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

Phase 3

Completed

Conditions: 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

Interventions: Drug: Fluconazole
Drug: Caspofungin Acetate
Other: Laboratory Biomarker Analysis

Registration Number: NCT01307579

Lead Sponsor: Children's Oncology Group

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 517

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (caspofungin acetate)	Laboratory Biomarker Analysis	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.
Arm II (fluconazole)	Fluconazole	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.
Arm II (fluconazole)	Laboratory Biomarker Analysis	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.
Arm I (caspofungin acetate)	Caspofungin Acetate	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.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI)	Up to 5 months since enrollment	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).

Secondary Outcome Measures

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

Trial Locations

Locations (179): Valley Children's Hospital
🇺🇸
Madera, California, United States
Children's Healthcare of Atlanta - Egleston
🇺🇸
Atlanta, Georgia, United States
Children's Hospital Los Angeles
🇺🇸
Los Angeles, California, United States
Sinai Hospital of Baltimore
🇺🇸
Baltimore, Maryland, United States
University of Illinois
🇺🇸
Chicago, Illinois, United States
Rainbow Babies and Childrens Hospital
🇺🇸
Cleveland, Ohio, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Saint Vincent Hospital and Health Care Center
🇺🇸
Indianapolis, Indiana, United States
University Medical Center of Southern Nevada
🇺🇸
Las Vegas, Nevada, United States
Nevada Cancer Research Foundation CCOP
🇺🇸
Las Vegas, Nevada, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸
Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Children's Hospital of San Antonio
🇺🇸
San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸
San Antonio, Texas, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
Children's Hospital of Alabama
🇺🇸
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Legacy Emanuel Children's Hospital
🇺🇸
Portland, Oregon, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Phoenix Childrens Hospital
🇺🇸
Phoenix, Arizona, United States
Nemours Children's Clinic - Pensacola
🇺🇸
Pensacola, Florida, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
Nemours Children's Clinic-Jacksonville
🇺🇸
Jacksonville, Florida, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Kaiser Permanente-Oakland
🇺🇸
Oakland, California, United States
Connecticut Children's Medical Center
🇺🇸
Hartford, Connecticut, United States
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
🇺🇸
Torrance, California, United States
Rady Children's Hospital - San Diego
🇺🇸
San Diego, California, United States
UCSF Medical Center-Mission Bay
🇺🇸
San Francisco, California, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸
Denver, Colorado, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Broward Health Medical Center
🇺🇸
Fort Lauderdale, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸
Hollywood, Florida, United States
Lee Memorial Health System
🇺🇸
Fort Myers, Florida, United States
Hurley Medical Center
🇺🇸
Flint, Michigan, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Saint Mary's Hospital
🇺🇸
West Palm Beach, Florida, United States
Memorial Health University Medical Center
🇺🇸
Savannah, Georgia, United States
University of Kentucky/Markey Cancer Center
🇺🇸
Lexington, Kentucky, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸
Oak Lawn, Illinois, United States
Floating Hospital for Children at Tufts Medical Center
🇺🇸
Boston, Massachusetts, United States
Columbia Regional
🇺🇸
Columbia, Missouri, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Saint Barnabas Medical Center
🇺🇸
Livingston, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸
Albuquerque, New Mexico, United States
Morristown Medical Center
🇺🇸
Morristown, New Jersey, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸
Las Vegas, Nevada, United States
Saint Joseph's Regional Medical Center
🇺🇸
Paterson, New Jersey, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Newark Beth Israel Medical Center
🇺🇸
Newark, New Jersey, United States
Overlook Hospital
🇺🇸
Summit, New Jersey, United States
NYU Winthrop Hospital
🇺🇸
Mineola, New York, United States
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
Geisinger Medical Center
🇺🇸
Danville, Pennsylvania, United States
The Toledo Hospital/Toledo Children's Hospital
🇺🇸
Toledo, Ohio, United States
Mercy Children's Hospital
🇺🇸
Toledo, Ohio, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸
Bethlehem, Pennsylvania, United States
Novant Health Presbyterian Medical Center
🇺🇸
Charlotte, North Carolina, United States
Dayton Children's Hospital
🇺🇸
Dayton, Ohio, United States
Greenville Cancer Treatment Center
🇺🇸
Greenville, South Carolina, United States
Palmetto Health Richland
🇺🇸
Columbia, South Carolina, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Sanford Broadway Medical Center
🇺🇸
Fargo, North Dakota, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Legacy Emanuel Hospital and Health Center
🇺🇸
Portland, Oregon, United States
Driscoll Children's Hospital
🇺🇸
Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸
Dallas, Texas, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸
Spokane, Washington, United States
Inova Fairfax Hospital
🇺🇸
Falls Church, Virginia, United States
Janeway Child Health Centre
🇨🇦
Saint John's, Newfoundland and Labrador, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦
Montreal, Quebec, Canada
Tampa General Hospital
🇺🇸
Tampa, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸
Tampa, Florida, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Children's Hospital and Medical Center of Omaha
🇺🇸
Omaha, Nebraska, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
Albany Medical Center
🇺🇸
Albany, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸
New Hyde Park, New York, United States
University of Rochester
🇺🇸
Rochester, New York, United States
New York Medical College
🇺🇸
Valhalla, New York, United States
Ascension Saint John Hospital
🇺🇸
Detroit, Michigan, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸
Fort Myers, Florida, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Summerlin Hospital Medical Center
🇺🇸
Las Vegas, Nevada, United States
Saint Luke's Mountain States Tumor Institute
🇺🇸
Boise, Idaho, United States
Kaiser Permanente Downey Medical Center
🇺🇸
Downey, California, United States
Arkansas Children's Hospital
🇺🇸
Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸
Long Beach, California, United States
Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Alfred I duPont Hospital for Children
🇺🇸
Wilmington, Delaware, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Johns Hopkins All Children's Hospital
🇺🇸
Saint Petersburg, Florida, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸
Saint Louis, Missouri, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Saint Peter's University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Mission Hospital Inc-Memorial Campus
🇺🇸
Asheville, North Carolina, United States
Columbia University/Herbert Irving Cancer Center
🇺🇸
New York, New York, United States
Natalie Warren Bryant Cancer Center at Saint Francis
🇺🇸
Tulsa, Oklahoma, United States
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
Texas Tech University Health Sciences Center-Amarillo
🇺🇸
Amarillo, Texas, United States
T C Thompson Children's Hospital
🇺🇸
Chattanooga, Tennessee, United States
Brooke Army Medical Center
🇺🇸
Fort Sam Houston, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Covenant Children's Hospital
🇺🇸
Lubbock, Texas, United States
University of Vermont College of Medicine
🇺🇸
Burlington, Vermont, United States
Scott and White Memorial Hospital
🇺🇸
Temple, Texas, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸
Tacoma, Washington, United States
West Virginia University Charleston Division
🇺🇸
Charleston, West Virginia, United States
British Columbia Children's Hospital
🇨🇦
Vancouver, British Columbia, Canada
Marshfield Medical Center-Marshfield
🇺🇸
Marshfield, Wisconsin, United States
Alberta Children's Hospital
🇨🇦
Calgary, Alberta, Canada
CancerCare Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Children's Hospital
🇨🇦
London, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦
Kingston, Ontario, Canada
IWK Health Centre
🇨🇦
Halifax, Nova Scotia, Canada
Children's Hospital of Eastern Ontario
🇨🇦
Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
San Jorge Children's Hospital
🇵🇷
San Juan, Puerto Rico
Michigan State University Clinical Center
🇺🇸
East Lansing, Michigan, United States
Helen DeVos Children's Hospital at Spectrum Health
🇺🇸
Grand Rapids, Michigan, United States
Eastern Maine Medical Center
🇺🇸
Bangor, Maine, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Blank Children's Hospital
🇺🇸
Des Moines, Iowa, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
Sunrise Hospital and Medical Center
🇺🇸
Las Vegas, Nevada, United States
Bronson Methodist Hospital
🇺🇸
Kalamazoo, Michigan, United States
East Carolina University
🇺🇸
Greenville, North Carolina, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Kalamazoo Center for Medical Studies
🇺🇸
Kalamazoo, Michigan, United States
Beaumont Children's Hospital-Royal Oak
🇺🇸
Royal Oak, Michigan, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸
New Brunswick, New Jersey, United States
Stony Brook University Medical Center
🇺🇸
Stony Brook, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
West Virginia University Healthcare
🇺🇸
Morgantown, West Virginia, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Children's Hospital Medical Center of Akron
🇺🇸
Akron, Ohio, United States
BI-LO Charities Children's Cancer Center
🇺🇸
Greenville, South Carolina, United States
University of Virginia Cancer Center
🇺🇸
Charlottesville, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸
Norfolk, Virginia, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸
Green Bay, Wisconsin, United States
University of Hawaii Cancer Center
🇺🇸
Honolulu, Hawaii, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
Florida Hospital Orlando
🇺🇸
Orlando, Florida, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Nemours Children's Hospital
🇺🇸
Orlando, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸
Orlando, Florida, United States
UF Cancer Center at Orlando Health
🇺🇸
Orlando, Florida, United States
Norton Children's Hospital
🇺🇸
Louisville, Kentucky, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
University of Florida Health Science Center - Gainesville
🇺🇸
Gainesville, Florida, United States
Kapiolani Medical Center for Women and Children
🇺🇸
Honolulu, Hawaii, United States
Tulane University Health Sciences Center
🇺🇸
New Orleans, Louisiana, United States
Children's Hospital New Orleans
🇺🇸
New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
🇺🇸
New Orleans, Louisiana, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸
Richmond, Virginia, United States
Madigan Army Medical Center
🇺🇸
Tacoma, Washington, United States
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦
Hamilton, Ontario, Canada
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States