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

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02642965
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 38
• Locations: 73
• Arm: 1
• Anticipated Duration (Months): 86.1
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia	Drug: Cytarabine; Biological: Filgrastim; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Other: Pharmacological Study	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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).

2. 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:

1. To estimate the response rate (CR + CRp + complete remission with incomplete blood count recovery [CRi]) after one cycle of CPX-351.

2. 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:

1. To describe the response in biomarkers of cardiac injury to a single cycle of CPX-351.

2. 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.

3. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: Apr 25, 2016
• Actual Primary Completion Date: Dec 31, 2018
• Anticipated Study Completion Date: Jun 30, 2023

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (CPX-351 and FLAG) 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; Given IT or IV; Other Names: .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 ; Biological: Filgrastim; Given SC or IV; Other Names: G-CSF Neupogen r-metHuG-CSF Recombinant Methionyl Human Granulocyte Colony Stimulating Factor rG-CSF Tevagrastim ; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Given IV; Other Names: CPX-351 Cytarabine-Daunorubicin Liposome for Injection Liposomal AraC-Daunorubicin CPX-351 Liposomal Cytarabine-Daunorubicin Liposome-encapsulated Combination of Daunorubicin and Cytarabine Vyxeos ; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Dose-limiting Toxicity [28 days]

   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.

2. Percentage of Responders (Complete Response or Complete Remission With Partial Platelet Recovery) After up to 2 Cycles [Up to 8 weeks]

   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.

Secondary Outcome Measures

1. Percentage of Responders (Complete Response or Complete Remission With Partial or Incomplete Platelet Recovery) After First Cycle of Therapy [Up to 4 weeks]

   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.

2. Liposome-encapsulated Daunorubicin Clearance [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   Geometric mean liposome-encapsulated daunorubicin clearance following IV infusion will be determined for patients in the dose-finding phase.

3. Liposome-encapsulated Daunorubicin Volume of Distribution [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   Geometric mean liposome-encapsulated daunorubicin volume of distribution following IV infusion will be determined for patients in the dose-finding phase.

4. Liposome-encapsulated Daunorubicin Time of Maximum Concentration [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   Median liposome-encapsulated daunorubicin time of maximum observed plasma concentration will be determined for patients in the dose-finding phase.

5. Liposome-encapsulated Daunorubicin Area Under the Curve [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   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.

6. Liposome-encapsulated Cytarabine Clearance [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   Geometric mean liposome-encapsulated cytarabine clearance following IV infusion will be determined for patients in the dose-finding phase.

7. Liposome-encapsulated Cytarabine Volume of Distribution [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   Geometric mean liposome-encapsulated cytarabine volume of distribution following IV infusion will be determined for patients in the dose-finding phase.

8. Liposome-encapsulated Cytarabine Time of Maximum Concentration [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   Median liposome-encapsulated cytarabine time of maximum observed plasma concentration will be determined for patients in the dose-finding phase.

9. Liposome-encapsulated Cytarabine Area Under the Curve [Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1]

   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.

Other Outcome Measures

1. Length of Hospitalization Time [Up to 1 year]

   Descriptive statistics will be used to summarize length of hospitalization time.

2. Time to Bone Marrow Count Recovery [Up to 1 year]

   Descriptive statistics will be used to summarize bone marrow count recovery.

3. Time to Peripheral Blood Cell Count Recovery [Up to 1 year]

   Descriptive statistics will be used to summarize peripheral blood cell count recovery.

4. Proportion of Patients Experiencing Toxicities [Up to 8 weeks post-treatment]

   Proportion of patients experiencing >= grade 3 non-hematologic toxicities, cardiac toxicities, and infections by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

5. Change in Troponin Levels [Baseline up to day 30]

   Spearman correlation coefficients will be used to correlate the post-treatment values of troponin with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in global longitudinal strain.

6. Change in N-terminal Pro B-type Natriuretic Peptide (NT-BNP) Levels [Baseline up to day 30]

   Spearman correlation coefficients will be used to correlate the post-treatment values of NT-BNP with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in in global longitudinal strain.

7. Change in High Sensitive C-reactive Protein (HS-CRP) Levels [Baseline up to day 30]

   Spearman correlation coefficients will be used to correlate the post-treatment values of HS-CRP with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in in global longitudinal strain.

8. Change in in Global Longitudinal Strain [Baseline up to 28 days]

   A paired t-test will be used to compare the mean global longitudinal strain between the pre-treatment (at relapse) baseline and post-course 1 echocardiogram.

9. Change in Micro Ribonucleic Acid (miRNA) Using TaqMan miRNA Assays [Baseline up to day 30]

   Plasma miR-29b and -499 fold change from pre-treatment baseline will be determined at each post-treatment time point using the delta-delta-Ct method. The relationship between 6-hour miR-29b and -499 expression and change in left ventricular global longitudinal strain between the pre-cycle and end of cycle 1 echocardiograms will be determined by calculating a Spearman correlation coefficient.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
4	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
5	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
6	Loma Linda University Medical Center	Loma Linda	California	United States	92354
7	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
8	Valley Children's Hospital	Madera	California	United States	93636
9	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
10	Children's Hospital of Orange County	Orange	California	United States	92868
11	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
12	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
13	Children's Hospital Colorado	Aurora	Colorado	United States	80045
14	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
15	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
16	Children's National Medical Center	Washington	District of Columbia	United States	20010
17	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
18	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
19	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
20	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
21	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
22	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
23	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
24	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
25	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
26	Eastern Maine Medical Center	Bangor	Maine	United States	04401
27	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
28	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
29	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
30	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
31	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
32	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
33	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
34	Mayo Clinic	Rochester	Minnesota	United States	55905
35	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
36	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
37	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
38	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
39	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
40	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
41	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
42	NYU Winthrop Hospital	Mineola	New York	United States	11501
43	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
44	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
45	University of Rochester	Rochester	New York	United States	14642
46	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
47	Mission Hospital	Asheville	North Carolina	United States	28801
48	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
49	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
50	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
51	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
52	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
53	Oregon Health and Science University	Portland	Oregon	United States	97239
54	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
55	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
56	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
57	The Children's Hospital at TriStar Centennial	Nashville	Tennessee	United States	37203
58	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
59	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
60	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
61	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
62	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
63	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
64	Seattle Children's Hospital	Seattle	Washington	United States	98105
65	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
66	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
67	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
68	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
69	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
70	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
71	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
72	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
73	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Todd M Cooper, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 22, 2018

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT02642965
• Other Study ID Numbers: AAML1421; NCI-2015-01917; AAML1421; PAAML1421_R02PAPP01; s16-00955; AAML1421; AAML1421; U10CA180886
• First Posted: Dec 30, 2015
• Last Update Posted: Jan 25, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Fludarabine; Fludarabine phosphate; Daunorubicin; Lenograstim

Study Results

Participant Flow

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	38
COMPLETED	25
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Overall Participants	38
Age (Count of Participants)
<=18 years	35 92.1%
Between 18 and 65 years	3 7.9%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	20 52.6%
Male	18 47.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 18.4%
Not Hispanic or Latino	29 76.3%
Unknown or Not Reported	2 5.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 5.3%
Native Hawaiian or Other Pacific Islander	1 2.6%
Black or African American	4 10.5%
White	26 68.4%
More than one race	1 2.6%
Unknown or Not Reported	4 10.5%
Region of Enrollment (participants) [Number]
United States	36 94.7%
Canada	2 5.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Dose-limiting Toxicity
Description	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.
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

First 6 patients evaluable for dose limiting toxicity (DLT).

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	6
Count of Participants [Participants]	1 2.6%

2. Primary Outcome

Title	Percentage of Responders (Complete Response or Complete Remission With Partial Platelet Recovery) After up to 2 Cycles
Description	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.
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

1 patient among the 38 eligible patients was not evaluable for response.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	37
Number (90% Confidence Interval) [Percantage of best responders]	68.30

3. Secondary Outcome

Title	Percentage of Responders (Complete Response or Complete Remission With Partial or Incomplete Platelet Recovery) After First Cycle of Therapy
Description	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.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

1 patient among the 38 eligible patients was not evaluable for response.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	37
Number (95% Confidence Interval) [Percentage of responders]	75.68

4. Secondary Outcome

Title	Liposome-encapsulated Daunorubicin Clearance
Description	Geometric mean liposome-encapsulated daunorubicin clearance following IV infusion will be determined for patients in the dose-finding phase.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Full Range) [MILLILITER / HOUR]	94.7

5. Secondary Outcome

Title	Liposome-encapsulated Daunorubicin Volume of Distribution
Description	Geometric mean liposome-encapsulated daunorubicin volume of distribution following IV infusion will be determined for patients in the dose-finding phase.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Full Range) [MILLILITER]	3827.7

6. Secondary Outcome

Title	Liposome-encapsulated Daunorubicin Time of Maximum Concentration
Description	Median liposome-encapsulated daunorubicin time of maximum observed plasma concentration will be determined for patients in the dose-finding phase.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Median (Full Range) [HOUR]	2

7. Secondary Outcome

Title	Liposome-encapsulated Daunorubicin Area Under the Curve
Description	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.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Full Range) [(NANOGRAM x HOUR) / MILLILITER]	1288010.3

8. Secondary Outcome

Title	Liposome-encapsulated Cytarabine Clearance
Description	Geometric mean liposome-encapsulated cytarabine clearance following IV infusion will be determined for patients in the dose-finding phase.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Full Range) [MILLILITER / HOUR]	71.76

9. Secondary Outcome

Title	Liposome-encapsulated Cytarabine Volume of Distribution
Description	Geometric mean liposome-encapsulated cytarabine volume of distribution following IV infusion will be determined for patients in the dose-finding phase.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Full Range) [MILLILITER]	4158.0

10. Secondary Outcome

Title	Liposome-encapsulated Cytarabine Time of Maximum Concentration
Description	Median liposome-encapsulated cytarabine time of maximum observed plasma concentration will be determined for patients in the dose-finding phase.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Median (Full Range) [HOUR]	5

11. Secondary Outcome

Title	Liposome-encapsulated Cytarabine Area Under the Curve
Description	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.
Time Frame	Prior to infusion on day 5 and, 45 and 90 minutes post day 5 infusion of cycle 1

Outcome Measure Data

Analysis Population Description

Patients in the efficacy phase excluded (n=32). 1 dose finding patient excluded because dose record was not consistent with treatment plan.

Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
Measure Participants	5
Geometric Mean (Full Range) [(NANOGRAM x HOUR) / MILLILITER]	4418582.5

12. Other Pre-specified Outcome

Title	Length of Hospitalization Time
Description	Descriptive statistics will be used to summarize length of hospitalization time.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Other Pre-specified Outcome

Title	Time to Bone Marrow Count Recovery
Description	Descriptive statistics will be used to summarize bone marrow count recovery.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Other Pre-specified Outcome

Title	Time to Peripheral Blood Cell Count Recovery
Description	Descriptive statistics will be used to summarize peripheral blood cell count recovery.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Other Pre-specified Outcome

Title	Proportion of Patients Experiencing Toxicities
Description	Proportion of patients experiencing >= grade 3 non-hematologic toxicities, cardiac toxicities, and infections by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time Frame	Up to 8 weeks post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Change in Troponin Levels
Description	Spearman correlation coefficients will be used to correlate the post-treatment values of troponin with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in global longitudinal strain.
Time Frame	Baseline up to day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Other Pre-specified Outcome

Title	Change in N-terminal Pro B-type Natriuretic Peptide (NT-BNP) Levels
Description	Spearman correlation coefficients will be used to correlate the post-treatment values of NT-BNP with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in in global longitudinal strain.
Time Frame	Baseline up to day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Other Pre-specified Outcome

Title	Change in High Sensitive C-reactive Protein (HS-CRP) Levels
Description	Spearman correlation coefficients will be used to correlate the post-treatment values of HS-CRP with previous cumulative anthracycline dose prior to liposome-encapsulated daunorubicin-cytarabine, change in ejection fraction between pre- and post-liposome-encapsulated daunorubicin-cytarabine baseline assessed by echocardiogram before and after course 1, and change in in global longitudinal strain.
Time Frame	Baseline up to day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Other Pre-specified Outcome

Title	Change in in Global Longitudinal Strain
Description	A paired t-test will be used to compare the mean global longitudinal strain between the pre-treatment (at relapse) baseline and post-course 1 echocardiogram.
Time Frame	Baseline up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Other Pre-specified Outcome

Title	Change in Micro Ribonucleic Acid (miRNA) Using TaqMan miRNA Assays
Description	Plasma miR-29b and -499 fold change from pre-treatment baseline will be determined at each post-treatment time point using the delta-delta-Ct method. The relationship between 6-hour miR-29b and -499 expression and change in left ventricular global longitudinal strain between the pre-cycle and end of cycle 1 echocardiograms will be determined by calculating a Spearman correlation coefficient.
Time Frame	Baseline up to day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	While patients were on Protocol Therapy (up to 8 weeks) or during follow-up (up to 3 years).
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Arm/Group Title	Treatment (CPX-351 and FLAG)
Arm/Group Description	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.
All Cause Mortality
	Treatment (CPX-351 and FLAG)
	Affected / at Risk (%)	# Events
Total	14/38 (36.8%)
Serious Adverse Events
	Treatment (CPX-351 and FLAG)
	Affected / at Risk (%)	# Events
Total	21/38 (55.3%)
Blood and lymphatic system disorders
Febrile neutropenia	11/38 (28.9%)
Gastrointestinal disorders
Dysphagia	1/38 (2.6%)
Gastrointestinal disorders - Other, specify	1/38 (2.6%)
Mucositis oral	1/38 (2.6%)
Typhlitis	2/38 (5.3%)
General disorders
Death NOS	5/38 (13.2%)
Fever	2/38 (5.3%)
Infections and infestations
Anorectal infection	1/38 (2.6%)
Catheter related infection	1/38 (2.6%)
Infections and infestations - Other, specify	6/38 (15.8%)
Kidney infection	1/38 (2.6%)
Lung infection	2/38 (5.3%)
Skin infection	1/38 (2.6%)
Small intestine infection	1/38 (2.6%)
Soft tissue infection	1/38 (2.6%)
Investigations
Blood bilirubin increased	1/38 (2.6%)
Ejection fraction decreased	1/38 (2.6%)
Lymphocyte count decreased	1/38 (2.6%)
White blood cell decreased	1/38 (2.6%)
Metabolism and nutrition disorders
Anorexia	1/38 (2.6%)
Hyperglycemia	2/38 (5.3%)
Nervous system disorders
Headache	1/38 (2.6%)
Nervous system disorders - Other, specify	1/38 (2.6%)
Syncope	1/38 (2.6%)
Renal and urinary disorders
Urinary frequency	1/38 (2.6%)
Reproductive system and breast disorders
Reproductive system and breast disorders - Other, specify	1/38 (2.6%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/38 (2.6%)
Stridor	1/38 (2.6%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	6/38 (15.8%)
Other (Not Including Serious) Adverse Events
	Treatment (CPX-351 and FLAG)
	Affected / at Risk (%)	# Events
Total	34/38 (89.5%)
Blood and lymphatic system disorders
Anemia	1/38 (2.6%)
Blood and lymphatic system disorders - Other, specify	2/38 (5.3%)
Febrile neutropenia	7/38 (18.4%)
Cardiac disorders
Ventricular arrhythmia	1/38 (2.6%)
Gastrointestinal disorders
Rectal pain	1/38 (2.6%)
General disorders
General disorders and administration site conditions - Other, specify	4/38 (10.5%)
Multi-organ failure	1/38 (2.6%)
Infections and infestations
Device related infection	1/38 (2.6%)
Enterocolitis infectious	2/38 (5.3%)
Infections and infestations - Other, specify	3/38 (7.9%)
Mucosal infection	2/38 (5.3%)
Periorbital infection	1/38 (2.6%)
Skin infection	3/38 (7.9%)
Upper respiratory infection	2/38 (5.3%)
Investigations
Alanine aminotransferase increased	4/38 (10.5%)
Aspartate aminotransferase increased	3/38 (7.9%)
Ejection fraction decreased	2/38 (5.3%)
Electrocardiogram QT corrected interval prolonged	14/38 (36.8%)
GGT increased	2/38 (5.3%)
Investigations - Other, specify	1/38 (2.6%)
Platelet count decreased	1/38 (2.6%)
Metabolism and nutrition disorders
Anorexia	2/38 (5.3%)
Hyperglycemia	1/38 (2.6%)
Hypokalemia	5/38 (13.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/38 (2.6%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	2/38 (5.3%)
Pleural effusion	1/38 (2.6%)
Pneumothorax	1/38 (2.6%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/38 (2.6%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	11/38 (28.9%)
Skin and subcutaneous tissue disorders - Other, specify	1/38 (2.6%)
Vascular disorders
Hypotension	1/38 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior sponsor approval