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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Acute Myeloid Leukemia Post Cytotoxic Therapy, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cytarabine
* Biological: Filgrastim
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Liposome-encapsulated Daunorubicin-Cytarabine
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (CPX-351 and FLAG)<br>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. | Drug: Cytarabine<br>* Given IT or IV<br>* Other names: WR-28453;Biological: Filgrastim<br>* Given SC or IV<br>* Other names: Tevagrastim;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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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 |