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

Secondary Acute Myeloid Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02642965
• Other study ID #: AAML1421
• Secondary ID: NCI-2015-01917AA
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 2, 2016
• Est. completion date: June 30, 2023

Study information

• Verified date: August 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: June 30, 2023
• Est. primary completion date: December 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Recurrent Childhood Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia

Intervention

Drug:
• Cytarabine
Given IT or IV

Biological:
• Filgrastim
Given SC or IV

Drug:
• Fludarabine Phosphate
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Liposome-encapsulated Daunorubicin-Cytarabine
Given IV

Other:
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont and State Agricultural College	Burlington	Vermont
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Valley Children's Hospital	Madera	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Length of Hospitalization Time	Descriptive statistics will be used to summarize length of hospitalization time.	Up to 1 year
Other	Time to Bone Marrow Count Recovery	Descriptive statistics will be used to summarize bone marrow count recovery.	Up to 1 year
Other	Time to Peripheral Blood Cell Count Recovery	Descriptive statistics will be used to summarize peripheral blood cell count recovery.	Up to 1 year
Other	Proportion of Patients Experiencing Toxicities	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.	Up to 8 weeks post-treatment
Other	Change in Troponin Levels	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.	Baseline up to day 30
Other	Change in N-terminal Pro B-type Natriuretic Peptide (NT-BNP) Levels	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.	Baseline up to day 30
Other	Change in High Sensitive C-reactive Protein (HS-CRP) Levels	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.	Baseline up to day 30
Other	Change in in Global Longitudinal Strain	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.	Baseline up to 28 days
Other	Change in Micro Ribonucleic Acid (miRNA) Using TaqMan miRNA Assays	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.	Baseline up to day 30
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive