Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01307579
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 517
• Locations: 179
• Arms: 2
• Actual Duration (Months): 110.9
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase III trial compares the effectiveness of caspofungin to fluconazole in preventing invasive fungal infections in patients receiving chemotherapy for acute myeloid leukemia (AML). Antifungal prophylaxis is considered standard of care in children and adults with prolonged neutropenia after chemotherapy for AML however the ideal antifungal agent for prophylaxis in children is not known. Caspofungin has activity against yeast and some molds while fluconazole coverage is limited to just yeasts. Adult randomized trials suggest that agents with activity against yeasts and molds are more effective than those with just activity against yeasts. There are limited data to answer this comparative question in children. This study will establish much needed pediatric data to guide clinical decision making on optimal antifungal prophylaxis.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Childhood Acute Monoblastic Leukemia; Childhood Acute Monocytic Leukemia; Childhood Acute Myeloid Leukemia in Remission; Childhood Acute Myeloid Leukemia With Maturation; Childhood Acute Myeloid Leukemia With Minimal Differentiation; Childhood Acute Myeloid Leukemia Without Maturation; Childhood Acute Myelomonocytic Leukemia; Fungal Infection; Myeloid Neoplasm; Neutropenia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Myeloid Neoplasm	Drug: Caspofungin Acetate; Drug: Fluconazole; Other: Laboratory Biomarker Analysis	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. To determine if prophylaxis with caspofungin administered during periods of neutropenia following chemotherapy for acute myeloid leukemia (AML) is associated with a lower incidence of proven or probable invasive fungal infections (IFI) compared with fluconazole.

SECONDARY OBJECTIVES:

1. To determine if prophylaxis with caspofungin will result in a lower incidence of proven or probable cases of invasive aspergillosis (IA) compared with fluconazole. (Clinical) II. To determine if prophylaxis with caspofungin will result in improved survival compared to fluconazole. (Clinical) III. To determine if prophylaxis with caspofungin will result in less empiric antifungal therapy compared to fluconazole. (Clinical) IV. To determine the sensitivity, specificity, and positive and negative predictive value of biweekly galactomannan (GM) and beta-D glucan testing in diagnosing IFI. (Biological) V. To test the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and proven or probable IFI. (Biological) VI. To develop predictive models of IFI using SNP in genes involved in immunity and clinical covariates. (Biological)

OUTLINE: Patients are randomized to one of two treatment arms during their first chemotherapy course for AML.

ARM I: Patients receive caspofungin acetate intravenously (IV) over one hour once daily (QD) beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until absolute neutrophil count (ANC) > 100-500/uL following the nadir or the next chemotherapy course begins.

ARM II: Patients receive fluconazole IV over 1-2 hours or orally (PO) QD beginning within 24-72 hours following the last dose of chemotherapy for each course.

Protocol prophylaxis was continued in both arms, until ANC increased to > 100-500/uL following the nadir or the next chemotherapy course began. Prophylaxis was given for all courses of planned AML chemotherapy or until the patient met one of the following off-protocol therapy criteria: development of proven or probable IFI according to institutional diagnosis, initiation of conditioning for hematopoietic cell transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML, refusal of further protocol therapy by patient, parent or guardian, or physician determines it is in the best interest of the patient.

Regardless of duration of prophylaxis, subjects in both arms are monitored for IFI until the earliest of the following criteria is met: two weeks after recovery of neutropenia following the last planned AML chemotherapy course, initiation of conditioning for hematopoietic cell transplantation, initiation of a new chemotherapy regimen for relapsed or refractory AML, withdrawal of consent for any further data submission, or death.

Patients were followed for overall survival up to two years from enrollment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 517 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Randomized Open-Label Trial of Caspofungin Versus Fluconazole to Prevent Invasive Fungal Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia (AML)
• Actual Study Start Date: Apr 4, 2011
• Actual Primary Completion Date: Jun 30, 2018
• Actual Study Completion Date: Jun 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (caspofungin acetate) Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins.	Drug: Caspofungin Acetate; Given IV; Other Names: Cancidas ; Other: Laboratory Biomarker Analysis; Correlative studies
Active Comparator: Arm II (fluconazole) Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course.	Drug: Fluconazole; Given IV or PO; Other Names: Diflucan ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI) [Up to 5 months since enrollment]

   Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG).

Secondary Outcome Measures

1. Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA) [Up to 5 months since enrollment]

   Proven or probable invasive aspergillosis (IA) is defined according to the criteria developed by the EORTC/MSG. Kaplan Meier approach will used to estimate the incidence.

2. Overall Survival [Up to 2 years post enrollment]

   Kaplan Meier method will be used to estimate overall survival. Time to event is from enrollment to date of death (by any cause). Participants are censored at last contact or 2 years anniversary of enrollment into this study, whichever occurred first.

3. Percentage of Participants That Need Empiric Antifungal Therapy [Up to 5 months since enrollment]

   The percentage of participants requiring empiric antifungal therapy will be determined based on the presence of prolonged fever and neutropenia during each neutropenia course.

Other Outcome Measures

1. Sensitivity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]

   Sensitivity for the diagnosis of proven or probable IFI will be determined for the fungal biomarkers galactomannan and beta-D glucan assays. Sensitivity will be estimated for the combination of the two fungal biomarkers.

2. Specificity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]

   Specificity of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Specificity will be estimated for the two fungal biomarkers together.

3. Positive Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]

   Positive predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Positive predictive value will be estimated for the two fungal biomarkers together.

4. Negative Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI [Up to 5 months since enrollment]

   Negative predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Negative predictive value will be estimated for the two fungal biomarkers together.

5. Genotyping Assays for Single Nucleotide Polymorphism Analysis [Up to 2 years post enrollment]

   Descriptive statistics will be used to summarize the prevalence of single nucleotide polymorphisms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have one of the following diagnoses and/or treatment plans:

• Newly diagnosed de novo AML

• First or subsequent relapse of AML

• Secondary AML

• Treatment with institutional standard AML therapy in those without AML (for example, myelodysplastic syndrome, bone marrow blasts > 5% or biphenotypia)

• Note: Patients with a history of prolonged antifungal therapy (example, relapsed AML) are eligible

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

• =< 0.4 mg/dL (age 1 month to < 6 months)

• =< 0.5 mg/dL (age 6 months to < 1 year)

• =< 0.6 mg/dL (age 1 to < 2 years)

• =< 0.8 mg/dL (age 2 to < 6 years)

• =< 1 mg/dL (age 6 to < 10 years)

• =< 1.2 mg/dL (age 10 to < 13 years)

• =< 1.4 mg/dL (females age >= 13 years)

• =< 1.5 mg/dL (males age 13 to < 16 years)

• =< 1.7 mg/dL (males age >= 16 years)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age AND Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x ULN for age

• All patients and/or their parents or legal guardians must sign a written informed consent

Exclusion Criteria:

• Patients with the following diagnoses are not eligible:

• Acute promyelocytic leukemia (APL)

• Down syndrome

• Juvenile myelomonocytic leukemia (JMML)

• Patients with a documented history of invasive fungal infection (IFI) within the previous 30 days are not eligible

• Patients with a history of echinocandin or fluconazole hypersensitivity are not eligible

• Patients receiving treatment for an IFI are not eligible

• Female patients of childbearing age must have a negative pregnancy test

• Patients must agree to use an effective birth control method

• Lactating patients must agree not to nurse a child while on this trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
3	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
4	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
5	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
6	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
7	Loma Linda University Medical Center	Loma Linda	California	United States	92354
8	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
9	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
10	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
11	Valley Children's Hospital	Madera	California	United States	93636
12	Kaiser Permanente-Oakland	Oakland	California	United States	94611
13	Children's Hospital of Orange County	Orange	California	United States	92868
14	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
15	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
16	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
17	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
18	Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center	Torrance	California	United States	90502
19	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
20	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
21	Yale University	New Haven	Connecticut	United States	06520
22	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
23	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
24	Children's National Medical Center	Washington	District of Columbia	United States	20010
25	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
26	Lee Memorial Health System	Fort Myers	Florida	United States	33901
27	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
28	University of Florida Health Science Center - Gainesville	Gainesville	Florida	United States	32610
29	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
30	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
31	Florida Hospital Orlando	Orlando	Florida	United States	32803
32	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
33	UF Cancer Center at Orlando Health	Orlando	Florida	United States	32806
34	Nemours Children's Hospital	Orlando	Florida	United States	32827
35	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
36	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
37	Tampa General Hospital	Tampa	Florida	United States	33606
38	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
39	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
40	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
41	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
42	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
43	Kapiolani Medical Center for Women and Children	Honolulu	Hawaii	United States	96826
44	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
45	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
46	University of Illinois	Chicago	Illinois	United States	60612
47	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
48	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois	United States	60453
49	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
50	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
51	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
52	Blank Children's Hospital	Des Moines	Iowa	United States	50309
53	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
54	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
55	Norton Children's Hospital	Louisville	Kentucky	United States	40202
56	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
57	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
58	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
59	Eastern Maine Medical Center	Bangor	Maine	United States	04401
60	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
61	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
62	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
63	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts	United States	02111
64	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
65	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
66	Ascension Saint John Hospital	Detroit	Michigan	United States	48236
67	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
68	Hurley Medical Center	Flint	Michigan	United States	48503
69	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
70	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
71	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
72	Beaumont Children's Hospital-Royal Oak	Royal Oak	Michigan	United States	48073
73	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
74	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
75	Mayo Clinic	Rochester	Minnesota	United States	55905
76	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
77	Columbia Regional	Columbia	Missouri	United States	65201
78	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
79	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
80	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
81	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
82	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
83	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
84	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
85	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
86	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
87	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
88	Summerlin Hospital Medical Center	Las Vegas	Nevada	United States	89144
89	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
90	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
91	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
92	Morristown Medical Center	Morristown	New Jersey	United States	07960
93	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
94	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
95	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
96	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
97	Overlook Hospital	Summit	New Jersey	United States	07902
98	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
99	Albany Medical Center	Albany	New York	United States	12208
100	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
101	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
102	NYU Winthrop Hospital	Mineola	New York	United States	11501
103	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
104	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
105	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
106	University of Rochester	Rochester	New York	United States	14642
107	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
108	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
109	New York Medical College	Valhalla	New York	United States	10595
110	Mission Hospital Inc-Memorial Campus	Asheville	North Carolina	United States	28801
111	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
112	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
113	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
114	Duke University Medical Center	Durham	North Carolina	United States	27710
115	East Carolina University	Greenville	North Carolina	United States	27834
116	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
117	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
118	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
119	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
120	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
121	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
122	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
123	Dayton Children's Hospital	Dayton	Ohio	United States	45404
124	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
125	Mercy Children's Hospital	Toledo	Ohio	United States	43608
126	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
127	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
128	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
129	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
130	Oregon Health and Science University	Portland	Oregon	United States	97239
131	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
132	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
133	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
134	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
135	Rhode Island Hospital	Providence	Rhode Island	United States	02903
136	Medical University of South Carolina	Charleston	South Carolina	United States	29425
137	Palmetto Health Richland	Columbia	South Carolina	United States	29203
138	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
139	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
140	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
141	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
142	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
143	Texas Tech University Health Sciences Center-Amarillo	Amarillo	Texas	United States	79106
144	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
145	Medical City Dallas Hospital	Dallas	Texas	United States	75230
146	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
147	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
148	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
149	Covenant Children's Hospital	Lubbock	Texas	United States	79410
150	Children's Hospital of San Antonio	San Antonio	Texas	United States	78207
151	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
152	Scott and White Memorial Hospital	Temple	Texas	United States	76508
153	University of Vermont College of Medicine	Burlington	Vermont	United States	05405
154	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
155	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
156	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
157	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
158	Seattle Children's Hospital	Seattle	Washington	United States	98105
159	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
160	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
161	Madigan Army Medical Center	Tacoma	Washington	United States	98431
162	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
163	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
164	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
165	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
166	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
167	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
168	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
169	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
170	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
171	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
172	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
173	Kingston Health Sciences Centre	Kingston	Ontario	Canada	K7L 2V7
174	Children's Hospital	London	Ontario	Canada	N6A 5W9
175	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
176	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
177	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
178	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
179	San Jorge Children's Hospital	San Juan		Puerto Rico	00912

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Theoklis E Zaoutis, Children's Oncology Group

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 22, 2014

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT01307579
• Other Study ID Numbers: ACCL0933; NCI-2011-02640; CDR0000695748; COG-ACCL0933; S12-00316; ACCL0933; COG-ACCL0933; ACCL0933; U10CA095861; UG1CA189955
• First Posted: Mar 3, 2011
• Last Update Posted: Mar 30, 2021
• Last Verified: Jun 1, 2019

• Keywords provided by Children's Oncology Group: Pediatrics; leukemia; invasive fungal infection
• Additional relevant MeSH terms: Infections; Communicable Diseases; Mycoses; Invasive Fungal Infections; Leukemia; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Monocytic, Acute; Neutropenia; Recurrence; Fluconazole; Caspofungin

Study Results

Participant Flow

Arm/Group Title	Arm I (Caspofungin Acetate)	Arm II (Fluconazole)
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies
Period Title: Overall Study
STARTED	257	260
COMPLETED	117	115
NOT COMPLETED	140	145

Baseline Characteristics

Arm/Group Title	Arm I (Caspofungin Acetate)	Arm II (Fluconazole)	Total
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies	Total of all reporting groups
Overall Participants	257	260	517
Age (Count of Participants)
<=18 years	235 91.4%	242 93.1%	477 92.3%
Between 18 and 65 years	22 8.6%	18 6.9%	40 7.7%
>=65 years	0 0%	0 0%	0 0%
Age (Years) [Median (Standard Deviation) ]
Median (Standard Deviation) [Years]	9.2 (6.5)	8.8 (6.0)	9.0 (6.3)
Sex: Female, Male (Count of Participants)
Female	114 44.4%	114 43.8%	228 44.1%
Male	143 55.6%	146 56.2%	289 55.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	41 16%	52 20%	93 18%
Not Hispanic or Latino	206 80.2%	203 78.1%	409 79.1%
Unknown or Not Reported	10 3.9%	5 1.9%	15 2.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	3 1.2%	4 0.8%
Asian	19 7.4%	19 7.3%	38 7.4%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	1 0.2%
Black or African American	29 11.3%	32 12.3%	61 11.8%
White	181 70.4%	179 68.8%	360 69.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	27 10.5%	26 10%	53 10.3%
Region of Enrollment (participants) [Number]
United States	234 91.1%	227 87.3%	461 89.2%
Canada	22 8.6%	33 12.7%	55 10.6%
United Arab Emirates	1 0.4%	0 0%	1 0.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Proven or Probable Invasive Fungal Infections (IFI)
Description	Proven or probable IFI is defined according to criteria developed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG).
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

Evaluable patients (ineligible and inevaluable due to having IFI before IFI monitoring period were excluded)

Arm/Group Title	Arm I (Caspofungin Acetate)	Arm II (Fluconazole)
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	253	255
Number (95% Confidence Interval) [Percentage of participants]	3.1 1.2%	7.2 2.8%

2. Secondary Outcome

Title	Percentage of Participants With Proven or Probable Invasive Aspergillosis (IA)
Description	Proven or probable invasive aspergillosis (IA) is defined according to the criteria developed by the EORTC/MSG. Kaplan Meier approach will used to estimate the incidence.
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

Evaluable patients (ineligible and inevaluable due to having IFI before IFI monitoring period were excluded)

Arm/Group Title	Arm I (Caspofungin Acetate)	Arm II (Fluconazole)
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	253	255
Number (95% Confidence Interval) [Percentage of participants]	0.5 0.2%	3.1 1.2%

3. Secondary Outcome

Title	Overall Survival
Description	Kaplan Meier method will be used to estimate overall survival. Time to event is from enrollment to date of death (by any cause). Participants are censored at last contact or 2 years anniversary of enrollment into this study, whichever occurred first.
Time Frame	Up to 2 years post enrollment

Outcome Measure Data

Analysis Population Description

Evaluable patients (ineligible and inevaluable due to having IFI before IFI monitoring period were excluded)

Arm/Group Title	Arm I (Caspofungin Acetate)	Arm II (Fluconazole)
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	253	255
Number (95% Confidence Interval) [Percentage of participants]	68.8 26.8%	70.8 27.2%

4. Secondary Outcome

Title	Percentage of Participants That Need Empiric Antifungal Therapy
Description	The percentage of participants requiring empiric antifungal therapy will be determined based on the presence of prolonged fever and neutropenia during each neutropenia course.
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

Evaluable patients (ineligible and inevaluable due to having IFI before IFI monitoring period were excluded)

Arm/Group Title	Arm I (Caspofungin Acetate)	Arm II (Fluconazole)
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies	Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies
Measure Participants	253	255
Number (95% Confidence Interval) [Percentage of participants]	71.9 28%	69.5 26.7%

5. Other Pre-specified Outcome

Title	Sensitivity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
Description	Sensitivity for the diagnosis of proven or probable IFI will be determined for the fungal biomarkers galactomannan and beta-D glucan assays. Sensitivity will be estimated for the combination of the two fungal biomarkers.
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Specificity of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
Description	Specificity of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Specificity will be estimated for the two fungal biomarkers together.
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Positive Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
Description	Positive predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Positive predictive value will be estimated for the two fungal biomarkers together.
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Negative Predictive Value of Galactomannan and Beta-D Glucan Assays for the Diagnosis of Proven or Probable IFI
Description	Negative predictive value of galactomannan and beta-D glucan assays for the diagnosis of proven or probable IFI. Negative predictive value will be estimated for the two fungal biomarkers together.
Time Frame	Up to 5 months since enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Genotyping Assays for Single Nucleotide Polymorphism Analysis
Description	Descriptive statistics will be used to summarize the prevalence of single nucleotide polymorphisms.
Time Frame	Up to 2 years post enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 12 months of receiving protocol treatment
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events.
Arm/Group Title	Arm I (Caspofungin Acetate)		Arm II (Fluconazole)
Arm/Group Description	Patients receive caspofungin acetate IV over one hour QD beginning within 24-72 hours following the last dose of chemotherapy for each course. and continuing until ANC > 100-500/uL following the nadir or the next chemotherapy course begins. Caspofungin Acetate: Given IV Laboratory Biomarker Analysis: Correlative studies		Patients receive fluconazole IV over 1-2 hours or PO QD beginning within 24-72 hours following the last dose of chemotherapy for each course. Fluconazole: Given IV or PO Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Arm I (Caspofungin Acetate)		Arm II (Fluconazole)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/253 (30%)		82/255 (32.2%)
Serious Adverse Events
	Arm I (Caspofungin Acetate)		Arm II (Fluconazole)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/253 (4.3%)		9/255 (3.5%)
Blood and lymphatic system disorders
Febrile neutropenia	2/253 (0.8%)		0/255 (0%)
Cardiac disorders
Heart failure	0/253 (0%)		1/255 (0.4%)
Left ventricular systolic dysfunction	2/253 (0.8%)		0/255 (0%)
Sinus tachycardia	1/253 (0.4%)		0/255 (0%)
General disorders
Death NOS	2/253 (0.8%)		3/255 (1.2%)
Multi-organ failure	2/253 (0.8%)		0/255 (0%)
Hepatobiliary disorders
Hepatic failure	0/253 (0%)		1/255 (0.4%)
Hepatic necrosis	1/253 (0.4%)		0/255 (0%)
Infections and infestations
Infections and infestations - Other, specify	2/253 (0.8%)		0/255 (0%)
Lung infection	1/253 (0.4%)		1/255 (0.4%)
Pleural infection	1/253 (0.4%)		0/255 (0%)
Sepsis	2/253 (0.8%)		1/255 (0.4%)
Upper respiratory infection	1/253 (0.4%)		0/255 (0%)
Investigations
Alanine aminotransferase increased	1/253 (0.4%)		0/255 (0%)
Electrocardiogram QT corrected interval prolonged	0/253 (0%)		1/255 (0.4%)
Investigations - Other, specify	1/253 (0.4%)		0/255 (0%)
Neutrophil count decreased	1/253 (0.4%)		0/255 (0%)
Metabolism and nutrition disorders
Metabolism and nutrition disorders - Other, specify	1/253 (0.4%)		0/255 (0%)
Nervous system disorders
Edema cerebral	1/253 (0.4%)		0/255 (0%)
Hydrocephalus	1/253 (0.4%)		0/255 (0%)
Intracranial hemorrhage	1/253 (0.4%)		0/255 (0%)
Renal and urinary disorders
Acute kidney injury	1/253 (0.4%)		0/255 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	0/253 (0%)		1/255 (0.4%)
Dyspnea	2/253 (0.8%)		0/255 (0%)
Pleural effusion	1/253 (0.4%)		0/255 (0%)
Pulmonary hypertension	0/253 (0%)		1/255 (0.4%)
Respiratory failure	1/253 (0.4%)		1/255 (0.4%)
Vascular disorders
Hypertension	1/253 (0.4%)		0/255 (0%)
Hypotension	1/253 (0.4%)		1/255 (0.4%)
Other (Not Including Serious) Adverse Events
	Arm I (Caspofungin Acetate)		Arm II (Fluconazole)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/253 (24.5%)		72/255 (28.2%)
Blood and lymphatic system disorders
Anemia	2/253 (0.8%)		0/255 (0%)
Febrile neutropenia	5/253 (2%)		2/255 (0.8%)
Cardiac disorders
Cardiac arrest	0/253 (0%)		1/255 (0.4%)
Heart failure	2/253 (0.8%)		4/255 (1.6%)
Left ventricular systolic dysfunction	1/253 (0.4%)		3/255 (1.2%)
Right ventricular dysfunction	0/253 (0%)		1/255 (0.4%)
Gastrointestinal disorders
Ascites	0/253 (0%)		1/255 (0.4%)
Diarrhea	1/253 (0.4%)		0/255 (0%)
Enterocolitis	0/253 (0%)		1/255 (0.4%)
Mucositis oral	0/253 (0%)		1/255 (0.4%)
Small intestinal obstruction	1/253 (0.4%)		0/255 (0%)
Typhlitis	3/253 (1.2%)		2/255 (0.8%)
General disorders
Fever	4/253 (1.6%)		1/255 (0.4%)
Multi-organ failure	1/253 (0.4%)		3/255 (1.2%)
Hepatobiliary disorders
Hepatic failure	0/253 (0%)		1/255 (0.4%)
Immune system disorders
Allergic reaction	1/253 (0.4%)		0/255 (0%)
Cytokine release syndrome	1/253 (0.4%)		0/255 (0%)
Immune system disorders - Other, specify	0/253 (0%)		1/255 (0.4%)
Infections and infestations
Appendicitis	1/253 (0.4%)		1/255 (0.4%)
Catheter related infection	1/253 (0.4%)		1/255 (0.4%)
Encephalitis infection	1/253 (0.4%)		0/255 (0%)
Encephalomyelitis infection	1/253 (0.4%)		0/255 (0%)
Enterocolitis infectious	0/253 (0%)		1/255 (0.4%)
Infections and infestations - Other, specify	8/253 (3.2%)		9/255 (3.5%)
Lung infection	0/253 (0%)		2/255 (0.8%)
Peritoneal infection	0/253 (0%)		1/255 (0.4%)
Salivary gland infection	0/253 (0%)		1/255 (0.4%)
Sepsis	20/253 (7.9%)		43/255 (16.9%)
Soft tissue infection	0/253 (0%)		1/255 (0.4%)
Urinary tract infection	1/253 (0.4%)		0/255 (0%)
Investigations
Alanine aminotransferase increased	3/253 (1.2%)		9/255 (3.5%)
Aspartate aminotransferase increased	1/253 (0.4%)		7/255 (2.7%)
Blood bilirubin increased	1/253 (0.4%)		3/255 (1.2%)
Ejection fraction decreased	1/253 (0.4%)		1/255 (0.4%)
Electrocardiogram QT corrected interval prolonged	0/253 (0%)		1/255 (0.4%)
GGT increased	1/253 (0.4%)		2/255 (0.8%)
Investigations - Other, specify	1/253 (0.4%)		0/255 (0%)
Lipase increased	1/253 (0.4%)		1/255 (0.4%)
Lymphocyte count decreased	2/253 (0.8%)		1/255 (0.4%)
Neutrophil count decreased	4/253 (1.6%)		1/255 (0.4%)
Platelet count decreased	3/253 (1.2%)		1/255 (0.4%)
White blood cell decreased	2/253 (0.8%)		1/255 (0.4%)
Metabolism and nutrition disorders
Hyperglycemia	1/253 (0.4%)		3/255 (1.2%)
Hyperkalemia	1/253 (0.4%)		1/255 (0.4%)
Hypernatremia	2/253 (0.8%)		0/255 (0%)
Hypoalbuminemia	0/253 (0%)		1/255 (0.4%)
Hypocalcemia	2/253 (0.8%)		4/255 (1.6%)
Hypoglycemia	0/253 (0%)		1/255 (0.4%)
Hypokalemia	20/253 (7.9%)		11/255 (4.3%)
Hyponatremia	1/253 (0.4%)		0/255 (0%)
Hypophosphatemia	3/253 (1.2%)		3/255 (1.2%)
Musculoskeletal and connective tissue disorders
Soft tissue necrosis lower limb	0/253 (0%)		1/255 (0.4%)
Nervous system disorders
Encephalopathy	1/253 (0.4%)		0/255 (0%)
Hydrocephalus	1/253 (0.4%)		0/255 (0%)
Somnolence	1/253 (0.4%)		0/255 (0%)
Renal and urinary disorders
Acute kidney injury	0/253 (0%)		3/255 (1.2%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/253 (0.4%)		4/255 (1.6%)
Atelectasis	0/253 (0%)		1/255 (0.4%)
Dyspnea	1/253 (0.4%)		1/255 (0.4%)
Hypoxia	2/253 (0.8%)		4/255 (1.6%)
Pleural effusion	0/253 (0%)		1/255 (0.4%)
Pulmonary edema	1/253 (0.4%)		1/255 (0.4%)
Respiratory failure	5/253 (2%)		8/255 (3.1%)
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	1/253 (0.4%)		0/255 (0%)
Vascular disorders
Hypotension	12/253 (4.7%)		12/255 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior sponsor approval.