Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 3, Multicenter, Randomized, Double-Blind Study of the Efficacy and Safety of Rezafungin for Injection Versus the Standard Antimicrobial Regimen to Prevent Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation (The ReSPECT Study)

Conditions
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Mycoses, Candidemia, Fungal Infection, Fungemia, Invasive Candidiasis, Pneumocystis, Mold Infection, Invasive Fungal Disease, Prophylaxis of Invasive Fungal Infections, Aspergillus

Intervention / Treatment
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* Drug: Rezafungin for Injection
* Drug: Posaconazole
* Drug: Fluconazole
* Drug: Trimethoprim-sulfamethoxazole (TMP/SMX)
* Drug: Intravenous Placebo
* Drug: Oral Placebo


Participation Criteria
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Eligibility Criteria
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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: 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 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). Receiving myeloablative or reduced-intensity conditioning regimens. 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: 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). 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. 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. Baseline Toxoplasma serologies available within 6 weeks prior to randomization. Baseline glucose-6-phosphate dehydrogenase (G6PD) deficiency testing with no evidence of G6PD deficiency performed any time prior to randomization. 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. Diagnosis of chemotherapy-resistant lymphoma: a first relapse can occur provided that a second complete remission has occurred. Suspected or diagnosed invasive fungal disease (IFD) within 4 weeks of screening. Diagnosed symptomatic heart failure with left ventricular ejection fraction (LVEF) at rest ≤50%, or shortening fraction ≤26%. 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. 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. Suspected or documented PCP within 2 years of screening. 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. Receipt of previous allogeneic BMT. Planned receipt of cord blood for transplantation. Planned peripheral blood or marrow autograft. Not applicable to protocol Amendment 6. 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. 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). . . 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. 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. Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole, posaconazole, other azole antifungal, or to any of their excipients. 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. 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. Known infection with HIV. Subjects with unknown HIV status should be tested for HIV antibodies per standard of care. Pregnant or lactating females. The Principal Investigator (PI) determines that the subject should not participate in the study. Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center). Known liver cirrhosis, diagnosed according to country or Medical Society specific guidelines and documented in the medical records prior to initiating conditioning regimen. Body weight >130 kilograms (kg) at screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Rezafungin for Injection<br>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. | Drug: Rezafungin for Injection<br>* Intravenous antifungal therapy<br>* Other names: Intravenous antifungal therapy;Drug: Intravenous Placebo<br>* Normal saline<br>* Other names: Placebo Infusion;Drug: Oral Placebo<br>* Microcrystalline cellulose<br>* Other names: encapsulated cellulose;|
| Active Comparator: Group 2: Oral Antifungal<br>Subjects in SAR treatment group will receive 400 mg oral fluconazole once daily for 13 weeks. Fluconazole may be switched, due to acute clinically significant graft versus-host disease (GVHD), to 300 mg oral posaconazole twice daily on the first day of the medication switch and 300 mg once daily, thereafter. However, subjects who are switched to posaconazole cannot be switched back to fluconazole. Azole-based antifungal therapy (fluconazole or posaconazole) can be switched from daily oral therapy to daily IV therapy at the discretion of the Investigator. 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. | Drug: Posaconazole<br>* Oral antifungal therapy<br>* Other names: Noxafil;Drug: Fluconazole<br>* Oral antifungal therapy<br>* Other names: Generic Fluconazole;Drug: Trimethoprim-sulfamethoxazole (TMP/SMX)<br>* Oral antibacterial therapy<br>* Other names: Septra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Noninferior Fungal-Free Survival (US FDA) | The number of subjects in each treatment group who are fungal-free and survive. | Day 90 (±7 days) | 
| Noninferior Fungal-Free Survival (US FDA) | The percentage of subjects in each treatment group who are fungal-free and survive. | Day 90 (±7 days) | 
| Superior Fungal-Free Survival (EMA) | The number of subjects in each treatment group who are fungal-free and survive. | Day 90 (±7 days) | 
| Superior Fungal-Free Survival (EMA) | The percentage of subjects in each treatment group who are fungal-free and survive. | Day 90 (±7 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare Discontinuation for Toxicity or Intolerance | The number of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance. | Day 90 (±7 days) | 
| Compare Discontinuation for Toxicity or Intolerance | The percentage of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance. | Day 90 (±7 days) | 
| Compare Proven and Probable IFD | The number of subjects in each treatment group who have proven and probable IFD including the number of invasive infections from Candida spp., Aspergillus spp., and Pneumocystis jirovecii. | Day 90 (±7 days) | 
| Compare Proven and Probable IFD | The percentage of subjects in each treatment group who have proven and probable IFD including the number of invasive infections from Candida spp., Aspergillus spp., and Pneumocystis jirovecii. | Day 90 (±7 days) | 
| Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD | The number of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD. | Day 90 (±7 days) | 
| Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD | The percentage of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD. | Day 90 (±7 days) | 
| Compare Time to IFD, or Death | Evaluate time to IFD (proven or probable IFD) or death in subjects randomized to Rezafungin for Injection compared to the standard antimicrobial regimen (SAR). | Day 90 (±7 days) | 
| Compare Mortality | 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. | Day 1 through follow-up visit (Day 120) | 
| Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] | The number of subjects with incidence of treatment emergent adverse events based on clinical chemistry, hematology and urine analysis laboratory test, vital sign, physical exams and ECG abnormalities. | Day 1 through follow-up visit (Day 120) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infection, Fluconazole, Mycoses, Prophylaxis of Invasive Fungal Infections, Aspergillus, Candidiasis, Candidemia, Candidiasis, Invasive, Fungemia, Sepsis, Blood and Marrow Transplant (BMT), Invasive Fungal Infections, Systemic Inflammatory Response Syndrome, Inflammation, Pathologic Processes, Posaconazole, Caspofungin, Trimethoprim-sulfamethoxazole (TMP/SMX), Echinocandins, Antifungal Agents, 14-alpha Demethylase Inhibitors, Cytochrome P-450 Enzyme Inhibitors, Enzyme Inhibitors, Molecular Mechanisms of Pharmacological Action, Steroid Synthesis Inhibitors, Physiological Effects of Drugs, Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors, Pneumocystis, Mold Infection, Rezafungin, Anti-Infective Agents