RESPECT

• To demonstrate superiority in subjects who received an allogeneic BMT
  
  randomized to Rezafungin for Injection compared to subjects randomized to
  
  the SAR for fungal-free survival at Day 90 (±7 days)

• Evaluate discontinuation of Rezafungin for Injection compared to the SAR secondary to toxicity or intolerance at Day 90 (±7 days)
• Evaluate cumulative incidence of proven and probable IFD including the number of invasive infections from Candida spp., Aspergillus spp., and Pneumocystis jirovecii in subjects randomized to Rezafungin for Injection compared to the SAR through Day 90 (±7 days)
• Evaluate fungal-free survival in subjects with or without a diagnosis of clinically significant GVHD who are randomized to Rezafungin for Injection compared to the SAR through Day 90 (±7 days)
• Evaluate time to IFD (proven or probable IFD) or death in subjects randomized to Rezafungin for Injection compared to the SAR
• Evaluate overall mortality and attributable mortality, with and without adjustment for patient comorbidity indices, in subjects randomized to Rezafungin for Injection compared to the SAR
• Evaluate the safety and tolerability of Rezafungin for Injection compared to the SAR

1. Willing and able to provide written informed consent.
2. Receiving a human leukocyte antigen (HLA) matched allogenic peripheral blood or marrow transplant (BMT) from a family or unrelated donor, HLA-mismatched related or unrelated donor, or haploidentical donor.
3. Diagnosed with 1 of the following underlying diseases:
   
   a. Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission.
   
   b. Acute lymphoblastic leukemia, in first or second complete remission.
   
   c. Acute undifferentiated leukemia in first or second remission.
   
   d. Acute biphenotypic leukemia in first or second complete remission.
   
   e. Chronic myelogenous leukemia in either chronic or accelerated phase.
   
   f. One of the following myelodysplastic syndrome(s) defined by the following:
   
   i.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).
   
   ix . Chronic myelomonocytic leukemia.
   
   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.
4. Receiving myeloablative or reduced-intensity conditioning regimens.
5. Adequate renal and hepatic function, within 6 weeks of initiation of conditioning, as measured by:
   
   a. Hepatic (within 72 hours of Day 0): alanine aminotransferase <5× upper Limit of normal (ULN) and total serum bilirubin <2.5 mg/dL.
   
   b. Renal (within 72 hours of Day 0): Serum creatinine within normal range for Age or if serum creatinine above ULN range for age, a creatinine clearance [CrCl]) ≥60 mL/min.
6. 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.
7. Baseline Toxoplasma serologies available within 6 weeks prior to randomization.
8. Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence of G6PD deficiency performed within 6 weeks prior to randomization.
9. Female subjects of child-bearing potential <2 years post-menopausal 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 while participating in this study. Male subjects must be vasectomized, abstain from sexual intercourse, agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm while participating in the study and for 120 days from the last IV dose of study drug.

1. Diagnosis of AML not in morphological remission.
2. Diagnosis of chemotherapy-resistant lymphoma.
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 ≤40%, LVEF >40% but fails to improve with exercise, or shortening fraction ≤26%.
5. Personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected (QTc) interval (>470 msec in males and >480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, or quinidine (Appendix 6).
6. Diagnosed reduced lung function with either diffusion capacity (corrected for hemoglobin), forced expiratory volume 1, forced vital capacity ≤45% of predicted value, or O2 saturation ≤85% 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 (≥80 pg/mL).
9. Receipt of previous allogeneic BMT.
10. Planned receipt of cord blood for transplantation.
11. Planned peripheral blood or marrow autograft.
12. Underlying diagnosis of multiple myeloma.
13. Grade 2 or higher ataxia, tremor, motor neuropathy, or sensory neuropathy, per NCI CTCAE version 5.0.
14. History of severe ataxia, neuropathy or tremors; or a diagnosis of multiple sclerosis or a movement disorder (including Parkinson’s disease or Huntington’s disease).
15. Planned or ongoing therapy at screening with a known neurotoxic medication (see Appendix 5) for a complete list of prohibited neurotoxic medications).
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.
18. Recent use of an investigational medicinal product within 28 days of the first dose of prophylactic study drug or presence of an investigational device at the time of screening.
19. Known infection with HIV.
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).

Rezafungin for Injection is administered IV with a 400 mg loading dose in Week 1, followed by 200 mg once weekly thereafter.

Subjects randomized to the SAR will receive the following antifungal regimen to prevent systemic candidiasis and mold infections:

• Fluconazole, 400 mg, by mouth once daily.
  
  Fluconazole may be switched to posaconazole due to acute clinically significant GVHD (Grade II or higher that requires immune suppressive therapy; see Appendix 7) at the discretion of the Investigator; the posaconazole regimen is 300 mg by mouth twice daily on the first day of the medication switch and 300 mg once daily, thereafter.
  
  
  
  Subjects randomized to SAR will also receive the following anti-PCP Regimen:

• TMP/SMX, 80 mg TMP/400 mg SMX, by mouth once daily