Liposome-encapsulated Daunorubicin-Cytarabine, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Condition: Acute Myeloid Leukemia Post Cytotoxic Therapy; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): Cytarabine; Filgrastim; Fludarabine Phosphate; Laboratory Biomarker Analysis; Liposome-encapsulated Daunorubicin-Cytarabine; Pharmacological Study
Intervention type(s): Drug; Biological; Drug; Other; Drug; Other
Intervention description(s): Given IT or IV; Given SC or IV; Given IV; Correlative studies; Given IV; Correlative studies
Other intervention name(s): .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; Filgrastim-aafi; Filgrastim-ayow; G-CSF; Neupogen; Nivestym; r-metHuG-CSF; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; Releuko; rG-CSF; Tevagrastim; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; 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
Intervention MeSH terms: Cytarabine; Fludarabine; Fludarabine phosphate; Daunorubicin; Lenograstim
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment