Infections

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Anti-Infective Agents

All Drugs and Chemicals

Clotrimazole

Miconazole

Antifungal Agents

Caspofungin

Enzyme Inhibitors

Empirical approach (fever driven) for starting antifungal therapy

Pre-emptive approach (diagnostic driven) for starting antifungal therapy

intravenous route, at a 70 mg loading dose on day 1 of antifungal therapy, followed by 50 mg once a day thereafter.

caspofungin acetate

RATIONALE: Caspofungin acetate may be effective in treating fungal infections in patients with acute myeloid leukemia or myelodysplastic syndrome who are receiving treatment for their cancer. It is not yet known whether caspofungin acetate is more effective when treatment starts after development of a fever or after the infection is shown in laboratory test, chest x-ray, or CT scan.

PURPOSE: This randomized phase III trial is studying the best time to start caspofungin acetate therapy in treating patients with acute myeloid leukemia or myelodysplastic syndrome that is newly diagnosed or in first relapse.

OBJECTIVES:

Primary

* To compare empirical approach (i.e., fever driven) versus preemptive approach (i.e., diagnostic driven), for starting antifungal therapy with caspofungin acetate, in patients with acute myeloid leukemia or myelodysplastic syndrome who are starting chemotherapy (for attaining remission induction) or myeloablation (to prepare for an allogeneic hematopoietic stem cell transplantation) for newly diagnosed disease or disease in first relapse.

Secondary

* To evaluate clinical validity and utility of a standardized Aspergillus PCR assay.
* To evaluate clinical validity and utility of beta-D-glucan.
* To determine the occurrence of single nucleotide polymorphisms (SNPs) and the predictive value of SNPs for identifying patients at higher risk of developing invasive fungal infection.

OUTLINE: This is a multicenter study. Patients are stratified according to institution, prior allogeneic stem cell transplantation (yes vs no), and type of air flow (laminar air flow vs high-efficiency particulate air). Patients are randomized to 1 of 2 treatment arms.

* Arm A (Empirical approach): Patients start caspofungin acetate treatment when one of the following criteria are met:

  * Presence of unexplained persistent fever refractory to 4 full days of broad-spectrum antibacterial therapy with any of the following regimens either alone or in combination with an aminoglycoside or a glycopeptide:

    * Ceftazidime
    * Cefepime
    * Piperacillin/tazobactam
    * Imipenem-cilastatin
    * Meropenem
  * New fever occurring \> 2 days after resolution of a first fever while continuing broad-spectrum antibacterial therapy as defined above for which no obvious cause has been documented and fungal infection cannot be excluded Patients receive caspofungin acetate IV once daily. Treatment continues until neutrophil recovers.
* Arm B (Preemptive approach): Patients start caspofungin acetate treatment when at least one of the following criteria\* are met:

  * Single plasma or serum galactomannan ELISA with index \> 0.5
  * New pulmonary infiltrate on chest x-ray and IFD cannot be readily excluded
  * New dense well-circumscribed lesions with or without a halo sign, on a CT scan, consistent with IFD
  * Aspergillus sp. recovered by culture from sputum Patients receive caspofungin acetate IV once daily. Treatment continues until neutrophil recovers.

NOTE: \*These criteria are not sufficient to warrant preemptive caspofungin acetate therapy: skin lesions evocative of IFD, sinusitis or orbititis, hepatosplenic abscesses (hypodensities on CT scan), or unexplained persistent fever for more than 7 days or recurrent fever whatever its duration.

All patients undergo blood sample collection periodically for the detection of galactomannan and beta-D-glucan and for the detection of single nucleotide polymorphisms. Some patients undergo blood sample collection for the detection of Aspergillus via PCR. An economic evaluation is performed for cost-effectiveness analysis.

After completion of study treatment, patients are followed periodically.

Empirical Versus Preemptive Antifungal Therapy

Empirical Versus Pre-emptive (Diagnostic-driven) Antifungal Therapy of Patients Treated for Haematological Malignancies or Receiving an Allogeneic Stem Cell Transplant. A Therapeutic Open Label Phase III Strategy Study of the EORTC Infectious Diseases and Leukemia Groups

European Organisation for Research and Treatment of Cancer - EORTC

Invasive Fungal Infections

Disease Attributes

Voriconazole

Fluconazole

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

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.

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.

Caspofungin Acetate

Laboratory Biomarker Analysis

Christopher C Dvorak

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.

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.

Caspofungin Acetate, Fluconazole, or Voriconazole in Preventing Fungal Infections in Patients Following Donor Stem Cell Transplant

A Phase III Open-Label Trial of Caspofungin vs. Azole Prophylaxis for Patients at High-Risk for Invasive Fungal Infections (IFI) Following Allogeneic Hematopoietic Cell Transplantation (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).

Defined as time to death or proven/probable IFI during the first 42 days following allogeneic HCT.

The percentage distribution of overall clinical grades III and IV will be estimated for each arm.

The percentage distribution of overall clinical grades II and IV will be estimated for each arm.

Defined as time to death or proven/probable IFI during the first 100 days following allogeneic HCT.

Sensitivity of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.

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 the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.

Negative predictive value of the beta-D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold standard.

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).

National Cancer Institute (NCI)

Children's Oncology Group

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

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

Arm I (Caspofungin Acetate)

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

Arm II (Fluconazole or Voriconazole)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Canada

Region of Enrollment

Results Reporting Coordinator

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.

42-day-cumulative Incidence of Proven or Probable Invasive Fungal Infections (IFI)

100-day-cumulative Incidence of Proven or Probable IFI

Fungal-free-survival

Incidence of Overall Clinical GVHD Grades III and IV

Incidence of Overall Clinical GVHD Grades II to IV

Sensitivity of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay

Specificity of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay

Positive Predictive Value of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay

Negative Predictive Value of Beta-D Glucan Assay for the Diagnosis of IFI Using Fungitell Assay

Overall Study

70 mg iv x 1 on day 1 (loading dose), followed by 50 mg iv daily on day 2 through day 84.

6mg/kg iv q12 hours x 2 doses OR 400mg po q12hours on day 1 (loading doses. Maintenance doses on day 2 through day 84 may be either 4 mg/kg iv q12 hours, or 200 mg po q12 hours (at least one hour before or after meals).

voriconazole

Lynne Strasfeld, MD

RATIONALE: Voriconazole and caspofungin acetate may control invasive fungal infections in patients who have weakened immune systems.

PURPOSE: This phase II trial is studying how well giving voriconazole together with caspofungin acetate works in treating invasive fungal infections in patients with weakened immune systems.

OBJECTIVES:

Primary

* Determine the 12-week complete and partial response rate in immunocompromised patients with invasive fungal infections treated with voriconazole and caspofungin acetate.

Secondary

* Determine the 12-week survival rate in patients treated with this regimen.
* Determine the safety of this regimen in these patients.

OUTLINE: Patients receive voriconazole orally or IV over 1 hour twice daily and caspofungin acetate IV over 1 hour once daily on days 1-84. Treatment continues in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 47 patients will be accrued for this study.

Voriconazole and Caspofungin Acetate in Treating Invasive Fungal Infections in Patients With Weakened Immune Systems

Phase II Trial of Voriconazole Plus Caspofungin for the Initial Treatment of Invasive Fungal Infections

Patients will be followed through day 84 (12 weeks), regardless of continuation of study drugs. Complete response: Resolution of all clinical signs and symptoms and more than 90 percent of the lesions due to invasive fungus that were visible by radiology. Partial response: Clinical improvement and greater than 50 percent improvement in the lesions due to invasive fungus that were visible by radiology.

OHSU Knight Cancer Institute

Voriconazole: 6mg/kg iv q12 hours x 2 doses OR 400mg po q12hours on day 1 (loading doses). Maintenance doses on day 2 through day 84 may be either 4 mg/kg iv q12 hours, or 200 mg po q12 hours

Caspofungin: 70 mg iv x 1 on day 1 (loading dose), followed by 50 mg iv daily on day 2 through day 84.

Voriconazole Plus Caspofungin

Age Continuous

Dr. Lynne Strasfeld

Number of Participants With a Complete or Partial Response Rate to the Combination of Voriconazole and Caspofungin at 12 Weeks.

Duration of Survival up to 12 Weeks

Safety

Neutropenia

Leukemia, Myelomonocytic, Acute

Leukemia, Monocytic, Acute

Leukemia, Myelomonocytic, Chronic

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Disease

Agranulocytosis

Leukopenia

Cytopenia

Leukocyte Disorders

Granulocytopenia

Acute Monoblastic Leukemia

Acute Myelomonocytic Leukemia

Acute Myeloblastic Leukemia With Maturation

Acute Myeloblastic Leukemia Without Maturation

Chronic Graft Versus Host Disease

Chronic Myelomonocytic Leukemia

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

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.

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.

Theoklis E Zaoutis

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.

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.

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

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

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.

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.

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.

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.

Descriptive statistics will be used to summarize the prevalence of single nucleotide polymorphisms.

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).

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.

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.

The percentage of participants requiring empiric antifungal therapy will be determined based on the presence of prolonged fever and neutropenia during each neutropenia course.

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events.

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.

Caspofungin Acetate: Given IV

Laboratory Biomarker Analysis: Correlative studies

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.

Fluconazole: Given IV or PO

Laboratory Biomarker Analysis: Correlative studies

Arm II (Fluconazole)

United Arab Emirates

Evaluable patients (ineligible and inevaluable due to having IFI before IFI monitoring period were excluded)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Empirical Versus Preemptive Antifungal Therapy	NCT01288378	Fungal Infectio... Leukemia Myelodysplastic...	caspofungin ace...	18 Years -	European Organisation for Research and Treatment of Cancer - EORTC
Caspofungin Acetate, Fluconazole, or Voriconazole in Preventing Fungal Infections in Patients Following Donor Stem Cell Transplant	NCT01503515	Fungal Infectio... Hematopoietic a...	Caspofungin Ace... Fluconazole Laboratory Biom... Voriconazole	3 Months - 20 Years	Children's Oncology Group
Voriconazole and Caspofungin Acetate in Treating Invasive Fungal Infections in Patients With Weakened Immune Systems	NCT00238355	Infection Unspecified Adu...	caspofungin ace... voriconazole	18 Years -	OHSU Knight Cancer Institute
Voriconazole and Caspofungin Acetate in Treating Invasive Fungal Infections in Patients With Weakened Immune Systems	NCT00238355	Infection Unspecified Adu...	caspofungin ace... voriconazole	18 Years -	OHSU Knight Cancer Institute
Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia	NCT01307579	Acute Myeloid L... Adult Acute Mon... Adult Acute Mon... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Adult Acute Mye... Alkylating Agen... Childhood Acute... Childhood Acute... Childhood Acute... Childhood Acute... Childhood Acute... Childhood Acute... Childhood Acute... Fungal Infectio... Myeloid Neoplas... Neutropenia Recurrent Adult... Recurrent Child... Secondary Acute... Untreated Adult... Untreated Child...	Caspofungin Ace... Fluconazole Laboratory Biom...	3 Months - 30 Years	Children's Oncology Group

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