Fungal Infection, Hematopoietic and Lymphoid Cell Neoplasm
Conditions
Brief summary
This randomized phase III trial studies how well caspofungin acetate works compared to fluconazole or voriconazole in preventing fungal infections in patients following donor stem cell transplant. Caspofungin acetate, fluconazole, and voriconazole may be effective in preventing fungal infections in patients following donor stem cell transplant. It is not yet known whether caspofungin acetate is more effective than fluconazole or voriconazole in preventing fungal infections in patients following donor stem cell transplant.
Detailed description
PRIMARY OBJECTIVES: I. To determine if caspofungin (caspofungin acetate) is associated with a lower incidence of proven/probable invasive fungal infections (IFI) during the first 42 days following allogeneic hematopoietic cell transplantation (HCT) at high-risk for IFI compared with azole (fluconazole or voriconazole) prophylaxis. EXPLORATORY OBJECTIVES: I. To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 100 days following high-risk allogeneic HCT compared with azole (fluconazole or voriconazole) prophylaxis. (Exploratory) II. To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 and 100 days following high-risk allogeneic HCT compared with fluconazole prophylaxis. (Exploratory) III. To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 and 100 days following high-risk allogeneic HCT compared with voriconazole prophylaxis. (Exploratory) IV. To determine if caspofungin is associated with a superior fungal-free survival (FFS) (time to death or proven/probable IFI) at 42 and 100 days following high-risk allogeneic HCT compared with azole prophylaxis. (Exploratory) V. To describe the effect that caspofungin and azoles have on the incidence and severity of acute graft-versus-host disease (GVHD). (Exploratory) VI. To define the test characteristics of weekly Fungitell assay testing for identifying IFI in pediatric hematopoietic stem cell transplantation (HSCT) recipients receiving antifungal prophylaxis during the post-transplant neutropenic period. (Exploratory) VII. To create a deoxyribonucleic acid (DNA) specimen bank in anticipation of the development of biology correlative studies exploring the relationship between IFI and single nucleotide polymorphisms (SNPs) of genes involved in immunity. (Exploratory) OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive caspofungin acetate intravenously (IV) over 1 hour once daily (QD) beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression. ARM II: Patients receive fluconazole IV over 1-2 hours QD or orally (PO) QD; or voriconazole IV over 1-2 hours QD or PO twice daily (BID) beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression. After completion of study treatment, patients are followed up until day 100.
Interventions
Given IV
DRUGFluconazole
Given IV or PO
OTHERLaboratory Biomarker Analysis
Optional correlative studies
DRUGVoriconazole
Given IV or PO
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 20 Years
Healthy volunteers
No
Inclusion criteria
* Age * For centers that will use fluconazole as the antifungal comparator: * Age \>= 3 months and \< 21 years * For centers that will use voriconazole as the antifungal comparator: * Age \>= 2 years and \< 21 years * The patient must be undergoing allogeneic HCT from any donor (including matched related) with any stem cell source for any underlying condition * Patients must have a performance status corresponding to 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 * 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 (1 month to \< 6 months of age) * 0.5 mg/dL (6 months to \< 1 year of age) * 0.6 mg/dL (1 to \< 2 years of age) * 0.8 mg/dL (2 to \< 6 years of age) * 1.0 mg/dL (6 to \< 10 years of age) * 1.2 mg/dL (10 to \< 13 years of age) * 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to \< 16 years of age) * 1.7 mg/dL (male) or 1.4 mg/dL (female) (\>= 16 years of age) * Total bilirubin \< 2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 5 x upper limit of normal (ULN) for age * 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
* Within 90 days of enrollment: * Patients with a proven or probable invasive mold infection are not eligible * Patients with an incompletely treated invasive yeast infection are not eligible * Patients with an elevated galactomannan level (\>= 0.5 index) within 30 days prior to time of enrollment (if performed) must have a full evaluation for invasive aspergillosis (including a negative chest computed tomography \[CT\] scan) during that time period to be eligible for enrollment * Patients receiving treatment for an IFI are not eligible * Patients with a history of echinocandin or azole hypersensitivity 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 * Lactating females are not eligible unless they have agreed not to breastfeed their infants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 42-day-cumulative Incidence of Proven or Probable Invasive Fungal Infections (IFI) | Up to 42 days following allogeneic HCT | Kaplan-Meier curves will be used to estimate the 42- day-cumulative incidence of proven/probable IFI following allogeneic HCT for patients randomized to the 2 arms. Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Fungal-free-survival | Up to 42 days following allogeneic HCT | Defined as time to death or proven/probable IFI during the first 42 days following allogeneic HCT. |
| Incidence of Overall Clinical GVHD Grades III and IV | Up to 100 days after allogeneic HCT | The percentage distribution of overall clinical grades III and IV will be estimated for each arm. |
| Incidence of Overall Clinical GVHD Grades II to IV | Up to 100 days after allogeneic HCT | The percentage distribution of overall clinical grades II and IV will be estimated for each arm. |
| 100-day-cumulative Incidence of Proven or Probable IFI | Up to day 100 following allogeneic HCT | Kaplan-Meier curves will be used to estimate the 100- day-cumulative incidence of proven/probable IFI following allogeneic HCT for patients randomized to the 2 arms. Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG). |
| Specificity of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay | Up to day 42 following allogeneic HCT | Specificity of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard. |
| Positive Predictive Value of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay | Up to day 42 following allogeneic HCT | Positive predictive value of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard. |
| Negative Predictive Value of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay | Up to day 42 following allogeneic HCT | Negative predictive value of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard. |
| Sensitivity of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay | Up to day 42 following allogeneic HCT | Sensitivity of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Caspofungin Acetate) Patients receive caspofungin acetate IV over 1 hour once daily (QD) beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression.
Caspofungin Acetate: Given IV
Laboratory Biomarker Analysis: Optional correlative studies | 145 |
| Arm II (Fluconazole or Voriconazole) Patients receive fluconazole IV over 1-2 hours QD or PO QD; or voriconazole IV over 1-2 hours QD or PO BID beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression.
Fluconazole: Given IV or PO
Laboratory Biomarker Analysis: Optional correlative studies
Voriconazole: Given IV or PO | 147 |
| Total | 292 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Ineligible | 1 | 1 |
| Overall Study | Institutional dx of proven/probable IFI | 2 | 4 |
| Overall Study | Physician Decision | 14 | 23 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Arm I (Caspofungin Acetate) | Arm II (Fluconazole or Voriconazole) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 134 Participants | 133 Participants | 267 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 14 Participants | 25 Participants |
| Age, Continuous | 9.2 years STANDARD_DEVIATION 5.7 | 9.1 years STANDARD_DEVIATION 6 | 9.2 years STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 27 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 107 Participants | 220 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 13 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 6 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 22 Participants | 33 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 20 Participants | 31 Participants |
| Race (NIH/OMB) White | 110 Participants | 97 Participants | 207 Participants |
| Region of Enrollment Canada | 9 participants | 15 participants | 24 participants |
| Region of Enrollment United States | 136 participants | 132 participants | 268 participants |
| Sex: Female, Male Female | 56 Participants | 56 Participants | 112 Participants |
| Sex: Female, Male Male | 89 Participants | 91 Participants | 180 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 144 | 10 / 146 |
| other Total, other adverse events | 29 / 144 | 30 / 146 |
| serious Total, serious adverse events | 4 / 144 | 3 / 146 |
Outcome results
Primary
42-day-cumulative Incidence of Proven or Probable Invasive Fungal Infections (IFI)
Kaplan-Meier curves will be used to estimate the 42- day-cumulative incidence of proven/probable IFI following allogeneic HCT for patients randomized to the 2 arms. Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG).
Time frame: Up to 42 days following allogeneic HCT
Population: study enrolled 292 patients (145 randomized to caspofungin and 147 randomized to an azole) . Two patients (1 caspofungin, 1 azole) were ineligible, resulting in 290 patients (144 caspofungin, 146 azole) included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Caspofungin Acetate) | 42-day-cumulative Incidence of Proven or Probable Invasive Fungal Infections (IFI) | 1.4 percentage of patients |
| Arm II (Fluconazole or Voriconazole) | 42-day-cumulative Incidence of Proven or Probable Invasive Fungal Infections (IFI) | 1.4 percentage of patients |
Other Pre-specified
100-day-cumulative Incidence of Proven or Probable IFI
Kaplan-Meier curves will be used to estimate the 100- day-cumulative incidence of proven/probable IFI following allogeneic HCT for patients randomized to the 2 arms. Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG).
Time frame: Up to day 100 following allogeneic HCT
Other Pre-specified
Fungal-free-survival
Defined as time to death or proven/probable IFI during the first 100 days following allogeneic HCT.
Time frame: Up to 100 days following allogeneic HCT
Other Pre-specified
Fungal-free-survival
Defined as time to death or proven/probable IFI during the first 42 days following allogeneic HCT.
Time frame: Up to 42 days following allogeneic HCT
Other Pre-specified
Incidence of Overall Clinical GVHD Grades III and IV
The percentage distribution of overall clinical grades III and IV will be estimated for each arm.
Time frame: Up to 100 days after allogeneic HCT
Other Pre-specified
Incidence of Overall Clinical GVHD Grades II to IV
The percentage distribution of overall clinical grades II and IV will be estimated for each arm.
Time frame: Up to 100 days after allogeneic HCT
Other Pre-specified
Negative Predictive Value of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay
Negative predictive value of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.
Time frame: Up to day 42 following allogeneic HCT
Other Pre-specified
Positive Predictive Value of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay
Positive predictive value of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.
Time frame: Up to day 42 following allogeneic HCT
Other Pre-specified
Sensitivity of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay
Sensitivity of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.
Time frame: Up to day 42 following allogeneic HCT
Other Pre-specified
Specificity of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay
Specificity of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.
Time frame: Up to day 42 following allogeneic HCT