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

Phase 3

Recruiting

• Conditions: Pneumocystis; Invasive Fungal Disease; Prophylaxis of Invasive Fungal Infections; Mycoses; Fungal Infection; Fungemia; Mold Infection; Aspergillus; Candidemia; Invasive Candidiasis
• Interventions: Drug: Rezafungin for Injection; Drug: Posaconazole; Drug: Intravenous Placebo; Drug: Fluconazole; Drug: Trimethoprim-sulfamethoxazole (TMP/SMX); Drug: Oral Placebo

• Registration Number: NCT04368559
• Lead Sponsor: Mundipharma Research Limited

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2020-04-22
• Study First Submitted QC: 2020-04-27
• Study First Posted: 2020-04-30
• Study Start: 2020-05-11
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-31
• Last Update Posted: 2025-02-03
• Primary Completion: 2025-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 600

Inclusion Criteria

1. 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

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 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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1: Rezafungin for Injection	Intravenous Placebo	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.
Group 2: Oral Antifungal	Trimethoprim-sulfamethoxazole (TMP/SMX)	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.
Group 1: Rezafungin for Injection	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.
Group 1: Rezafungin for Injection	Oral Placebo	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.
Group 2: Oral Antifungal	Posaconazole	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.
Group 2: Oral Antifungal	Fluconazole	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Compare Discontinuation for Toxicity or Intolerance	Day 90 (±7 days)	The percentage of subjects that discontinued Rezafungin for Injection compared to the standard antimicrobial regimen (SAR) secondary to toxicity or intolerance.
Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD	Day 90 (±7 days)	The percentage of subjects in each treatment group who are fungal-free survival with or without a diagnosis of clinically significant GVHD.
Compare Time to IFD, or Death	Day 90 (±7 days)	Evaluate time to IFD (proven or probable IFD) or death in subjects randomized to Rezafungin for Injection compared to the standard antimicrobial regimen (SAR).
Compare Proven and Probable IFD	Day 90 (±7 days)	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.
Compare Mortality	Day 1 through follow-up visit (Day 120)	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.
Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]	Day 1 through follow-up visit (Day 120)	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.

Trial Locations

Locations (51)

Stanford University School of Medicine; 🇺🇸 Stanford, California, United States

University of Minnesota Physicians; 🇺🇸 Minneapolis, Minnesota, United States

Mary Hitchcock Memorial Hospital Dartmouth-Hitchcock; 🇺🇸 Lebanon, New Hampshire, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

VCU Medical Center Main Hospital; 🇺🇸 Richmond, Virginia, United States

Addenbrookes Hospital; 🇬🇧 Cambridge, United Kingdom

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

UCLA Center for Health Sciences; 🇺🇸 Los Angeles, California, United States

Augusta University Medical Center; 🇺🇸 Augusta, Georgia, United States

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

University of Maryland Medical Center; 🇺🇸 Baltimore, Maryland, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Stony Brook University Hospital; 🇺🇸 Stony Brook, New York, United States

The University of Oklahoma College of Medicine; 🇺🇸 Oklahoma City, Oklahoma, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

AZ Sint-Jan; 🇧🇪 Brugge, West Vlaanderen, Belgium

University Hospitals Leuven, Campus Gasthuisberg - UZ Leuven; 🇧🇪 Leuven, Belgium

Hamilton Health Sciences' Juravinski Hospital; 🇨🇦 Hamilton, Canada

McGill University Health Center; 🇨🇦 Montréal, Canada

Jean Minjoz Hospital; 🇫🇷 Besançon, France

Henri Mondor Hospital; 🇫🇷 Créteil, France

Grenoble Alpes University Hospital Center; 🇫🇷 Grenoble, France

University Hospital of Limoges; 🇫🇷 Limoges, France

University Hospital of Nantes; 🇫🇷 Nantes, France

Hospital Saint Antoine Ap-Hp; 🇫🇷 Paris, France

University Hospital of Bordeaux; 🇫🇷 Pessac, France

Lyon-Sud Hospital Center; 🇫🇷 Pierre-Bénite, France

University Hospital Carl Gustav Carus Dresden; 🇩🇪 Dresden, Germany

Essen University Hospital; 🇩🇪 Essen, Germany

University Hospital of Cologne; 🇩🇪 Köln, Germany

Johannes Gutenberg University Medical Center; 🇩🇪 Mainz, Germany

University Hospital Münster; 🇩🇪 Münster, Germany

San Martino Polyclinic Hospital; 🇮🇹 Genova, Italy

IEO Istituto Europeo di Oncologia; 🇮🇹 Milan, Italy

Agostino Gemelli University Policlinic; 🇮🇹 Rome, Italy

Humanitas Cancer Center; 🇮🇹 Rozzano, Italy

University Hospital Vall d'Hebron; 🇪🇸 Barcelona, Spain

Hospital Clinic of Barcelona; 🇪🇸 Barcelona, Spain

Hospital de la Princesa; 🇪🇸 Madrid, Spain

University Hospital Ramon y Cajal; 🇪🇸 Madrid, Spain

Puerta de Hierro Majadahonda University Hospital; 🇪🇸 Majadahonda, Spain

University Hospital of Salamanca; 🇪🇸 Salamanca, Spain

University Hospital of Valencia; 🇪🇸 Valencia, Spain

La Fe University and Polytechnic Hospital; 🇪🇸 Valencia, Spain

University Hospitals Geneva; 🇨🇭 Geneva, Switzerland

Hacettepe University School of Medicine; 🇹🇷 Ankara, Turkey

Ankara University School of Medicine; 🇹🇷 Ankara, Turkey

Kings College Hospital NHS Foundation Trust; 🇬🇧 London, United Kingdom