Comparison of Fluconazole Versus Voriconazole to Treat Fungal Infections in Individuals Receiving Blood and Marrow Transplants

Condition(s) targeted: Lymphoma; Infection; Leukemia

Intervention: Fluconazole (Drug); Voriconazole (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: National Heart, Lung, and Blood Institute (NHLBI)

Official(s) and/or principal investigator(s):
Donna Salzman, MD, Principal Investigator, Affiliation: University of Alabama at Birmingham
Jeffrey Andrey, MD, Principal Investigator, Affiliation: Scripps Cancer Center
Janice Brown, MD, Principal Investigator, Affiliation: Stanford Hospital and Clinics
Edward Ball, MD, Principal Investigator, Affiliation: UCSD Medical Center
Naynesh Kamani, MD, Principal Investigator, Affiliation: Children's Research Institute
Claudio Anasetti, MD, Principal Investigator, Affiliation: H. Lee Moffitt Cancer Center
John Wingard, MD, Study Chair, Affiliation: University of Florida College of Medicine (Shands)
Reggie Duerst, MD, Principal Investigator, Affiliation: Children's Memorial - Northwestern
Paul Haut, MD, Principal Investigator, Affiliation: Indiana University School of Medicine
Lindsey Robert Baden, MD, Principal Investigator, Affiliation: Dana Farber Cancer Institute/Brigham & Womens
Leslie Lehmann, MD, Principal Investigator, Affiliation: Dana Farber Cancer Institute/Children's Hospital of Boston
Richard Jones, MD, Principal Investigator, Affiliation: Johns Hopkins/SKCCC
Voravit Ratanatharathorn, MD, Principal Investigator, Affiliation: Karmanos Cancer Institute/BMT
Choon-Kee Lee, MD, Principal Investigator, Affiliation: University of Michigan
Jo-Anne van Burik, MD, Principal Investigator, Affiliation: University of Minnesota - Clinical and Translational Science Institute
William Ferguson, MD, Principal Investigator, Affiliation: Cardinal Glennon Children's Hospital
Alan Gamis, MD, Principal Investigator, Affiliation: Children's Mercy Hospital Kansas City
Joseph McGuirk, MD, Principal Investigator, Affiliation: Kansas City Cancer Centers
John DiPersio, MD, Principal Investigator, Affiliation: Washington University/Barnes Jewish Hospital
Shalini Shenoy, MD, Principal Investigator, Affiliation: Washington University/St. Louis Children's Hospital
Joanne Kurtzberg, MD, Principal Investigator, Affiliation: Duke University
Kevin High, MD, Principal Investigator, Affiliation: Wake Forest School of Medicine
Marcel Devetten, MD, Principal Investigator, Affiliation: University of Nebraska
Scott Rowley, MD, Principal Investigator, Affiliation: Hackensack University Medical Center
Joel Brochstein, MD, Principal Investigator, Affiliation: Hackensack University Medical Center
Trudy Small, MD, Principal Investigator, Affiliation: Memorial Sloan Kettering Cancer Center
Brahm Segal, MD, Principal Investigator, Affiliation: Roswell Park Cancer Institute
Hillard Lazarus, MD, Principal Investigator, Affiliation: University Hospitals of Cleveland/Case Western
Richard Maziarz, MD, Principal Investigator, Affiliation: Oregon Health and Science University
H. Stacy Nicholson, MD, Principal Investigator, Affiliation: Oregon Health and Science University
Nancy Bunin, MD, Principal Investigator, Affiliation: Children's Hospital of Philadelphia
Edward Stadtmauer, MD, Principal Investigator, Affiliation: University of Pennsylvania
Paul Shaughnessy, MD, Principal Investigator, Affiliation: Texas Transplant Institute
Michael Grimley, MD, Principal Investigator, Affiliation: Texas Transplant Institute
Sergio Giralt, MD, Principal Investigator, Affiliation: University of Texas/MD Anderson CRC
Michael Pulsipher, MD, Principal Investigator, Affiliation: Utah BMT/Primary Children's Medical Center
Kieren Marr, MD, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center

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.

Official title: A Randomized Double-blind Trial of Fluconazole Versus Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood and Marrow Transplant Patients (BMT CTN #0101)

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Fungal-free survival (proportion of participants alive and free from proven, probable, or presumptive invasive fungal infection) at 180 days post-transplant

Secondary outcome:

Frequency of invasive fungal infections

Time to invasive fungal infection

survival

Frequency and duration of use of amphotericin B or caspofungin

Time to and severity of acute and chronic GVHD

Utility of galactomannan assay in diagnosis of aspergillus and response to therapy

Time to neutrophil engraftment

Time to platelet engraftment

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

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.

Minimum age: 2 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

Scripps Cancer Center, La Jolla, California 92037, United States

UCSD Medical Center, La Jolla, California 92093, United States

Stanford Hospital and Clinics, Stanford, California 94305, United States

Children's National Medical Center, Washington, District of Columbia 20010, United States

University of Florida College of Medicine (Shands), Gainesville, Florida 32610, United States

H. Lee Moffitt Cancer Center, Tampa, Florida 33624, United States

Children's Memorial - Northwestern, Chicago, Illinois 60614, United States

Indiana University Medical Center, Indianapolis, Indiana 46202, United States

Johns Hopkins/SKCCC, Baltimore, Maryland 21231, United States

Dana Farber Cancer Institute/Brigham & Womens, Boston, Massachusetts 02114, United States

Dana Farber Cancer Institute/Children's Hospital of Boston, Boston, Massachusetts 02114, United States

University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States

Karmanos Cancer Institute/BMT, Detroit, Michigan 48201, United States

University of Minnesota, Minneapolis, Minnesota 55455, United States

Children's Mercy Hospitals and Clinics, Kansas City, Missouri 64108, United States

Kansas City Cancer Centers, Kansas City, Missouri 64111, United States

Cardinal Glennon Children's Hospital, St. Louis, Missouri 63110, United States

Washington University/Barnes Jewish Hospital, St. Louis, Missouri 63110, United States

Washington University/St. Louis Children's Hospital, St. Louis, Missouri 63110, United States

University of Nebraska Medical Center, Omaha, Nebraska 68198, United States

Hackensack University Medical Center, Hackensack, New Jersey 07601, United States

Roswell Park Cancer Institute, Buffalo, New York 14263, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States

Duke University Medical Center, Durham, North Carolina 27705, United States

Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, United States

University Hospitals of Cleveland/Case Western, Cleveland, Ohio 44106, United States

Oregon Health Sciences University, Portland, Oregon 97239, United States

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States

University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, United States

University of Texas/MD Anderson CRC, Houston, Texas 77030, United States

Texas Transplant Institute, San Antonio, Texas 78229, United States

Utah BMT/Primary Children's Medical Center, Salt Lake City, Utah 84132, United States

Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States

Starting date: November 2003
Last updated: November 20, 2009