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

Hematopoietic and Lymphoid Cell Neoplasm Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01503515
• Other study ID #: ACCL1131
• Secondary ID: NCI-2012-00102CD
• Status: Completed
• Phase: Phase 3
• Start date: March 21, 2013
• Est. completion date: September 30, 2021

Study information

• Verified date: January 2022
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 292
• Est. completion date: September 30, 2021
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 20 Years

Eligibility

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

Related Conditions & MeSH terms

• Communicable Diseases
• Fungal Infection
• Hematopoietic and Lymphoid Cell Neoplasm
• Infections
• Mycoses

Intervention

Drug:
• Caspofungin Acetate
Given IV
• Fluconazole
Given IV or PO

Other:
• Laboratory Biomarker Analysis
Optional correlative studies

Drug:
• Voriconazole
Given IV or PO

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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).	Up to day 100 following allogeneic HCT
Other	Fungal-free-survival	Defined as time to death or proven/probable IFI during the first 42 days following allogeneic HCT.	Up to 42 days following allogeneic HCT
Other	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.	Up to 100 days after allogeneic HCT
Other	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.	Up to 100 days after allogeneic HCT
Other	Fungal-free-survival	Defined as time to death or proven/probable IFI during the first 100 days following allogeneic HCT.	Up to 100 days following allogeneic HCT
Other	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.	Up to day 42 following allogeneic HCT
Other	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.	Up to day 42 following allogeneic HCT
Other	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.	Up to day 42 following allogeneic HCT
Other	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.	Up to day 42 following allogeneic HCT
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).	Up to 42 days following allogeneic HCT