Clinical trial NCT04368559: Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Candidemia
Mycoses
Fungal Infection
Fungemia
Invasive Candidiasis
Pneumocystis
Mold Infection
Invasive Fungal Disease
Prophylaxis of Invasive Fungal Infections
Aspergillus
Keywords: Mycoses
Prophylaxis of Invasive Fungal Infections
Aspergillus
Candidiasis
Candidemia
Candidiasis, Invasive
Fungemia
Sepsis
Blood and Marrow Transplant (BMT)
Infection
Invasive Fungal Infections
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Fluconazole
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
Lead sponsor: Mundipharma Research Limited
Sponsor class: INDUSTRY
First posted: 2020-04-30
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Noninferior Fungal-Free Survival (US FDA)
timeFrame: Day 90 (±7 days)
measure: Noninferior Fungal-Free Survival (US FDA)
timeFrame: Day 90 (±7 days)
measure: Superior Fungal-Free Survival (EMA)
timeFrame: Day 90 (±7 days)
measure: Superior Fungal-Free Survival (EMA)
timeFrame: Day 90 (±7 days)
Secondary outcomes:
measure: Compare Discontinuation for Toxicity or Intolerance
timeFrame: Day 90 (±7 days)
measure: Compare Discontinuation for Toxicity or Intolerance
timeFrame: Day 90 (±7 days)
measure: Compare Proven and Probable IFD
timeFrame: Day 90 (±7 days)
measure: Compare Proven and Probable IFD
timeFrame: Day 90 (±7 days)
measure: Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD
timeFrame: Day 90 (±7 days)
measure: Compare Fungal-Free Survival with or without a Diagnosis of Clinically Significant GVHD
timeFrame: Day 90 (±7 days)
measure: Compare Time to IFD, or Death
timeFrame: Day 90 (±7 days)
measure: Compare Mortality
timeFrame: Day 1 through follow-up visit (Day 120)
measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability]
timeFrame: Day 1 through follow-up visit (Day 120)
Other outcomes:
measure: Comparison of Fungal-Free
timeFrame: Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), and Day 120 (±7 days)
measure: Comparison of Fungal-Free
timeFrame: Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), and Day 120 (±7 days)
measure: Comparison of Presence and Severity of GHVD
timeFrame: Day 90 (±7 days)
measure: Comparison of Fungal-Free with AML
timeFrame: Day 90 (±7 days)
measure: Comparison of Fungal-Free with AML
timeFrame: Day 90 (±7 days)
measure: Compare Incidence of IFD
timeFrame: Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)
measure: Compare Relapse-Free Survival
timeFrame: Day 1 through follow-up visit (Day 120)
measure: Evaluate PK (Cmax)
timeFrame: Day 0 (±2 days) within 10 minutes before end of infusion, and one sample between end of infusion and 12 hours after end of infusion; Days 1-4, one sample at any time; Day 7 (±1 day), Day 28 (±1 day), and Day 63 (±1 day) prior to dosing; and EOT visit
measure: Evaluate PK (Tmax)
timeFrame: Day 0 (±2 days) within 10 minutes before end of infusion, and one sample between end of infusion and 12 hours after end of infusion; Days 1-4, one sample at any time; Day 7 (±1 day), Day 28 (±1 day), and Day 63 (±1 day) prior to dosing; and EOT visit
measure: Evaluate PK (AUC)
timeFrame: Day 0 (±2 days) within 10 minutes before end of infusion, and one sample between end of infusion and 12 hours after end of infusion; Days 1-4, one sample at any time; Day 7 (±1 day), Day 28 (±1 day), and Day 63 (±1 day) prior to dosing; and EOT visit
measure: Compare Post-Engraftment Cytopenias and Transfusion Requirements
timeFrame: Day 1 through follow-up visit (Day 120)
measure: Compare Infections Caused by TMP/SMX-Sensitive Organisms
timeFrame: Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)
measure: Compare Antifungal Prophylaxis
timeFrame: Day 14 (±1 day), Day 28 (±1 day), Day 60 (±5 days), Day 90 (±7 days), and Day 120 (±7 days)
measure: Compare the health economics outcome research (HEOR) variable of "Days in Hospital"
timeFrame: Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]
measure: Compare the health economics outcome research (HEOR) variable of "Days in Intensive Care Unit (ICU)"
timeFrame: Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]
measure: Compare the health economics outcome research (HEOR) variable of "Readmission due to Infectious Disease Diagnosis"
timeFrame: Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]
measure: Compare the health economics outcome research (HEOR) variable of "Readmission due to Invasive Fungal Disease Diagnosis"
timeFrame: Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]
measure: Compare the health economics outcome research (HEOR) variable of "Alternative Antifungal Therapy"
timeFrame: Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]
measure: Compare the health economics outcome research (HEOR) variable of "Antibiotic Therapy"
timeFrame: Once weekly for outpatient, or twice weekly for inpatient, at completion of study drug therapy [Day 90 (±7 days)] and for 30 days [Day 120 (±7 days)]
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Center for Health Sciences
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Augusta
country: United States
facility: Augusta University Medical Center
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Physicians
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Lebanon
country: United States
facility: Mary Hitchcock Memorial Hospital Dartmouth-Hitchcock
state: New Hampshire
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Oklahoma City
country: United States
facility: The University of Oklahoma College of Medicine
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Richmond
country: United States
facility: VCU Medical Center Main Hospital
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Brugge
country: Belgium
facility: AZ Sint-Jan
state: West Vlaanderen
city: Leuven
country: Belgium
facility: University Hospitals Leuven, Campus Gasthuisberg - UZ Leuven
city: Hamilton
country: Canada
facility: Hamilton Health Sciences' Juravinski Hospital
city: Montréal
country: Canada
facility: McGill University Health Center
city: Besançon
country: France
facility: Jean Minjoz Hospital
city: Créteil
country: France
facility: Henri Mondor Hospital
city: Grenoble
country: France
facility: Grenoble Alpes University Hospital Center
city: Limoges
country: France
facility: University Hospital of Limoges
city: Nantes
country: France
facility: University Hospital of Nantes
city: Paris
country: France
facility: Hospital Saint Antoine Ap-Hp
city: Pessac
country: France
facility: University Hospital of Bordeaux
city: Pierre-Bénite
country: France
facility: Lyon-Sud Hospital Center
city: Dresden
country: Germany
facility: University Hospital Carl Gustav Carus Dresden
city: Essen
country: Germany
facility: Essen University Hospital
city: Köln
country: Germany
facility: University Hospital of Cologne
city: Mainz
country: Germany
facility: Johannes Gutenberg University Medical Center
city: Münster
country: Germany
facility: University Hospital Münster
city: Genova
country: Italy
facility: San Martino Polyclinic Hospital
city: Milan
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Rome
country: Italy
facility: Agostino Gemelli University Policlinic
city: Rozzano
country: Italy
facility: Humanitas Cancer Center
city: Barcelona
country: Spain
facility: University Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic of Barcelona
city: Madrid
country: Spain
facility: Hospital de la Princesa
city: Madrid
country: Spain
facility: University Hospital Ramon y Cajal
city: Majadahonda
country: Spain
facility: Puerta de Hierro Majadahonda University Hospital
city: Salamanca
country: Spain
facility: University Hospital of Salamanca
city: Valencia
country: Spain
facility: University Hospital of Valencia
city: Valencia
country: Spain
facility: La Fe University and Polytechnic Hospital
city: Geneva
country: Switzerland
facility: University Hospitals Geneva
city: Ankara
country: Turkey
facility: Hacettepe University School of Medicine
city: Ankara
country: Turkey
facility: Ankara University School of Medicine
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
Study officials:
affiliation: Mundipharma Research Limited
name: Laura Cox, PhD
role: STUDY_DIRECTOR
References:
citation: Ham YY, Lewis JS 2nd, Thompson GR 3rd. Rezafungin: a novel antifungal for the treatment of invasive candidiasis. Future Microbiol. 2021 Jan;16(1):27-36. doi: 10.2217/fmb-2020-0217.