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

Trial Status: Closed to Accrual and Intervention

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.

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

Alabama

Birmingham
Children's Hospital of Alabama
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Arizona

Phoenix
Phoenix Childrens Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 602-546-0920

Arkansas

Little Rock
Arkansas Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

California

Downey
Kaiser Permanente Downey Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 626-564-3455
Duarte
City of Hope Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-826-4673
Loma Linda
Loma Linda University Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 909-558-3375
Los Angeles
Children's Hospital Los Angeles
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Madera
Valley Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Oakland
UCSF Benioff Children's Hospital Oakland
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Orange
Children's Hospital of Orange County
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Sacramento
University of California Davis Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 916-734-3089
San Francisco
UCSF Medical Center-Mission Bay
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 877-827-3222

Colorado

Aurora
Children's Hospital Colorado
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Connecticut

Hartford
Connecticut Children's Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Delaware

Wilmington
Alfred I duPont Hospital for Children
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 302-651-6884

District of Columbia

Washington
Children's National Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Florida

Gainesville
University of Florida Health Science Center - Gainesville
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Jacksonville
Nemours Children's Clinic-Jacksonville
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Pensacola
Nemours Children's Clinic - Pensacola
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 888-823-5923
Saint Petersburg
Johns Hopkins All Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Indiana

Indianapolis
Riley Hospital for Children
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-248-1199
Saint Vincent Hospital and Health Care Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 317-338-2194

Kentucky

Lexington
University of Kentucky / Markey Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 859-257-3379

Maine

Bangor
Eastern Maine Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 207-973-4274
Scarborough
Maine Children's Cancer Program
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 410-955-8804

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 877-442-3324
Massachusetts General Hospital Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 877-726-5130

Michigan

Ann Arbor
C S Mott Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Detroit
Ascension Saint John Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 734-712-3671

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Rochester
Mayo Clinic in Rochester
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 855-776-0015

Mississippi

Jackson
University of Mississippi Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 601-815-6700

Missouri

Kansas City
Children's Mercy Hospitals and Clinics
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Saint Louis
Mercy Hospital Saint Louis
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 314-251-6770
Washington University School of Medicine
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-600-3606

Nebraska

Omaha
Children's Hospital and Medical Center of Omaha
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
University of Nebraska Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 402-559-6941

New York

Buffalo
Roswell Park Cancer Institute
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-767-9355
Mineola
NYU Winthrop Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 516-663-3115
New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: COMPLETED
Contact: Site Public Contact
Phone: 212-263-4434
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 212-305-6361
Rochester
University of Rochester
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 585-275-5830
Syracuse
State University of New York Upstate Medical University
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 315-464-5476

North Carolina

Asheville
Mission Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 828-213-4150

Ohio

Akron
Children's Hospital Medical Center of Akron
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Cincinnati
Cincinnati Children's Hospital Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Cleveland
Rainbow Babies and Childrens Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 216-844-5437
Columbus
Nationwide Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Oklahoma

Oklahoma City
University of Oklahoma Health Sciences Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 405-271-8777

Oregon

Portland
Oregon Health and Science University
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 503-494-1080

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Pittsburgh
Children's Hospital of Pittsburgh of UPMC
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Tennessee

Memphis
Saint Jude Children's Research Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Nashville
The Children's Hospital at TriStar Centennial
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 214-648-7097
Houston
Baylor College of Medicine / Dan L Duncan Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 713-798-1354
San Antonio
Children's Hospital of San Antonio
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Utah

Salt Lake City
Primary Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Vermont

Burlington
University of Vermont and State Agricultural College
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 802-656-8990

Virginia

Norfolk
Children's Hospital of The King's Daughters
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Washington

Seattle
Seattle Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Spokane
Providence Sacred Heart Medical Center and Children's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-622-8922
Milwaukee
Children's Hospital of Wisconsin
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 414-955-4727

Manitoba

Winnipeg
CancerCare Manitoba
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 866-561-1026

Nova Scotia

Halifax
IWK Health Centre
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 902-470-6767

Ontario

Kingston
Kingston Health Sciences Centre
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 613-549-6666

Quebec

Montreal
Centre Hospitalier Universitaire Sainte-Justine
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 514-345-4931
The Montreal Children's Hospital of the MUHC
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Quebec
Centre Hospitalier Universitaire de Quebec
Status: CLOSED_TO_ACCRUAL
Contact: Site Public Contact

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.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Children's Oncology Group

Principal Investigator
Todd Michael Cooper

  • Primary ID AAML1421
  • Secondary IDs NCI-2015-01917, PAAML1421_R02PAPP01, s16-00955
  • Clinicaltrials.gov ID NCT02642965