Comparison of Fluconazole vs Voriconazole to Treat Fungal Infections for Blood and Marrow Transplants (BMT CTN 0101)

Phase 3

Completed

Conditions: Infection
Lymphoma
Leukemia

Interventions: Drug: Voriconazole
Drug: Fluconazole

Registration Number: NCT00075803

Lead Sponsor: Medical College of Wisconsin

Brief Summary: The study is designed as a Phase III, randomized, double-blind, multicenter, prospective, comparative study of fluconazole versus voriconazole for the prevention of fungal infections in allogeneic transplant recipients. Recipients will be stratified by center and donor type (sibling vs. unrelated) and will be randomized to either the fluconazole or voriconazole arm in a 1:1 ratio.

Detailed Description: BACKGROUND:

Allogeneic blood and marrow transplant patients are highly susceptible to invasive fungal infection prior to engraftment, due to neutropenia and mucosal injury. After engraftment, an impairment of cell mediated immunity from graft-versus-host disease (GVHD) and the use of aggressive immunosuppressive therapies, such as corticosteroids, leave patients vulnerable to invasive fungal infections. Recipients of alternate donor transplants are especially susceptible due to slow reconstitution of cell mediated immunity.

Fluconazole prophylaxis in prospective randomized trials of both autologous and allogeneic transplant recipients has been demonstrated to reduce invasive fungal infections due to yeasts prior to engraftment. A prolonged course of fluconazole given during the first 75 days (to cover the early post-engraftment period of risk) is highly effective in the prevention of early and later yeast infections. This has translated into a survival benefit. A recent analysis of long-term outcomes of these individuals demonstrated a continuing benefit beyond the course of prophylaxis with a further benefit in survival. In another study of various factors associated with survival after matched unrelated donor transplants, fluconazole prophylaxis was an independent predictor for overall survival in a multivariate analysis. Fluconazole prophylaxis has been found to be effective and safe with few substantive drug interactions and has been widely adopted by transplant clinicians.

DESIGN NARRATIVE:

This is a randomized, double-blind, multicenter, prospective, comparative study of fluconazole versus voriconazole for the prevention of fungal infections in allogeneic hematopoietic transplant recipients and cord blood recipients in children under the age of 12. Prior to the start of the pre-transplant conditioning regimen, participants will give written informed consent and be screened for eligibility. Participants who meet all entry criteria will be assigned randomly to voriconazole or fluconazole within 72 hours of Day 0. Participants will begin the study drug on Day 0 (after completion of the conditioning regimen). Day 0 is defined as the day infusion of the stem cell product is completed. The study drug will be continued until Day 100 following transplant or until one or more criteria for early withdrawal are met. Continuation of the study drug beyond Day 100 is permitted for participants who meet specific criteria. The development of any fungal infection during prophylaxis will be classified according to the definitions listed in the protocol.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 600

Inclusion Criteria

Must receive an allogeneic peripheral blood or marrow transplant from a family or unrelated donor, or for children under the age of 12, a cord blood transplant from either a sibling or other donor
Must have a 5 or 6 of 6 human leukocyte antigens (HLA)-matched donor. The match may be determined at serologic level for HLA-A and HLA-B loci. For sibling donors, matching may be determined at serologic level for HLA-DR; for unrelated donors, matching for HLA-DRB1 must be at the high-resolution molecular level
Must have one of the following underlying diseases:
1. Acute myelogenous leukemia (AML)
2. Acute lymphocytic leukemia (ALL)
3. Acute undifferentiated leukemia (AUL)
4. Acute biphenotypic leukemia in first or second complete remission
5. Chronic myelogenous leukemia (CML) in either chronic or accelerated phase
6. One of the following myelodysplastic syndrome(s) (MDS):
  1. Refractory anemia
  2. Refractory anemia with ringed sideroblasts
  3. Refractory cytopenia with multilineage dysplasia
  4. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
  5. Refractory anemia with excess blasts-1 (5-10% blasts)
  6. Refractory anemia with excess blasts-2 (10-20% blasts)
  7. MDS, unclassified
  8. MDS associated with isolated del (5q)
  9. Chronic myelomonocytic leukemia (CMML)
7. Lymphoma (including Hodgkin's) with chemosensitive disease (at least 50% response to chemotherapy) and receiving a related donor transplant
Receiving myeloablative conditioning regimens
Adequate physical function (cardiac, hepatic, renal, and pulmonary), within 6 weeks of initiation of conditioning (preferably within 4 weeks) unless otherwise specified
Baseline galactomannan blood samples drawn within 30 days prior to randomization with the results available prior to randomization (72 hours prior to transplant)
Chest computed tomography (CT) scans within 6 weeks prior to randomization if the results of the baseline galactomannan blood sample are not available prior to randomization (72 hours prior to transplant)

Exclusion Criteria

Invasive yeast infection within the 8 weeks prior to conditioning regimen initiation. Patients are eligible if colonized or have had superficial infection. Patients with a history of candidemia greater than 8 weeks prior to conditioning must have a negative blood culture within 14 days of conditioning (within 7 days is recommended), no clinical signs of candidemia, and may not still require antifungal therapy
Presumptive, proven, or probable aspergillus or other mold infection or deep mycoses (including hepatosplenic candidiasis) within 4 months prior to conditioning regimen initiation
Uncontrolled viral or bacterial infection at the time of study registration
Pregnant or breastfeeding. Women of child-bearing age must avoid becoming pregnant while receiving antifungal agents
Karnofsky performance status less than 70% or Lansky status less than 50% for patients under 16 years old unless approved by the medical monitor or protocol chair
History of allergy or intolerance to azoles (e.g., fluconazole, itraconazole, voriconazole, posaconazole, ketoconazole, miconazole, clotrimazole)
Requiring therapy with rifampin, rifabutin, carbamazepine, cisapride (Propulsid®), terfenadine (Seldane®), astemizole (Hismanal®), ergot alkaloids, long-acting barbiturates, or who have received more than 3 days treatment with rifampin or carbamazepine within 7 days prior to conditioning regimen initiation. Patients on therapeutic anticoagulation with coumadin (1 mg/day for port prophylaxis is permitted)
Receiving sirolimus
Prolonged QTc syndrome at study entry
HIV positive
Receiving another investigational drug unless cleared by the medical monitors
Received a prior allogeneic or autologous transplant
Active central nervous system disease
On fungal prophylaxis during conditioning regimen (it is recommended that fungal prophylaxis be suspended once patient is enrolled)
Prior cancer, other than resected basal cell carcinoma or treated carcinoma in-situ. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the medical monitor or protocol chair. Cancer previously treated with curative intent over 5 years ago will be allowed

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Voriconazole	Voriconazole	The dose of oral voriconazole is 200 mg twice daily. When voriconazole must be given intravenously, it will be given at a dose of 200 mg every 12 hours for the duration of intravenous therapy.
Fluconazole	Fluconazole	The dose of fluconazole is 400 mg by mouth or intravenous drip.

Primary Outcome Measures

Name	Time	Method
Fungal-free Survival (Percentage of Participants Alive and Free From Proven, Probable, or Presumptive Invasive Fungal Infection) at 180 Days Post-transplant	180 days

Secondary Outcome Measures

Name	Time	Method
Failure to Engraft	day 42
Freedom From Possible, Presumptive, Probable, or Proven Invasive Fungal Infection, Death, or Withdrawal of Study Drug Due to Toxicity, Intolerance, or an Empirical Trial of Amphotericin B or Caspofungin Greater Than 14 Consecutive Days	1 year
Relapse Free Survival	100, 180, and 365 days
Duration of Use of Amphotericin B or Caspofungin	180 days
Frequency of Invasive Fungal Infections (IFI)	1 year	Incidence of proven, probably, or presumptive IFI
Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days	100, 180, and 365 days
Overall Survival	100, 180, and 365 days
Frequency of Use of Amphotericin B or Caspofungin	1 year
Time to Neutrophil Engraftment	28 days
Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD)	100 and 365 days
Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy	1 year	Although there were 82 Galactomannan (GM) positives, 4 were excluded due to piperacillin/tazobactam administration, without other documentation of IFI, and were deemed false positives.
Time to Platelet Engraftment	180 days

Trial Locations

Locations (33): Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
University of Pennsylvania Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
University Hospitals of Cleveland/Case Western
🇺🇸
Cleveland, Ohio, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸
Chicago, Illinois, United States
Indiana University Medical Center
🇺🇸
Indianapolis, Indiana, United States
Texas Transplant Institute
🇺🇸
San Antonio, Texas, United States
Utah BMT/Univ of Utah Med School
🇺🇸
Salt Lake City, Utah, United States
Karmanos Cancer Institute/BMT
🇺🇸
Detroit, Michigan, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Washington University/St. Louis Children's Hospital
🇺🇸
Saint Louis, Missouri, United States
Cardinal Glennon Children's Hospital
🇺🇸
Saint Louis, Missouri, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Stanford Hospital and Clinics
🇺🇸
Stanford, California, United States
University of Texas/MD Anderson CRC
🇺🇸
Houston, Texas, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Fred Hutchinson Cancer Research Center
🇺🇸
Seattle, Washington, United States
UCSD Medical Center
🇺🇸
La Jolla, California, United States
University of Florida College of Medicine (Shands)
🇺🇸
Gainesville, Florida, United States
Washington University/Barnes Jewish Hospital
🇺🇸
Saint Louis, Missouri, United States
Oregon Health Sciences University
🇺🇸
Portland, Oregon, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
H. Lee Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
University of Michigan Medical Center
🇺🇸
Ann Arbor, Michigan, United States
Kansas City Cancer Centers
🇺🇸
Kansas City, Missouri, United States
Children's Mercy Hospitals and Clinics
🇺🇸
Kansas City, Missouri, United States
Johns Hopkins/SKCCC
🇺🇸
Baltimore, Maryland, United States
Dana Farber Cancer Institute/Children's Hospital of Boston
🇺🇸
Boston, Massachusetts, United States
Dana Farber Cancer Institute/Brigham & Womens
🇺🇸
Boston, Massachusetts, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States