the pharmacokinetics of plasma cytarabine and daunorubicin after CPX-351 administration to pediatric and young adult patients with relapsed/refractory AML.

TERTIARY OBJECTIVES:

I. To describe the response in biomarkers of cardiac injury to a single cycle of CPX-351.

II. To explore the effect of CPX-351 on novel biochemical and imaging markers of cardiotoxicity, including plasma micro ribonucleic acid (RNAs) (miRNA) and myocardial deformation.

III. To explore the role of rare coding variants as risk factors for anthracycline-induced cardiomyopathy.

OUTLINE:

COURSE 1: Patients receive cytarabine intrathecally (IT) on day 0 and at day 28-30 or up to 7 days prior to day 1 of course 2, and liposome-encapsulated daunorubicin-cytarabine intravenously (IV) over 90 minutes on days 1, 3, and 5. Patients without evidence of central nervous system (CNS) disease (CNS1) receive no further CNS-directed therapy in course 1. Patients with < 5 white blood cells per microliter of blood with blast cells (CNS2) disease may receive additional 4-6 doses of cytarabine IT twice weekly starting 48 hours after the third dose of liposome-encapsulated daunorubicin-cytarabine until CNS is clear at the discretion of the investigator. Patients meeting criteria for CR, CRp, and CRi may proceed to course 2.

COURSE 2: Patients receive filgrastim on days 1-5 and then on day 15 until blood count recovery, and fludarabine phosphate IV over 30 minutes and high-dose cytarabine IV over 1-3 hours once daily (QD) on days 1-5.

After completion of study treatment, patients are followed up periodically for 12 months, and then yearly for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • The Montreal Children's Hospital of the MUHC
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Kaiser Permanente Downey Medical Center
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93636
      • Valley Children's Hospital
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital Oakland
    • Orange, California, United States, 92868
      • Children'S Hospital of Orange County
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Francisco, California, United States, 94158
      • UCSF Medical Center-Mission Bay
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health Science Center - Gainesville
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • Johns Hopkins All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Indianapolis, Indiana, United States, 46260
      • Ascension Saint Vincent Indianapolis Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
    • Scarborough, Maine, United States, 04074
      • Maine Children's Cancer Program
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48236
      • Ascension Saint John Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center of Omaha
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Mineola, New York, United States, 11501
      • NYU Winthrop Hospital
    • New York, New York, United States, 10032
      • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • Saint Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • San Antonio, Texas, United States, 78207
      • Children's Hospital of San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont and State Agricultural College
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center and Children's Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Carbone Cancer Center
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have had histologic verification of AML at original diagnosis

• Patient must have one of the following:

  • Recurrent disease with >= 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease.
  • Recurrent disease with an absolute blast count greater than 1,000 per microliter in the peripheral blood with or without extramedullary disease

• To be eligible for the dose-finding phase: (the dose-finding phase completed in 12/2016)

  • Relapsed patients

    • Patients must be in first relapse, and
    • Patients must not have received prior re-induction therapy

  • Refractory patients

    • Patients must not have received more than one attempt at remission induction, which may consist of up to two different therapy courses; Children Oncology Group (COG) AAML1031 de novo therapy including induction I and induction II is an example

  • Treatment-related AML (t-AML)

    • Patients must be previously untreated for secondary AML

• To be eligible for the phase 2 efficacy phase:

  • Relapse patients:

    • Patients must be in first marrow relapse, and
    • Patients must not have received prior re-induction therapy; donor lymphocyte infusion (DLI) is considered a re-induction attempt
• Patients must have the status of CNS1 or CNS2 only, and no clinical signs or neurologic symptoms suggestive of CNS leukemia, such as cranial palsy
• Patients must have a performance status corresponding to an Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age; Note: patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, stem cell transplant or radiotherapy prior to entering this study; all prior treatment-related toxicities must have resolved to =< grade 2 prior to enrollment

• Myelosuppressive chemotherapy: must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this study (excluding hydroxyurea)

  • Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of CPX-351
• Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent such as steroids, retinoids; Note: for agents that have known adverse events occurring beyond 7 days after administration (i.e. monoclonal antibodies), this period must be extended beyond the time during which acute adverse events are known to occur
• Radiation therapy (RT): >= 2 weeks for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation; Note: patients must have received =< than 13.6 Gray (Gy) prior radiation to the mediastinum

• Stem cell transplant (SCT): no evidence of active graft vs. host disease for at least 4 weeks; for allogeneic SCT patients, >= 3 months must have elapsed since transplant

  • Must have received no more than 1 prior autologous or allogeneic stem cell transplant.
  • Patients must be off all systemic immunosuppressive therapy for at least 2 weeks, excluding hydrocortisone for physiologic cortisol replacement

• Intrathecal cytotoxic therapy:

  • No waiting period is required for patients having received intrathecal cytarabine, methotrexate, and/or hydrocortisone
  • At least 14 days must have elapsed since receiving liposomal cytarabine (DepoCyte) by intrathecal injection

• Growth factors:

  • Patients must not have received growth factors for 7 days prior to CPX-351
  • Patients must not have received pegfilgrastim for 14 days prior to CPX-351

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

  • Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (males and females)
  • Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (males and females)
  • Age 6 to < 10 years: maximum serum creatinine 1.0 mg/dL (males and females)
  • Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (males and females)
  • Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (males) and 1.4 mg/dL (females)
  • Age >= 16 years: maximum serum creatinine 1.7 mg/dL (males) and 1.4 mg/dL (females)
• Direct bilirubin < 1.5 x upper limit of normal (ULN) for age and institution
• Serum glutamate pyruvate (SGPT) (alanine aminotransferase [ALT]) =< 3.0 x upper limit of normal (ULN) for age and institution (unless it is related to leukemic involvement)
• Shortening fraction of >= 27% by echocardiogram, or
• Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram
• Corrected QT (using Bazett's formula [QTcB]) interval < 500 msecs
• Patients with seizure disorder may be enrolled if on anticonvulsants and if seizures are well controlled
• Central nervous system (CNS) toxicity =< grade 2

• Patients with a known history of human immunodeficiency virus (HIV) are eligible, if they meet all of the following conditions:

  • No history of HIV complications with the exception of cluster of differentiation (CD)4 count < 200 cells/mm^3
  • No antiretroviral therapy with overlapping toxicity such as myelosuppression
  • HIV viral loads below the limit of detection
  • No history of highly active antiretroviral therapy (HAART)-resistant HIV
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Patients who have received > 450 mg/m^2 daunorubicin equivalents; patients who relapse after receiving AAML0531/AAML1031 therapy will be eligible for this study, provided they have not received any additional anthracyclines; NOTE: for the purposes of determining eligibility for this protocol, the following cardiotoxicity multipliers will be used to determine daunorubicin equivalents:

  • Doxorubicin (doxorubicin hydrochloride): 1
  • Mitoxantrone: 3
  • Idarubicin: 3
  • Epirubicin: 0.5
• Patients who are currently receiving another investigational drug
• Patients receiving medications for treatment of left ventricular systolic dysfunction

• Patients with any of the following diagnoses:

  • Acute promyelocytic leukemia (APL)
  • Down syndrome
  • Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome
  • Wilson's disease and any other disorder of copper metabolism
  • Juvenile myelomonocytic leukemia (JMML)
• Patients with documented active, uncontrolled infection at the time of study entry
• Patients with known active hepatitis B virus (HBV) and hepatitis C virus (HCV) infections
• Patients with prior allergy to daunorubicin and/or cytarabine
• Female patients who are pregnant are ineligible
• Lactating females are not eligible
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 6 months after the last dose of chemotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (CPX-351 and FLAG); COURSE 1: Patients receive cytarabine IT on day 0 and at day 28-30 or up to 7 days prior to day 1 of course 2, and liposome-encapsulated daunorubicin-cytarabine IV over 90 minutes on days 1, 3, and 5. Patients with CNS1 receive no further CNS-directed therapy in course 1. Patients with CNS2 disease may receive additional 4-6 doses of cytarabine IT twice weekly starting 48 hours after the third dose of liposome-encapsulated daunorubicin-cytarabine until CNS is clear at the discretion of the investigator. Patients meeting criteria for CR, CRp, and CRi may proceed to course 2. COURSE 2: Patients receive filgrastim on days 1-5 and then on day 15 until blood count recovery, and fludarabine phosphate IV over 30 minutes and high-dose cytarabine IV over 1-3 hours QD on days 1-5.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Biological: Filgrastim; Given SC or IV; Other Names: G-CSF; r-metHuG-CSF; Neupogen; Filgrastim-aafi; Nivestym; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tevagrastim; Filgrastim-ayow; Releuko; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Given IV; Other Names: CPX-351; Cytarabine-Daunorubicin Liposome for Injection; Daunorubicin and Cytarabine (Liposomal); Liposomal AraC-Daunorubicin CPX-351; Liposomal Cytarabine-Daunorubicin; Liposome-encapsulated Combination of Daunorubicin and Cytarabine; Vyxeos; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Cytarabine; Given IT or IV; Other Names: .beta.-Cytosine arabinoside; 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-.beta.-D-Arabinofuranosylcytosine; 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone; 1-Beta-D-arabinofuranosylcytosine; 1.beta.-D-Arabinofuranosylcytosine; 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-; 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-; Alexan; Ara-C; ARA-cell; Arabine; Arabinofuranosylcytosine; Arabinosylcytosine; Aracytidine; Aracytin; Aracytine; Beta-Cytosine Arabinoside; CHX-3311; Cytarabinum; Cytarbel; Cytosar; Cytosine Arabinoside; Cytosine-.beta.-arabinoside; Cytosine-beta-arabinoside; Erpalfa; Starasid; Tarabine PFS; U 19920; U-19920; Udicil; WR-28453

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Dose-limiting Toxicity	Number of patients in the dose-finding phase with a dose-limiting toxicity, graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	28 days
Percentage of Responders (Complete Response or Complete Remission With Partial Platelet Recovery) After up to 2 Cycles	Best response (complete response or complete remission with partial platelet recovery) after up to 2 cycles of therapy, where response is assessed using the revised Acute Myeloid Leukemia International Working Group Criteria. Percentage of responders is calculated using the methods of Jung and Kim. 90% confidence interval is determined using the methods of Koyama and Chen.	Up to 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Responders (Complete Response or Complete Remission With Partial or Incomplete Platelet Recovery) After First Cycle of Therapy	Response (complete response or complete remission with partial or incomplete platelet recovery) after first cycle of therapy, where response is assessed using the revised Acute Myeloid Leukemia International Working Group Criteria. Percentage of responders is calculated by the total of number of patients with complete response or complete remission with partial or incomplete platelet recovery divided by the number of patients evaluable for response after the first cycle. 95% confidence interval is determined using a binomial exact method.	Up to 4 weeks
Liposome-encapsulated Daunorubicin Clearance	Geometric mean liposome-encapsulated daunorubicin clearance following IV infusion will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Daunorubicin Volume of Distribution	Geometric mean liposome-encapsulated daunorubicin volume of distribution following IV infusion will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Daunorubicin Time of Maximum Concentration	Median liposome-encapsulated daunorubicin time of maximum observed plasma concentration will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Daunorubicin Area Under the Curve	Geometric mean liposome-encapsulated daunorubicin area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Cytarabine Clearance	Geometric mean liposome-encapsulated cytarabine clearance following IV infusion will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Cytarabine Volume of Distribution	Geometric mean liposome-encapsulated cytarabine volume of distribution following IV infusion will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Cytarabine Time of Maximum Concentration	Median liposome-encapsulated cytarabine time of maximum observed plasma concentration will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Liposome-encapsulated Cytarabine Area Under the Curve	Geometric mean liposome-encapsulated cytarabine area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration will be determined for patients in the dose-finding phase.	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Hospitalization Time	Descriptive statistics will be used to summarize length of hospitalization time.	Up to 1 year
Time to Bone Marrow Count Recovery	Descriptive statistics will be used to summarize bone marrow count recovery.	Up to 1 year
Time to Peripheral Blood Cell Count Recovery	Descriptive statistics will be used to summarize peripheral blood cell count recovery.	Up to 1 year
Proportion of Patients Experiencing Toxicities	Proportion of patients experiencing >= grade 3 non-hematologic toxicities, cardiac toxicities, and infections by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	Up to 8 weeks post-treatment
Change in Troponin Levels	Spearman correlation coefficients will be used to correlate the post-treatment values of troponin with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in global longitudinal strain.	Baseline up to day 30
Change in N-terminal Pro B-type Natriuretic Peptide (NT-BNP) Levels	Spearman correlation coefficients will be used to correlate the post-treatment values of NT-BNP with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in in global longitudinal strain.	Baseline up to day 30
Change in High Sensitive C-reactive Protein (HS-CRP) Levels	Spearman correlation coefficients will be used to correlate the post-treatment values of HS-CRP with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in in global longitudinal strain.	Baseline up to day 30
Change in in Global Longitudinal Strain	A paired t-test will be used to compare the mean global longitudinal strain between the pre-treatment (at relapse) baseline and post-course 1 echocardiogram.	Baseline up to 28 days
Change in Micro Ribonucleic Acid (miRNA) Using TaqMan miRNA Assays	Plasma miR-29b and -499 fold change from pre-treatment baseline will be determined at each post-treatment time point using the delta-delta-Ct method. The relationship between 6-hour miR-29b and -499 expression and change in left ventricular global longitudinal strain between the pre-cycle and end of cycle 1 echocardiograms will be determined by calculating a Spearman correlation coefficient.	Baseline up to day 30

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Todd M Cooper, Children's Oncology Group

Publications and helpful links

General Publications

• Cooper TM, Absalon MJ, Alonzo TA, Gerbing RB, Leger KJ, Hirsch BA, Pollard J, Razzouk BI, Aplenc R, Kolb EA. Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children's Oncology Group. J Clin Oncol. 2020 Jul 1;38(19):2170-2177. doi: 10.1200/JCO.19.03306. Epub 2020 May 13.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2016
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: December 2, 2015
• First Submitted That Met QC Criteria: December 28, 2015
• First Posted (Estimated): December 30, 2015

Study Record Updates

• Last Update Posted (Actual): September 8, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Lenograstim; Fludarabine; Fludarabine phosphate; Cytarabine; Daunorubicin
• Other Study ID Numbers: AAML1421 (Other Identifier: CTEP); U10CA180886 (U.S. NIH Grant/Contract); NCI-2015-01917 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); PAAML1421_R02PAPP01; s16-00955