Myeloproliferative Neoplasms Clinical Trial
Comparison of Fluconazole vs Voriconazole to Treat Fungal Infections for Blood and Marrow Transplants (BMT CTN 0101)
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.
Full 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.
Eligibility 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:
Acute myelogenous leukemia (AML)
Acute lymphocytic leukemia (ALL)
Acute undifferentiated leukemia (AUL)
Acute biphenotypic leukemia in first or second complete remission
Chronic myelogenous leukemia (CML) in either chronic or accelerated phase
One of the following myelodysplastic syndrome(s) (MDS):
Refractory anemia
Refractory anemia with ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
Refractory anemia with excess blasts-1 (5-10% blasts)
Refractory anemia with excess blasts-2 (10-20% blasts)
MDS, unclassified
MDS associated with isolated del (5q)
Chronic myelomonocytic leukemia (CMML)
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
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There are 29 Locations for this study
Birmingham Alabama, 35294, United States
La Jolla California, 92093, United States
Stanford California, 94305, United States
Washington District of Columbia, 20010, United States
Gainesville Florida, 32610, United States
Tampa Florida, 33624, United States
Chicago Illinois, 60614, United States
Indianapolis Indiana, 46202, United States
Baltimore Maryland, 21231, United States
Boston Massachusetts, 02114, United States
Boston Massachusetts, 02114, United States
Ann Arbor Michigan, 48109, United States
Detroit Michigan, 48201, United States
Minneapolis Minnesota, 55455, United States
Kansas City Missouri, 64108, United States
Kansas City Missouri, 64111, United States
Saint Louis Missouri, 63110, United States
Saint Louis Missouri, 63110, United States
Saint Louis Missouri, 63110, United States
Omaha Nebraska, 68198, United States
Hackensack New Jersey, 07601, United States
Buffalo New York, 14263, United States
New York New York, 10021, United States
Durham North Carolina, 27705, United States
Winston-Salem North Carolina, 27157, United States
Cleveland Ohio, 44106, United States
Portland Oregon, 97239, United States
Philadelphia Pennsylvania, 19104, United States
Philadelphia Pennsylvania, 19104, United States
Houston Texas, 77030, United States
San Antonio Texas, 78229, United States
Salt Lake City Utah, 84132, United States
Seattle Washington, 98109, United States
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