Clinical trial NCT02642965: Liposome-encapsulated Daunorubicin-Cytarabine, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia Post Cytotoxic Therapy
Recurrent Childhood Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2015-12-30
Enrollment: 38
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With a Dose-limiting Toxicity
timeFrame: 28 days
measure: Percentage of Responders (Complete Response or Complete Remission With Partial Platelet Recovery) After up to 2 Cycles
timeFrame: Up to 8 weeks
Secondary outcomes:
measure: Percentage of Responders (Complete Response or Complete Remission With Partial or Incomplete Platelet Recovery) After First Cycle of Therapy
timeFrame: Up to 4 weeks
measure: Liposome-encapsulated Daunorubicin Clearance
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Daunorubicin Volume of Distribution
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Daunorubicin Time of Maximum Concentration
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Daunorubicin Area Under the Curve
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Cytarabine Clearance
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Cytarabine Volume of Distribution
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Cytarabine Time of Maximum Concentration
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
measure: Liposome-encapsulated Cytarabine Area Under the Curve
timeFrame: Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1
Other outcomes:
measure: Length of Hospitalization Time
timeFrame: Up to 1 year
measure: Time to Bone Marrow Count Recovery
timeFrame: Up to 1 year
measure: Time to Peripheral Blood Cell Count Recovery
timeFrame: Up to 1 year
measure: Proportion of Patients Experiencing Toxicities
timeFrame: Up to 8 weeks post-treatment
measure: Change in Troponin Levels
timeFrame: Baseline up to day 30
measure: Change in N-terminal Pro B-type Natriuretic Peptide (NT-BNP) Levels
timeFrame: Baseline up to day 30
measure: Change in High Sensitive C-reactive Protein (HS-CRP) Levels
timeFrame: Baseline up to day 30
measure: Change in in Global Longitudinal Strain
timeFrame: Baseline up to 28 days
measure: Change in Micro Ribonucleic Acid (miRNA) Using TaqMan miRNA Assays
timeFrame: Baseline up to day 30
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Downey
country: United States
facility: Kaiser Permanente Downey Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Madera
country: United States
facility: Valley Children's Hospital
state: California
city: Oakland
country: United States
facility: UCSF Benioff Children's Hospital Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic-Jacksonville
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Indianapolis
country: United States
facility: Ascension Saint Vincent Indianapolis Hospital
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Scarborough
country: United States
facility: Maine Children's Cancer Program
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Detroit
country: United States
facility: Ascension Saint John Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center of Omaha
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Mineola
country: United States
facility: NYU Winthrop Hospital
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: The Children's Hospital at TriStar Centennial
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Children's Hospital of San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Burlington
country: United States
facility: University of Vermont and State Agricultural College
state: Vermont
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: The Montreal Children's Hospital of the MUHC
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Quebec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
Study officials:
affiliation: Children's Oncology Group
name: Todd M Cooper
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.