The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) Study

• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00419770
• Collaborator: Gilead Sciences (Industry), Astellas Pharma Inc (Industry), Novartis (Industry)
• Enrollment: 20
• Locations: 7
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Mucormycosis	Drug: deferasirox; Drug: Placebo; Drug: Liposomal amphotericin B	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) Study
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: B Deferasirox	Drug: deferasirox; 20 mg/kg enterally per day; Other Names: Exjade ; Drug: Liposomal amphotericin B
Placebo Comparator: A	Drug: Placebo; Drug: Liposomal amphotericin B

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability of Adjunctive Deferasirox Therapy in Patients Being Treated With LAmB for Mucormycosis [14 days]

2. Global Response Rate (Composite of Clinical and Radiographic Response) at End of Study Drug Administration, as Determined by a Blinded Adjudication Committee [14 days]

3. Total Adverse Events [30 Days After End of Therapy]

Secondary Outcome Measures

1. Deferasirox Pharmacokinetic and Pharmacodynamic Parameters [7 days]

2. Survival, Radiographic Improvement, Clinical Response, Time to Survival, Deferasirox vs. Free Iron Level Correlation [Up to 90 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	UCSF	San Francisco	California	United States	94143
3	University of Miami	Miami	Florida	United States	33136
4	Duke University	Durham	North Carolina	United States	27710
5	Summa Health Systems	Akron	Ohio	United States	44304
6	MD Anderson Cancer Center	Houston	Texas	United States	77030
7	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Gilead Sciences
• Astellas Pharma Inc
• Novartis

Investigators

• Principal Investigator: Brad Spellberg, MD, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Boelaert JR, Van Cutsem J, de Locht M, Schneider YJ, Crichton RR. Deferoxamine augments growth and pathogenicity of Rhizopus, while hydroxypyridinone chelators have no effect. Kidney Int. 1994 Mar;45(3):667-71.
• Ibrahim AS, Edwards JE Jr, Fu Y, Spellberg B. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J Antimicrob Chemother. 2006 Nov;58(5):1070-3. Epub 2006 Aug 23.
• Reed C, Ibrahim A, Edwards JE Jr, Walot I, Spellberg B. Deferasirox, an iron-chelating agent, as salvage therapy for rhinocerebral mucormycosis. Antimicrob Agents Chemother. 2006 Nov;50(11):3968-9. Epub 2006 Sep 25.
• Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev. 2005 Jul;18(3):556-69. Review.

• Responsible Party: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• ClinicalTrials.gov Identifier: NCT00419770
• Other Study ID Numbers: 12842
• First Posted: Jan 9, 2007
• Last Update Posted: Oct 6, 2011
• Last Verified: Aug 1, 2011

• Keywords provided by Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center: zygomycosis; Rhizopus; iron; iron-chelation; adjunctive therapy
• Additional relevant MeSH terms: Mucormycosis; Zygomycosis; Amphotericin B; Liposomal amphotericin B; Deferasirox

Study Results

Participant Flow

Arm/Group Title	Deferasirox	Placebo
Arm/Group Description	Deferasirox plus liposomal amphotericin	Placebo control plus background liposomal amphotericin
Period Title: Overall Study
STARTED	11	9
COMPLETED	6	8
NOT COMPLETED	5	1

Baseline Characteristics

Arm/Group Title	Deferasirox	Placebo	Total
Arm/Group Description	Deferasirox plus liposomal amphotericin	Placebo control plus background liposomal amphotericin	Total of all reporting groups
Overall Participants	11	9	20
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	8 72.7%	7 77.8%	15 75%
>=65 years	3 27.3%	2 22.2%	5 25%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59	47	52
Sex: Female, Male (Count of Participants)
Female	2 18.2%	3 33.3%	5 25%
Male	9 81.8%	6 66.7%	15 75%
Region of Enrollment (participants) [Number]
United States	11 100%	9 100%	20 100%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability of Adjunctive Deferasirox Therapy in Patients Being Treated With LAmB for Mucormycosis
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

2. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Deferasirox Pharmacokinetic and Pharmacodynamic Parameters
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Survival, Radiographic Improvement, Clinical Response, Time to Survival, Deferasirox vs. Free Iron Level Correlation
Time Frame	Up to 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Primary Outcome

Title	Total Adverse Events
Time Frame	30 Days After End of Therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Deferasirox	Placebo
Arm/Group Description	Deferasirox plus liposomal amphotericin	Placebo control plus background liposomal amphotericin
Measure Participants	11	9
Number [Events]	16	16

Adverse Events

Arm/Group Title	Deferasirox		Placebo
Arm/Group Description	Deferasirox plus liposomal amphotericin		Placebo control plus background liposomal amphotericin
All Cause Mortality
	Deferasirox		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Deferasirox		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)		4/9 (44.4%)
Cardiac disorders
Myocardial infarction	1/11 (9.1%)	1	0/9 (0%)	0
arrhythmia	0/11 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Liver failure	1/11 (9.1%)	1	0/9 (0%)	0
Vomiting/interolerance of study drug	1/11 (9.1%)	1	1/9 (11.1%)	1
General disorders
Respiratory Failure	2/11 (18.2%)	2	2/9 (22.2%)	2
Renal Failure	1/11 (9.1%)	1	0/9 (0%)	0
Fever	0/11 (0%)	0	1/9 (11.1%)	1
Hepatobiliary disorders
alveolar hemorrhage	0/11 (0%)	0	1/9 (11.1%)	1
Infections and infestations
Progressive Infection	1/11 (9.1%)	1	0/9 (0%)	0
bacterial pneumonia	1/11 (9.1%)	1	1/9 (11.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Progression of underlying disease	3/11 (27.3%)	3	0/9 (0%)	0
Nervous system disorders
Intracranial bleeding	1/11 (9.1%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Deferasirox		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)		7/9 (77.8%)
Blood and lymphatic system disorders
Thrombocytopenia	0/11 (0%)	0	1/9 (11.1%)	1
Exophthalmos	0/11 (0%)	0	1/9 (11.1%)	1
Eye disorders
Blurry vision	0/11 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Diarrhea	1/11 (9.1%)	1	1/9 (11.1%)	1
Vomiting	0/11 (0%)	0	1/9 (11.1%)	1
General disorders
Respiratory distress	1/11 (9.1%)	1	0/9 (0%)	0
Metabolism and nutrition disorders
Elevated creatinine	0/11 (0%)	0	1/9 (11.1%)	1
Electrolyte abnormalities	5/11 (45.5%)	5	1/9 (11.1%)	1
Musculoskeletal and connective tissue disorders
Myoclonus	0/11 (0%)	0	1/9 (11.1%)	1
Rash	1/11 (9.1%)	1	0/9 (0%)	0
Nervous system disorders
Altered mental status	0/11 (0%)	0	2/9 (22.2%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.