Brief Summary
This randomized phase III trial compares the effectiveness of caspofungin to fluconazole in preventing invasive fungal infections in patients receiving chemotherapy for acute myeloid leukemia (AML). Antifungal prophylaxis is considered standard of care in children and adults with prolonged neutropenia after chemotherapy for AML however the ideal antifungal agent for prophylaxis in children is not known. Caspofungin has activity against yeast and some molds while fluconazole coverage is limited to just yeasts. Adult randomized trials suggest that agents with activity against yeasts and molds are more effective than those with just activity against yeasts. There are limited data to answer this comparative question in children. This study will establish much needed pediatric data to guide clinical decision making on optimal antifungal prophylaxis.
Brief Title
Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia
Detailed Description
PRIMARY OBJECTIVES:
I. To determine if prophylaxis with caspofungin administered during periods of neutropenia following chemotherapy for acute myeloid leukemia (AML) is associated with a lower incidence of proven or probable invasive fungal infections (IFI) compared with fluconazole.
SECONDARY OBJECTIVES:
I. To determine if prophylaxis with caspofungin will result in a lower incidence of proven or probable cases of invasive aspergillosis (IA) compared with fluconazole. (Clinical) II. To determine if prophylaxis with caspofungin will result in improved survival compared to fluconazole. (Clinical) III. To determine if prophylaxis with caspofungin will result in less empiric antifungal therapy compared to fluconazole. (Clinical) IV. To determine the sensitivity, specificity, and positive and negative predictive value of biweekly galactomannan (GM) and beta-D glucan testing in diagnosing IFI. (Biological) V. To test the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and proven or probable IFI. (Biological) VI. To develop predictive models of IFI using SNP in genes involved in immunity and clinical covariates. (Biological)
OUTLINE: Patients are randomized to one of two treatment arms during their first chemotherapy course for AML.
ARM I: Patients receive caspofungin acetate intravenously (IV) over one hour once daily (QD) beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until absolute neutrophil count (ANC) \> 100-500/uL following the nadir or the next chemotherapy course begins.
ARM II: Patients receive fluconazole IV over 1-2 hours or orally (PO) QD beginning within 24-72 hours following the last dose of chemotherapy for each course.
Protocol prophylaxis was continued in both arms, until ANC increased to \> 100-500/uL following the nadir or the next chemotherapy course began. Prophylaxis was given for all courses of planned AML chemotherapy or until the patient met one of the following off-protocol therapy criteria: development of proven or probable IFI according to institutional diagnosis, initiation of conditioning for hematopoietic cell transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML, refusal of further protocol therapy by patient, parent or guardian, or physician determines it is in the best interest of the patient.
Regardless of duration of prophylaxis, subjects in both arms are monitored for IFI until the earliest of the following criteria is met: two weeks after recovery of neutropenia following the last planned AML chemotherapy course, initiation of conditioning for hematopoietic cell transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML, withdrawal of consent for any further data submission, or death.
Patients were followed for overall survival up to two years from enrollment.
I. To determine if prophylaxis with caspofungin administered during periods of neutropenia following chemotherapy for acute myeloid leukemia (AML) is associated with a lower incidence of proven or probable invasive fungal infections (IFI) compared with fluconazole.
SECONDARY OBJECTIVES:
I. To determine if prophylaxis with caspofungin will result in a lower incidence of proven or probable cases of invasive aspergillosis (IA) compared with fluconazole. (Clinical) II. To determine if prophylaxis with caspofungin will result in improved survival compared to fluconazole. (Clinical) III. To determine if prophylaxis with caspofungin will result in less empiric antifungal therapy compared to fluconazole. (Clinical) IV. To determine the sensitivity, specificity, and positive and negative predictive value of biweekly galactomannan (GM) and beta-D glucan testing in diagnosing IFI. (Biological) V. To test the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and proven or probable IFI. (Biological) VI. To develop predictive models of IFI using SNP in genes involved in immunity and clinical covariates. (Biological)
OUTLINE: Patients are randomized to one of two treatment arms during their first chemotherapy course for AML.
ARM I: Patients receive caspofungin acetate intravenously (IV) over one hour once daily (QD) beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until absolute neutrophil count (ANC) \> 100-500/uL following the nadir or the next chemotherapy course begins.
ARM II: Patients receive fluconazole IV over 1-2 hours or orally (PO) QD beginning within 24-72 hours following the last dose of chemotherapy for each course.
Protocol prophylaxis was continued in both arms, until ANC increased to \> 100-500/uL following the nadir or the next chemotherapy course began. Prophylaxis was given for all courses of planned AML chemotherapy or until the patient met one of the following off-protocol therapy criteria: development of proven or probable IFI according to institutional diagnosis, initiation of conditioning for hematopoietic cell transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML, refusal of further protocol therapy by patient, parent or guardian, or physician determines it is in the best interest of the patient.
Regardless of duration of prophylaxis, subjects in both arms are monitored for IFI until the earliest of the following criteria is met: two weeks after recovery of neutropenia following the last planned AML chemotherapy course, initiation of conditioning for hematopoietic cell transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML, withdrawal of consent for any further data submission, or death.
Patients were followed for overall survival up to two years from enrollment.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Acute Myeloid Leukemia
Adult Acute Monoblastic Leukemia
Adult Acute Monocytic Leukemia
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With Maturation
Adult Acute Myeloid Leukemia With Minimal Differentiation
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1
Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A
Adult Acute Myeloid Leukemia Without Maturation
Adult Acute Myelomonocytic Leukemia
Alkylating Agent-Related Acute Myeloid Leukemia
Childhood Acute Monoblastic Leukemia
Childhood Acute Monocytic Leukemia
Childhood Acute Myeloid Leukemia in Remission
Childhood Acute Myeloid Leukemia With Maturation
Childhood Acute Myeloid Leukemia With Minimal Differentiation
Childhood Acute Myeloid Leukemia Without Maturation
Childhood Acute Myelomonocytic Leukemia
Fungal Infection
Myeloid Neoplasm
Neutropenia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Untreated Adult Acute Myeloid Leukemia
Untreated Childhood Myeloid Neoplasm
Eligibility Criteria
Inclusion Criteria:
* Patients must have one of the following diagnoses and/or treatment plans:
* Newly diagnosed de novo AML
* First or subsequent relapse of AML
* Secondary AML
* Treatment with institutional standard AML therapy in those without AML (for example, myelodysplastic syndrome, bone marrow blasts \> 5% or biphenotypia)
* Note: Patients with a history of prolonged antifungal therapy (example, relapsed AML) are eligible
* 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:
* =\< 0.4 mg/dL (age 1 month to \< 6 months)
* =\< 0.5 mg/dL (age 6 months to \< 1 year)
* =\< 0.6 mg/dL (age 1 to \< 2 years)
* =\< 0.8 mg/dL (age 2 to \< 6 years)
* =\< 1 mg/dL (age 6 to \< 10 years)
* =\< 1.2 mg/dL (age 10 to \< 13 years)
* =\< 1.4 mg/dL (females age \>= 13 years)
* =\< 1.5 mg/dL (males age 13 to \< 16 years)
* =\< 1.7 mg/dL (males age \>= 16 years)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age AND Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 2.5 x ULN for age
* All patients and/or their parents or legal guardians must sign a written informed consent
Exclusion Criteria:
* Patients with the following diagnoses are not eligible:
* Acute promyelocytic leukemia (APL)
* Down syndrome
* Juvenile myelomonocytic leukemia (JMML)
* Patients with a documented history of invasive fungal infection (IFI) within the previous 30 days are not eligible
* Patients with a history of echinocandin or fluconazole hypersensitivity are not eligible
* Patients receiving treatment for an IFI are not eligible
* Female patients of childbearing age must have a negative pregnancy test
* Patients must agree to use an effective birth control method
* Lactating patients must agree not to nurse a child while on this trial
* Patients must have one of the following diagnoses and/or treatment plans:
* Newly diagnosed de novo AML
* First or subsequent relapse of AML
* Secondary AML
* Treatment with institutional standard AML therapy in those without AML (for example, myelodysplastic syndrome, bone marrow blasts \> 5% or biphenotypia)
* Note: Patients with a history of prolonged antifungal therapy (example, relapsed AML) are eligible
* 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:
* =\< 0.4 mg/dL (age 1 month to \< 6 months)
* =\< 0.5 mg/dL (age 6 months to \< 1 year)
* =\< 0.6 mg/dL (age 1 to \< 2 years)
* =\< 0.8 mg/dL (age 2 to \< 6 years)
* =\< 1 mg/dL (age 6 to \< 10 years)
* =\< 1.2 mg/dL (age 10 to \< 13 years)
* =\< 1.4 mg/dL (females age \>= 13 years)
* =\< 1.5 mg/dL (males age 13 to \< 16 years)
* =\< 1.7 mg/dL (males age \>= 16 years)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age AND Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 2.5 x ULN for age
* All patients and/or their parents or legal guardians must sign a written informed consent
Exclusion Criteria:
* Patients with the following diagnoses are not eligible:
* Acute promyelocytic leukemia (APL)
* Down syndrome
* Juvenile myelomonocytic leukemia (JMML)
* Patients with a documented history of invasive fungal infection (IFI) within the previous 30 days are not eligible
* Patients with a history of echinocandin or fluconazole hypersensitivity are not eligible
* Patients receiving treatment for an IFI are not eligible
* Female patients of childbearing age must have a negative pregnancy test
* Patients must agree to use an effective birth control method
* Lactating patients must agree not to nurse a child while on this trial
Inclusion Criteria
Inclusion Criteria:
* Patients must have one of the following diagnoses and/or treatment plans:
* Newly diagnosed de novo AML
* First or subsequent relapse of AML
* Secondary AML
* Treatment with institutional standard AML therapy in those without AML (for example, myelodysplastic syndrome, bone marrow blasts \> 5% or biphenotypia)
* Note: Patients with a history of prolonged antifungal therapy (example, relapsed AML) are eligible
* 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:
* =\< 0.4 mg/dL (age 1 month to \< 6 months)
* =\< 0.5 mg/dL (age 6 months to \< 1 year)
* =\< 0.6 mg/dL (age 1 to \< 2 years)
* =\< 0.8 mg/dL (age 2 to \< 6 years)
* =\< 1 mg/dL (age 6 to \< 10 years)
* =\< 1.2 mg/dL (age 10 to \< 13 years)
* =\< 1.4 mg/dL (females age \>= 13 years)
* =\< 1.5 mg/dL (males age 13 to \< 16 years)
* =\< 1.7 mg/dL (males age \>= 16 years)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age AND Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 2.5 x ULN for age
* All patients and/or their parents or legal guardians must sign a written informed consent
* Patients must have one of the following diagnoses and/or treatment plans:
* Newly diagnosed de novo AML
* First or subsequent relapse of AML
* Secondary AML
* Treatment with institutional standard AML therapy in those without AML (for example, myelodysplastic syndrome, bone marrow blasts \> 5% or biphenotypia)
* Note: Patients with a history of prolonged antifungal therapy (example, relapsed AML) are eligible
* 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:
* =\< 0.4 mg/dL (age 1 month to \< 6 months)
* =\< 0.5 mg/dL (age 6 months to \< 1 year)
* =\< 0.6 mg/dL (age 1 to \< 2 years)
* =\< 0.8 mg/dL (age 2 to \< 6 years)
* =\< 1 mg/dL (age 6 to \< 10 years)
* =\< 1.2 mg/dL (age 10 to \< 13 years)
* =\< 1.4 mg/dL (females age \>= 13 years)
* =\< 1.5 mg/dL (males age 13 to \< 16 years)
* =\< 1.7 mg/dL (males age \>= 16 years)
* Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age AND Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 2.5 x ULN for age
* All patients and/or their parents or legal guardians must sign a written informed consent
Gender
All
Gender Based
false
Keywords
Pediatrics
leukemia
invasive fungal infection
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
30 Years
Minimum Age
3 Months
NCT Id
NCT01307579
Org Class
Network
Org Full Name
Children's Oncology Group
Org Study Id
ACCL0933
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Randomized Open-Label Trial of Caspofungin Versus Fluconazole to Prevent Invasive Fungal Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia (AML)
Primary Outcomes
Outcome Description
Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG).
Outcome Measure
Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI)
Outcome Time Frame
Up to 5 months since enrollment
Secondary Ids
Secondary Id
NCI-2011-02640
Secondary Id
CDR0000695748
Secondary Id
COG-ACCL0933
Secondary Id
S12-00316
Secondary Id
ACCL0933
Secondary Id
COG-ACCL0933
Secondary Id
ACCL0933
Secondary Id
U10CA095861
Secondary Id
UG1CA189955
Secondary Outcomes
Outcome Description
Proven or probable invasive aspergillosis (IA) is defined according to the criteria developed by the EORTC/MSG. Kaplan Meier approach will used to estimate the incidence.
Outcome Time Frame
Up to 5 months since enrollment
Outcome Measure
Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA)
Outcome Description
Kaplan Meier method will be used to estimate overall survival. Time to event is from enrollment to date of death (by any cause). Participants are censored at last contact or 2 years anniversary of enrollment into this study, whichever occurred first.
Outcome Time Frame
Up to 2 years post enrollment
Outcome Measure
Overall Survival
Outcome Description
The percentage of participants requiring empiric antifungal therapy will be determined based on the presence of prolonged fever and neutropenia during each neutropenia course.
Outcome Time Frame
Up to 5 months since enrollment
Outcome Measure
Percentage of Participants That Need Empiric Antifungal Therapy
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Maximum Age Number (converted to Years and rounded down)
30
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
Lisa Gennarini
Investigator Email
lfigueir@montefiore.org
Investigator Phone
Categories Mesh Debug
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID, ACUTE
Cancer --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID
Cancer --- NEOPLASMS
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
COVID-19 --- INFECTIONS
Infectious Disease --- INFECTIONS
MeSH Terms
LEUKEMIA, MYELOID, ACUTE
LEUKEMIA, MONOCYTIC, ACUTE
LEUKEMIA, MYELOMONOCYTIC, ACUTE
MYCOSES
NEUTROPENIA
LEUKEMIA
INVASIVE FUNGAL INFECTIONS
LEUKEMIA, MYELOID
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
BACTERIAL INFECTIONS AND MYCOSES
INFECTIONS
AGRANULOCYTOSIS
LEUKOPENIA
CYTOPENIA
LEUKOCYTE DISORDERS
CASPOFUNGIN
FLUCONAZOLE
LIPOPEPTIDES
LIPIDS
PEPTIDES
AMINO ACIDS, PEPTIDES, AND PROTEINS
ECHINOCANDINS
PEPTIDES, CYCLIC
TRIAZOLES
AZOLES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS