A Phase 3 Study of Rezafungin for Injection Versus the Standard Antimicrobial Regimen to Prevent Invasive Fungal Diseases in AdultsUndergoing an Allogeneic Blood and Marrow Transplant.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Mundipharma Research Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

13 May 2020 → 29 Jan 2026

Decision date (initial)

2024-06-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514471-18-00

EudraCT number

2017-004981-85

ClinicalTrials.gov

NCT04368559

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Efficacy, Pharmacokinetic, Safety

To demonstrate non-inferiority (NI) in subjects who received an allogeneic BMT for subjects randomized to Rezafungin for Injection compared to subjects randomized to the standard antimicrobial regimen (SAR) for fungal-free survival at Day 90 (±7 days), and then to assess superiority of Rezafungin over the SAR for fungal-free survival at Day 90 (±7 days).

Secondary objectives 7

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

Conditions and MedDRA coding

Invasive Fungal Diseases in Adults undergoing Allogeneic Blood and Marrow Transplantation (BMT)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Medicines Evaluation Board, Medicines And Healthcare Products Regulatory Agency, European Medicines Agency, Food And Drug Administration, Ministry Of Health

Plan to share IPD

No

IPD plan description

Information was not required under CTD.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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: 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). 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: a. Hepatic: alanine aminotransferase ≤2.5 × upper limit of normal (ULN) and total serum bilirubin ≤1.5 × ULN (excluding Gilbert’s Syndrome). b. Renal: serum creatinine ≤2 mg/dL and with creatinine clearance (CrCl) ≥30 mL/min without a history of renal transplant, or undergoing weekly dialysis within 4 weeks of the BMT.
7. Baseline blood samples drawn for serum 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 evidence of known 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 Electronic Data Capture (EDC) system.
10. Female subjects of child-bearing potential <2 years post-menopausal (unless surgically sterile) must agree to and comply with using one 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 24

1. Diagnosis of AML not in morphological remission.
2. 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.
3. Known infection with human immunodeficiency virus (HIV). Subjects with unknown HIV status should be tested for HIV antibodies per standard of care.
4. Receipt of previous allogeneic BMT.
5. Pregnant or lactating females.
6. The Principal Investigator (PI) determines that the subject should not participate in the study.
7. Considered unlikely to follow up for 90 days after receipt of the BMT due to logistic concerns (i.e., location relative to transplant center).
8. Known liver cirrhosis, diagnosed according to country or Medical Society specific guidelines and documented in the medical records prior to initiating conditioning regimen.
9. Planned peripheral blood or marrow autograft.
10. Not applicable for protocol Amendment 6.
11. 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.
12. Suspected or diagnosed IFD within 4 weeks of randomization.
13. 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).
14. a. 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. b. 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.
15. Planned receipt of cord blood for transplantation.
16. Diagnosis of chemotherapy-resistant lymphoma; a first relapse can occur provided that a second complete remission has been achieved.
17. Diagnosed symptomatic heart failure or with left ventricular ejection fraction (LVEF) at rest ≤50%, or shortening fraction ≤26%.
18. Personal or family history of Long QT interval on ECG (QT) syndrome or a prolonged QT interval corrected for heart rate by Fridericia’s formula (QTcF) (>470 msec in males and >480 msec in females); or concurrent administration of terfenadine, cisapride, astemizole, erythromycin, pimozide, quinidine, or halofantrine.
19. Reduced lung function, that would significantly impact on clinical outcomes, based on routine clinical practice and assessments conducted at the Investigator site. If any of the following tests are conducted, the criteria for reduced lung function are as follows: a. Diffusion capacity (corrected for hemoglobin) or forced expiratory volume in 1 second (FEV1) ≤65% of predicted value b. O2 saturation ≤82% on room air.
20. Suspected or documented PCP within 2 years of screening.
21. Positive baseline serum Platelia GM EIA (≥ 0.5) and/or β-D-glucan assay (Fungitell ≥80 pg/mL or Fujifilm Wako >11 pg/mL) within 15 days prior to transplant.
22. Known hypersensitivity to Rezafungin for Injection, any echinocandin, fluconazole, posaconazole, other azole antifungal, or to any of their excipients.
23. 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.
24. Toxoplasma IgM positive serology in the 6 weeks prior to randomisation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. The primary efficacy endpoint is fungal-free survival at Day 90 (±7 days), as defined by:
2. a) Survival
3. b) Absence of proven or probable IFD. Proven and probable IFD are defined per the modified 2020 European Organization for Research and Treatment of Cancer Mycoses Study Group Education and Research Consortium (EORTC-MSGERC) criteria (see Appendix 4 for complete IFD definitions)
4. c) Absence of receipt of non-study drug systemic antifungal therapy (including anti-PCP drugs) for a cumulative exposure >10 days. Anti-PCP drugs include TMP-SMX, dapsone, atovaquone, pentamidine (IV or inhaled), and combined clindamycin and primaquine.

Secondary endpoints 6

1. To evaluate secondary efficacy objectives, secondary efficacy endpoints include (a-e):
2. a) Study drug withdrawal due to toxicities or intolerance
3. b) Cumulative incidence of proven and probable IFD including numbers of invasive infection from Candida spp., Aspergillus spp., and Pneumocystis jirovecii
4. c) Time to IFD or death, defined as the number days from the first dose of study drug to the date of proven or probable IFD or death (all-cause). Subjects who do not have an event will be censored at the date last known to be IFD-free or alive. Subjects who are lost to follow-up will be censored at the date of last contact.
5. d) All-cause mortality
6. e) Attributable mortality associated with IFD

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 6

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Mundipharma Research Limited

Sponsor organisation

Mundipharma Research Limited

Address

Cambridge Science Park, Milton Road Milton Road

City

Cambridge

Postcode

CB4 0GW

Country

United Kingdom

Scientific contact point

Organisation

Mundipharma Research Limited

Contact name

Clinical Trial Information Desk

Public contact point

Organisation

Mundipharma Research Limited

Contact name

Clinical Trial Information Desk

Third parties 10

Locations

5 EU/EEA countries · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 65 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications