Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation
Purpose
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.
Conditions
- Candidemia
- Mycoses
- Fungal Infection
- Fungemia
- Invasive Candidiasis
- Pneumocystis
- Mold Infection
- Invasive Fungal Disease
- Prophylaxis of Invasive Fungal Infections
- Aspergillus
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Willing and able to provide written informed consent. 2. Males or females ≥18 years of age. 3. 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. 4. Diagnosed with 1 of the following underlying diseases: 1. Acute myeloid leukemia (AML), with or without a history of myelodysplastic syndrome, in first or second complete remission. 2. Acute lymphoblastic leukemia, in first or second complete remission. 3. Acute undifferentiated leukemia in first or second remission. 4. Acute biphenotypic leukemia in first or second complete remission. 5. Chronic myelogenous leukemia in either chronic or accelerated phase. 6. 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). g. Lymphoma (including Hodgkin's) with chemosensitive disease (i.e., response to chemotherapy) and receiving a related or unrelated 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 15 days before randomization, with results available prior to randomization. 8. Baseline Toxoplasma serologies available within 6 weeks prior to randomization. Subjects with a positive toxoplasma IgG serology at any time prior to randomization do not need to repeat the toxoplasma serologies (IgG and IgM) and will be considered to have a prior history of toxoplasmosis. 9. Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency determination by the investigator prior to randomization with no known evidence of G6PD deficiency performed any time prior to randomization. If the Investigator assesses the subject as G6PD sufficient, the G6PD test result does not need to be entered into the EDC system. 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
- 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 randomisation. 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) ≤65% 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 15 days prior to the 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 5 half-lives of the investigational medicinal product, whichever is greater, to prevent overlapping toxicities when this study's investigational product is dosed, or presence of an investigational device at the time of screening. In some cases, use of investigational products may be acceptable in consultation with the Sponsor's Medical Monitor. 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.
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Prevention
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Group 1: Rezafungin for Injection |
Subjects in Rezafungin treatment group will receive a 400 mg loading dose in Week 1, followed by 200 mg once weekly, for a total of 13 weeks. Subjects will receive oral placebo for standard antimicrobial regimen (SAR) azole prophylaxis and oral placebo for SAR anti-Pneumocystis pneumonia (PCP) prophylaxis in accordance with the respective SAR dosing regimens for each. For subjects who are switched to a SAR IV regimen, oral placebo for SAR azole prophylaxis will be changed to IV placebo. There is no IV option for SAR anti-PCP prophylaxis. |
|
|
Active Comparator Group 2: Oral Antifungal |
Subjects randomized to the SAR will receive either fluconazole or posaconazole as the first-line SAR as per site's standard practice. Fluconazole will be administered orally at once daily doses of 400 mg for 13 weeks. Posaconazole will be administered orally as 300 mg twice daily on the first day and 300 mg once daily thereafter for 13 weeks. Azole-based antifungal therapy (fluconazole or posaconazole) can be switched from oral therapy to IV therapy if there is oral intolerance, at the discretion of the Investigator. Subjects who started on fluconazole SAR may be switched to posaconazole at the discretion of the Investigator if they develop acute clinically significant GVHD; In addition, subjects in the SAR group will receive anti PCP prophylaxis with oral TMP/SMX (80 mg TMP/ 400 mg SMX) once daily. There is no IV option for SAR anti-PCP prophylaxis. |
|
Recruiting Locations
University of Alabama at Birmingham
Birmingham, Alabama 35233
Birmingham, Alabama 35233
More Details
- Status
- Recruiting
- Sponsor
- Mundipharma Research Limited
Detailed 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.