Infection, Leukemia, Lymphoma
Conditions
Keywords
Myelodysplastic and Myeloproliferative Diseases
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.
Interventions
DRUGFluconazole
Fluconazole will be administered orally once daily. Fluconazole capsules should be taken at least one hour before or one hour after a meal. If oral drug is not possible, it will be given intravenously once daily in a total volume of 200 mL in patients \> 12 years. For adults, each 200 mL infusion will be administered over 2 hours. In patients \< 12 years, intravenous doses will be prepared.
DRUGVoriconazole
Voriconazole will be administered orally twice daily. Voriconazole capsules should be taken at least one hour before or one hour after a meal. Taken concomitantly with food, bioavailability of voriconazole is reduced. If oral drug is not possible, it will be given intravenously at a dosage of 200 mg every 12 hours over two hours in patients \> 12 years. Each voriconazole dose will be diluted to a total volume of 200 mL in patients \> 12 years. Volumes of the formulation required to provide 4 mg/kg doses for children age \< 12 years.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Relapse Free Survival | 100, 180, and 365 days | — |
| Frequency of Use of Amphotericin B or Caspofungin | 1 year | — |
| 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 |
| 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 Neutrophil Engraftment | 28 days | — |
| Time to Platelet Engraftment | 180 days | — |
| 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 | — |
| Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | 100 and 365 days | — |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled from November 2003 through September 2006
Participants by arm
| Arm | Count |
|---|---|
| Fluconazole fluconazole prophylaxis | 295 |
| Voriconazole voriconazole prophylaxis | 305 |
| Total | 600 |
Baseline characteristics
| Characteristic | Fluconazole | Total | Voriconazole |
|---|---|---|---|
| Age, Customized <18 years | 24 participants | 51 participants | 27 participants |
| Age, Customized ≥18 years | 271 participants | 549 participants | 278 participants |
| Age, Customized | 43 years | 43 years | 43 years |
| Graft Source Bone marrow | 109 participants | 215 participants | 106 participants |
| Graft Source Cord blood | 0 participants | 2 participants | 2 participants |
| Graft Source Peripheral blood | 186 participants | 383 participants | 197 participants |
| Human Leukocyte Antigen (HLA) Match 5 of 6 | 13 participants | 25 participants | 12 participants |
| Human Leukocyte Antigen (HLA) Match 6 of 6 | 282 participants | 575 participants | 293 participants |
| Karnofsky/Lansky Performance Status < 90% | 46 participants | 83 participants | 37 participants |
| Karnofsky/Lansky Performance Status 90% - 100% | 249 participants | 517 participants | 268 participants |
| Primary Disease Acute lymphoblastic leukemia | 64 participants | 122 participants | 58 participants |
| Primary Disease Acute myeloid leukemia | 101 participants | 234 participants | 133 participants |
| Primary Disease Chronic myelogenous leukemia | 60 participants | 103 participants | 43 participants |
| Primary Disease Myelodysplastic syndrome | 49 participants | 98 participants | 49 participants |
| Primary Disease Non-Hodgkin lymphoma | 21 participants | 43 participants | 22 participants |
| Race/Ethnicity, Customized Other | 30 participants | 59 participants | 29 participants |
| Race/Ethnicity, Customized White | 265 participants | 541 participants | 276 participants |
| Sex: Female, Male Female | 134 Participants | 269 Participants | 135 Participants |
| Sex: Female, Male Male | 161 Participants | 331 Participants | 170 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 196 / 295 | 199 / 305 |
| serious Total, serious adverse events | 78 / 295 | 73 / 305 |
Outcome results
Primary
Fungal-free Survival (Percentage of Participants Alive and Free From Proven, Probable, or Presumptive Invasive Fungal Infection) at 180 Days Post-transplant
Time frame: 180 days
Population: All randomized patients were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Fungal-free Survival (Percentage of Participants Alive and Free From Proven, Probable, or Presumptive Invasive Fungal Infection) at 180 Days Post-transplant | 74.9 percentage of patients |
| Voriconazole | Fungal-free Survival (Percentage of Participants Alive and Free From Proven, Probable, or Presumptive Invasive Fungal Infection) at 180 Days Post-transplant | 78.2 percentage of patients |
Secondary
Duration of Use of Amphotericin B or Caspofungin
Time frame: 180 days
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Fluconazole | Duration of Use of Amphotericin B or Caspofungin | Number of days on study drug | 91 days |
| Fluconazole | Duration of Use of Amphotericin B or Caspofungin | Start day of empiric antifungal therapy | 16 days |
| Fluconazole | Duration of Use of Amphotericin B or Caspofungin | Days of empiric antifungal therapy | 7 days |
| Voriconazole | Duration of Use of Amphotericin B or Caspofungin | Number of days on study drug | 96 days |
| Voriconazole | Duration of Use of Amphotericin B or Caspofungin | Start day of empiric antifungal therapy | 12 days |
| Voriconazole | Duration of Use of Amphotericin B or Caspofungin | Days of empiric antifungal therapy | 7 days |
Secondary
Failure to Engraft
Time frame: day 42
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Failure to Engraft | 11 participants |
| Voriconazole | Failure to Engraft | 9 participants |
Secondary
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
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluconazole | 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 | IFI after aGVHD (grades II-IV) | 11 participants |
| Fluconazole | 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 | IFI after relapse/progression | 2 participants |
| Fluconazole | 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 | IFI before engraftment | 12 participants |
| Fluconazole | 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 | IFI who had failure to engraft | 2 participants |
| Fluconazole | 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 | IFI while on study drug (up to day 100) | 19 participants |
| Fluconazole | 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 | IFI after premature withdrawal of study drug | 11 participants |
| Fluconazole | 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 | IFI after start other prophylaxis (not study drug) | 8 participants |
| Fluconazole | 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 | IFI after empiric therapy | 13 participants |
| Voriconazole | 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 | IFI after empiric therapy | 12 participants |
| Voriconazole | 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 | IFI while on study drug (up to day 100) | 10 participants |
| Voriconazole | 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 | IFI after relapse/progression | 8 participants |
| Voriconazole | 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 | IFI after start other prophylaxis (not study drug) | 11 participants |
| Voriconazole | 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 | IFI before engraftment | 8 participants |
| Voriconazole | 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 | IFI after premature withdrawal of study drug | 16 participants |
| Voriconazole | 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 | IFI who had failure to engraft | 1 participants |
| Voriconazole | 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 | IFI after aGVHD (grades II-IV) | 14 participants |
Secondary
Frequency of Invasive Fungal Infections (IFI)
Incidence of proven, probably, or presumptive IFI
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Frequency of Invasive Fungal Infections (IFI) | 13.7 percentage of patients |
| Voriconazole | Frequency of Invasive Fungal Infections (IFI) | 12.7 percentage of patients |
Secondary
Frequency of Use of Amphotericin B or Caspofungin
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Frequency of Use of Amphotericin B or Caspofungin | 30.2 percentage of patients |
| Voriconazole | Frequency of Use of Amphotericin B or Caspofungin | 24.1 percentage of patients |
Secondary
Overall Survival
Time frame: 100, 180, and 365 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluconazole | Overall Survival | 100 days | 85.4 percentage of patients |
| Fluconazole | Overall Survival | 180 days | 80.0 percentage of patients |
| Fluconazole | Overall Survival | 365 days | 70.2 percentage of patients |
| Voriconazole | Overall Survival | 100 days | 90.1 percentage of patients |
| Voriconazole | Overall Survival | 180 days | 81.2 percentage of patients |
| Voriconazole | Overall Survival | 365 days | 67.8 percentage of patients |
Secondary
Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days
Time frame: 100, 180, and 365 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluconazole | Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days | 180 days | 11.2 percentage of patients |
| Fluconazole | Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days | 365 days | 13.7 percentage of patients |
| Fluconazole | Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days | 100 days | 9.5 percentage of patients |
| Voriconazole | Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days | 100 days | 5.6 percentage of patients |
| Voriconazole | Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days | 180 days | 7.3 percentage of patients |
| Voriconazole | Percentage of Patients With Invasive Fungal Infection at 100, 180, and 365 Days | 365 days | 12.7 percentage of patients |
Secondary
Relapse Free Survival
Time frame: 100, 180, and 365 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluconazole | Relapse Free Survival | 100 days | 83.1 percentage of patients |
| Fluconazole | Relapse Free Survival | 180 days | 74.9 percentage of patients |
| Fluconazole | Relapse Free Survival | 365 days | 63.3 percentage of patients |
| Voriconazole | Relapse Free Survival | 100 days | 86.1 percentage of patients |
| Voriconazole | Relapse Free Survival | 180 days | 73.9 percentage of patients |
| Voriconazole | Relapse Free Survival | 365 days | 61.2 percentage of patients |
Secondary
Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD)
Time frame: 100 and 365 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluconazole | Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | Acute GVHD grade II-IV at day 100 | 132 participants |
| Fluconazole | Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | Acute GVHD grade III-IV at day 100 | 42 participants |
| Fluconazole | Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | Chronic GVHD at 1 year | 138 participants |
| Voriconazole | Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | Acute GVHD grade II-IV at day 100 | 116 participants |
| Voriconazole | Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | Acute GVHD grade III-IV at day 100 | 27 participants |
| Voriconazole | Time to and Severity of Acute and Chronic Graft vs Host Disease (GVHD) | Chronic GVHD at 1 year | 137 participants |
Secondary
Time to Neutrophil Engraftment
Time frame: 28 days
Secondary
Time to Platelet Engraftment
Time frame: 180 days
Secondary
Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy
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 frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluconazole | Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy | GM+ | 43 participants |
| Fluconazole | Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy | GM- | 252 participants |
| Voriconazole | Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy | GM+ | 35 participants |
| Voriconazole | Utility of Galactomannan Assay in Diagnosis of Aspergillus and Response to Therapy | GM- | 270 participants |