Liposomal Cytarabine-Daunorubicin CPX-351, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia


NCT ID: NCT02642965
Sponsor Protocol Number: AAML1421

About this study

This phase I/II trial studies the side effects and best dose of liposomal cytarabine-daunorubicin CPX-351 (CPX-351) 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). Liposomal cytarabine-daunorubicin CPX-351 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 liposomal cytarabine-daunorubicin CPX-351 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Patients must have had histologic verification of AML at original diagnosis; AML is defined according to World Health Organization (WHO) classification with ≥ 5% blasts in the bone marrow (M2/M3 bone marrow), with or without extramedullary disease
  • To be eligible for the dose-finding phase:
    • 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 efficacy phase:
    • Relapsed patients:
      • Patients must be in first relapse, and
      • Patients must not have received prior re-induction therapy
  • 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, or DLI (donor lymphocyte infusion without conditioning); 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

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, cytarabine and allergy to liposomal lipids
  • 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 30 days after the last dose of chemotherapy

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