Overview
The purpose of this pivotal study is to determine if intravenous Rezafungin is efficacious and safe in the prevention of invasive fungal diseases when compared to the standard antimicrobial regimen.
Description
A Phase 3, multicenter, prospective, randomized, double-blind, efficacy and safety study of Rezafungin for injection versus the standard antimicrobial regimen for the prevention of invasive fungal diseases in subjects undergoing allogeneic blood and marrow transplantation.
Eligibility
Inclusion Criteria:
- Willing and able to provide written informed consent.
- Males or females ≥18 years of age.
- Receiving a human leukocyte antigen (HLA) matched allogeneic peripheral BMT from a family or unrelated donor, HLA-mismatched related or unrelated donor, or haploidentical donor.
- Diagnosed with 1 of the following underlying diseases:
- Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.
- Acute lymphoblastic leukemia, in first or second complete remission.
- Acute undifferentiated leukemia in first or second remission.
- Acute biphenotypic leukemia in first or second complete remission.
- Chronic myelogenous leukemia in either chronic or accelerated phase.
- One of the following myelodysplastic syndrome(s) defined by the following:
- Refractory anemia.
ii. Refractory anemia with ringed sideroblasts.
iii. Refractory cytopenia with multilineage dysplasia.
iv. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts.
v. Refractory anemia with excess blasts - 1 (5-10% blasts).
vi. Refractory anemia with excess blasts - 2 (10-20% blasts).
vii. Myelodysplastic syndrome, unclassified.
viii. Myelodysplastic syndrome associated with isolated del (5q).
g. Lymphoma (including Hodgkin's) with chemosensitive disease (i.e., response to
chemotherapy) and receiving a related donor transplant.
h. Aplastic anemia.
i. Primary or secondary myelofibrosis.
j. Chronic myelomonocytic leukemia.
k. Chronic lymphocytic leukemia.
l. Drepanocytosis (sickle cell anemia).
m. Red blood cell aplasia.
n. Myeloproliferative disorder, unclassified.
o. Multiple myeloma (plasma cell myeloma).
5. Receiving myeloablative or reduced-intensity conditioning regimens.
6. Adequate renal and hepatic function prior to initiation of conditioning regimen,
therefore between 40 days prior and 10 days prior to BMT, documented as follows:
1. Hepatic: alanine aminotransferase less than or equal to (≤) 2.5 × upper limit of
normal (ULN) and total serum bilirubin ≤1.5 × ULN (excluding Gilbert's Syndrome).
2. Renal: serum creatinine ≤2 milligrams (mg)/deciliter (dL) and with creatinine
clearance (CrCl) greater than or equal to (≥) 30 milliliters (mL)/minute (min)
without a history of renal transplant, or undergoing weekly dialysis within 4
weeks of the BMT.
7. Baseline blood samples drawn for Platelia galactomannan enzyme immunoassay (GM EIA)
and β-D glucan levels within 14 days before randomization, with results available
prior to randomization.
8. Baseline Toxoplasma serologies available within 6 weeks prior to randomization.
9. Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence
of G6PD deficiency performed any time prior to randomization.
10. Female subjects of child-bearing potential <2 years post-menopausal (unless surgically
sterile) must agree to and comply with using 1 barrier method (e.g., female condom
with spermicide) plus one other highly effective method of birth control (e.g., oral
contraceptive, implant, injectable, indwelling intrauterine device, vasectomized
partner), or sexual abstinence (only possible if it corresponds to the subject's usual
lifestyle) while participating in this study, and for 30 days after the last dose of
study drug. Male subjects must be vasectomized, abstain from sexual intercourse, or
agree to use barrier contraception (condom with spermicide), and agree not to donate
sperm while participating in the study and for 120 days from the last IV dose of study
drug.
Exclusion Criteria:
1. Diagnosis of AML not in morphological remission.
2. Diagnosis of chemotherapy-resistant lymphoma: a first relapse can occur provided that
a second complete remission has occurred.
3. Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening.
4. Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at
rest ≤50%, or shortening fraction ≤26%.
5. Personal or family history of Long QT interval on electrocardiogram (ECG) (QT)
syndrome or a prolonged QT interval corrected for heart rate by Fridericia's formula
(QTcF) (>470 milliseconds [msec] in males and >480 msec in females); or concurrent
administration of terfenadine, cisapride, astemizole, erythromycin, pimozide,
quinidine, or halofantrine.
6. Diagnosed reduced lung function with either diffusion capacity (corrected for
hemoglobin) or forced expiratory volume in 1 second (FEV1) ≤70% of predicted value, or
O2 saturation ≤82% on room air.
7. Suspected or documented PCP within 2 years of screening.
8. Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D glucan assay (Fungitell ≥80
picograms [pg]/mL or Fujifilm Wako >11 pg/mL) within 14 days of transplant.
9. Receipt of previous allogeneic BMT.
10. Planned receipt of cord blood for transplantation.
11. Planned peripheral blood or marrow autograft.
12. Not applicable to protocol Amendment 6.
13. Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 5.0.
14. History of severe (Grade ≥3) ataxia, neuropathy or tremors; or a diagnosis of multiple
sclerosis or a movement disorder (including Parkinson's disease or Huntington's
disease).
15. . .
1. Planned or ongoing intake at screening of a known severe neurotoxic medication or
with a known moderate neurotoxic medication in a patient with ataxia, tremor,
motor neuropathy, or sensory neuropathy of CTCAE version 5.0 Grade 1 or higher.
2. Any contraindication or a medication or supplement known to severely interact
with the standard antimicrobial regimen (SAR) as detailed in the US Prescribing
Information (USPI) or Summary of Product Characteristics (SmPC) of fluconazole,
posaconazole, or TMP/SMX.
16. Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole,
posaconazole, other azole antifungal, or to any of their excipients.
17. Known hypersensitivity or inability to receive TMP/SMX or any of its excipients,
including but not limited to anaphylaxis, exfoliative skin disorders, or acute
porphyria.
18. Recent use of an investigational medicinal product within 28 days or greater to assure
more than 5 half-lives have passed to prevent overlapping toxicities when this study's
investigational product is dosed, or presence of an investigational device at the time
of screening.
19. Known infection with HIV. Subjects with unknown HIV status should be tested for HIV
antibodies per standard of care.
20. Pregnant or lactating females.
21. The Principal Investigator (PI) determines that the subject should not participate in
the study.
22. Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic
concerns (i.e., location relative to transplant center).
23. Known liver cirrhosis, diagnosed according to country or Medical Society specific
guidelines and documented in the medical records prior to initiating conditioning
regimen.
24. Body weight >130 kilograms (kg) at screening.