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

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.

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