NCT01307579 · CITED IN SOURCE DOCUMENTS

Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2021-03-30

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI)

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outcome · POSTED

Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA)

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outcome · POSTED

Overall Survival

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outcome · POSTED

Percentage of Participants That Need Empiric Antifungal Therapy

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outcome · NOT POSTED

Sensitivity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI

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outcome · NOT POSTED

Specificity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI

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outcome · NOT POSTED

Positive Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI

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outcome · NOT POSTED

Negative Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI

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outcome · NOT POSTED

Genotyping Assays for Single Nucleotide Polymorphism Analysis

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

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
healthy Volunteers: false
maximum Age: 30 Years
minimum Age: 3 Months
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC \> 100-500/uL following the nadir or the next chemotherapy course begins.
intervention Names
Drug: Caspofungin Acetate
Other: Laboratory Biomarker Analysis
label
Arm I (caspofungin acetate)
type
EXPERIMENTAL
description
Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course.
intervention Names
Drug: Fluconazole
Other: Laboratory Biomarker Analysis
label
Arm II (fluconazole)
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
Arm I (caspofungin acetate)
description
Given IV
name
Caspofungin Acetate
other Names
Cancidas
type
DRUG
arm Group Labels
Arm II (fluconazole)
description
Given IV or PO
name
Fluconazole
other Names
Diflucan
type
DRUG
arm Group Labels
Arm I (caspofungin acetate)
Arm II (fluconazole)
description
Correlative studies
name
Laboratory Biomarker Analysis
type
OTHER

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

SUPPORTIVE_CARE

Enrollment

count: 517
type: ACTUAL

Registered outcome plans (not posted results)

other Outcomes

description
Sensitivity for the diagnosis of proven or probable IFI will be determined for the fungal biomarkers galactomannan and beta-D glucan assays. Sensitivity will be estimated for the combination of the two fungal biomarkers.
measure
Sensitivity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
time Frame
Up to 5 months since enrollment
description
Specificity of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Specificity will be estimated for the two fungal biomarkers together.
measure
Specificity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
time Frame
Up to 5 months since enrollment
description
Positive predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Positive predictive value will be estimated for the two fungal biomarkers together.
measure
Positive Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
time Frame
Up to 5 months since enrollment
description
Negative predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Negative predictive value will be estimated for the two fungal biomarkers together.
measure
Negative Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
time Frame
Up to 5 months since enrollment
description
Descriptive statistics will be used to summarize the prevalence of single nucleotide polymorphisms.
measure
Genotyping Assays for Single Nucleotide Polymorphism Analysis
time Frame
Up to 2 years post enrollment

primary Outcomes

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).
measure
Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI)
time Frame
Up to 5 months since enrollment

secondary Outcomes

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.
measure
Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA)
time Frame
Up to 5 months since enrollment
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.
measure
Overall Survival
time Frame
Up to 2 years post enrollment
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.
measure
Percentage of Participants That Need Empiric Antifungal Therapy
time Frame
Up to 5 months since enrollment

Full study description

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.
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.

Source references

references

citation
Fisher BT, Zaoutis T, Dvorak CC, Nieder M, Zerr D, Wingard JR, Callahan C, Villaluna D, Chen L, Dang H, Esbenshade AJ, Alexander S, Wiley JM, Sung L. Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial. JAMA. 2019 Nov 5;322(17):1673-1681. doi: 10.1001/jama.2019.15702.
pmid
31688884
type
DERIVED