Mucormycosis
Conditions
Keywords
zygomycosis, Rhizopus, iron, iron-chelation, adjunctive therapy
Brief summary
The purpose of this study is to determine if the addition of the medication, deferasirox, to standard antifungal therapy for the infection, mucormycosis, is safe and effective
Detailed description
Because of its extremely high morbidity and mortality, it is imperative to look for new antifungal therapies to treat mucormycosis. The agents of mucormycosis are exquisitely sensitive to iron availability, and we and others have demonstrated that iron chelation therapy improves the survival of rodents with mucormycosis. Deferasirox (Exjade) is the first orally bioavailable iron chelator approved for use in the United States (US) by the Food and Drug Administration (FDA), with an indication for treatment of iron overload from chronic transfusions. In clinical studies, deferasirox has been well tolerated and effective in iron-overloaded patients. Although the safety and efficacy of deferasirox have been extensively evaluated in iron-overloaded patients, there are minimal data in non-iron-overloaded patients or in infected patients. Therefore, the safety and efficacy of deferasirox in patients with mucormycosis is unclear, and confirming safety in the current study, at the currently planned dose, is required to lay the groundwork for a future phase III clinical trial. This is a prospective, phase II, randomized, double-blinded, placebo-controlled study of liposomal amphotericin B (LAmB; AmBisome) plus deferasirox vs. LAmB plus placebo for mucormycosis infection. Twenty patients with proven or probable mucormycosis (except for isolated skin infection) by consensus EORTC/MSG criteria, who have received less than 14 days of antifungal therapy for mucormycosis, and who have had radiographic imaging by CT or MRI within the past 72 hours that shows evidence of infection, will be randomized to receive LAmB plus deferasirox or placebo (n = 10 per arm), with randomization stratified by study site. The primary objective is to determine the safety and tolerability of adjunctive deferasirox therapy in patients being treated with LAmB for mucormycosis, and to obtain exploratory data on the efficacy of the iron chelation treatment. The exploratory efficacy endpoint will be the global response rate (composite of clinical and radiographic response) at end of study drug administration, as determined by a blinded adjudication committee.
Interventions
DRUGdeferasirox
20 mg/kg enterally per day
DRUGPlacebo
DRUGLiposomal amphotericin B
Sponsors
Gilead Sciences
Astellas Pharma Inc
Novartis
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age greater than 2 years. * Proven or probable invasive mucormycosis, as defined by modification of consensus European Organization for Research and Treatment of Cancer (EORTC)/Mycosis Study Group (MSG) criteria. In brief, proven mucormycosis is defined as: 1) histopathologic or cytopathologic examination showing broad-based, aseptate, ribbon-like hyphae consistent with Mucorales from needle aspiration or biopsy specimen, with evidence of associated tissue damage (either microscopically or unequivocally by imaging); OR 2) a positive culture result for a sample obtained by sterile procedure from normally sterile and clinically or radiologically abnormal site consistent with infection, excluding urine and mucous membranes. Probable mucormycosis is defined as: 1) an at-risk host; AND 2) positive culture, cytology, or polymerase chain reaction (PCR) test (run at a CLIA-certified clinical microbiology laboratory) from sputum, bronchoalveolar lavage (BAL), endoscopy/colonoscopy, or sinus aspirate/biopsy; AND 3) 1 major or 2 minor clinical criteria. * Radiographic study by Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI) has been obtained within 4 calendar days prior to enrollment and shows evidence of infection (i.e. focal nodule, mass, or abscess, or enhancement, or evidence of tissue edema or destruction that is not attributed to post-surgical reaction). * Subject or authorized decision maker able to provide informed consent.
Exclusion criteria
* High likelihood of death within the 48 h after enrollment (investigator's discretion). * High likelihood of death due to factors unrelated to mucormycosis (e.g. due to uncontrolled and/or relapsed malignancy, severe graft versus host disease, other underlying diseases, etc.) within 30 days following enrollment (investigator's discretion). * Patient unable to receive enteral medication (oral or via feeding tube). * Infection limited to the supra-fascial skin (skin lesions in the presence of disseminated disease, deep invasive tissue infection spreading from a primary skin site, or subcutaneous infections extending to fascia are allowed). * Patient has received \> 14 days of polyene antifungal therapy (i.e. amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex, or amphotericin B colloidal dispersion) at the time of screening. * Patient is already taking deferasirox therapy for any reason at the time of screening. * Patient is allergic to or intolerant of deferasirox or LAmB. * Patient has significant renal dysfunction at the time of screening, defined as serum creatinine of \> 3 mg/dL or a calculated creatinine clearance of \< 30 ml/min (by the Cockroft-Gault formula: (140 - age (yrs) \* wt (kg)) \* 0.85 (for females) / (72 \* serum creatinine (mg/dL)). * Patient has significant hepatic dysfunction at the time of screening, defined as BOTH an AST or ALT \> 10 times the upper limit of normal, AND a direct (not total) bilirubin \> 5 times the upper limit of normal. * Women of child-bearing potential (those with menses within the last year) with a positive serum pregnancy test. * Enrollment refused by the primary physician.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and Tolerability of Adjunctive Deferasirox Therapy in Patients Being Treated With LAmB for Mucormycosis | 14 days |
| Global Response Rate (Composite of Clinical and Radiographic Response) at End of Study Drug Administration, as Determined by a Blinded Adjudication Committee | 14 days |
| Total Adverse Events | 30 Days After End of Therapy |
Secondary
| Measure | Time frame |
|---|---|
| Deferasirox Pharmacokinetic and Pharmacodynamic Parameters | 7 days |
| Survival, Radiographic Improvement, Clinical Response, Time to Survival, Deferasirox vs. Free Iron Level Correlation | Up to 90 days |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox Deferasirox plus liposomal amphotericin | 11 |
| Placebo Placebo control plus background liposomal amphotericin | 9 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Placebo | Deferasirox | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 3 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 15 Participants |
| Age, Continuous | 47 years | 59 years | 52 years |
| Region of Enrollment United States | 9 participants | 11 participants | 20 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 11 | 7 / 9 |
| serious Total, serious adverse events | 8 / 11 | 4 / 9 |
Outcome results
Primary
Global Response Rate (Composite of Clinical and Radiographic Response) at End of Study Drug Administration, as Determined by a Blinded Adjudication Committee
Time frame: 14 days
Primary
Safety and Tolerability of Adjunctive Deferasirox Therapy in Patients Being Treated With LAmB for Mucormycosis
Time frame: 14 days
Primary
Total Adverse Events
Time frame: 30 Days After End of Therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deferasirox | Total Adverse Events | 16 Events |
| Placebo | Total Adverse Events | 16 Events |
Secondary
Deferasirox Pharmacokinetic and Pharmacodynamic Parameters
Time frame: 7 days
Secondary
Survival, Radiographic Improvement, Clinical Response, Time to Survival, Deferasirox vs. Free Iron Level Correlation
Time frame: Up to 90 days