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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Open-Label Trial of Caspofungin Versus Fluconazole to Prevent Invasive Fungal Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia (AML)

Conditions
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Neutropenia, 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, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia, Untreated Childhood Myeloid Neoplasm

Intervention / Treatment
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* Drug: Caspofungin Acetate
* Drug: Fluconazole
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (caspofungin acetate)<br>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. | Drug: Caspofungin Acetate<br>* Given IV<br>* Other names: Cancidas;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Active Comparator: Arm II (fluconazole)<br>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. | Drug: Fluconazole<br>* Given IV or PO<br>* Other names: Diflucan;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI) | 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). | Up to 5 months since enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA) | 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. | Up to 5 months since enrollment | 
| Overall Survival | 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. | Up to 2 years post enrollment | 
| Percentage of Participants That Need Empiric Antifungal Therapy | The percentage of participants requiring empiric antifungal therapy will be determined based on the presence of prolonged fever and neutropenia during each neutropenia course. | Up to 5 months since enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leukemia, Pediatrics, invasive fungal infection