A Randomized Open-Label Trial of Caspofungin Versus Fluconazole to Prevent Invasive Fungal Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia (AML)
Phase: PHASE3
Conditions: 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
Sponsor: Children's Oncology Group

 
 
ACCL0933 
Version Date: 04/22/14 
 
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Activated: 
04/04/11      
Version Date: 
04/22/14 
Closed: 
   11/11/16      
Amendment: 
#2 
 
 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
ACCL0933 
 
A Randomized Open-Label Trial of Caspofungin versus Fluconazole to Prevent Invasive Fungal 
Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia (AML)  
 
 
A Groupwide Phase III Study 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY 
PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING 
PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 

 
 
ACCL0933 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
4 
ABSTRACT 
6 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Objective 
8 
1.2 
Secondary Objectives 
8 
2.0 
BACKGROUND 
8 
2.1 
Overview and Rationale for Study 
8 
2.2 
Selection of Study Medication 
9 
2.3 
Rationale for Platelia EIA Aspergillus GM and Serum Beta-D Glucan Assays 
12 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
13 
3.1 
Study Enrollment 
13 
3.2 
Patient Eligibility Criteria 
14 
4.0 
TREATMENT PLAN 
16 
4.1 
Overview of Treatment Plan 
16 
4.2 
Administration Schedule- FLUCONAZOLE ARM 
18 
4.3 
Administration Schedule- CASPOFUNGIN ARM 
20 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
22 
5.1 
Impaired Renal Function 
22 
5.2 
Impaired Liver Function 
22 
6.0 
DRUG INFORMATION 
23 
6.1 
FLUCONAZOLE (Diflucan) 
23 
6.2 
CASPOFUNGIN (caspofungin acetate, Cancidas)   (11/08/11) 
26 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
29 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
29 
7.2 
Optional Studies 
30 
7.3 
Follow-up 
30 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
30 
8.1 
Criteria for Removal from Protocol Therapy 
30 
8.2 
Off Study Criteria 
30 
8.3 
Discontinuation from IFI Observation Criteria 
31 
9.0 
STATISTICAL CONSIDERATIONS 
31 
9.1 
Statistical Design 
31 
9.2 
Patient Accrual and Expected Duration of Trial 
31 
9.3 
Statistical Analysis Methods 
31 
9.4 
Gender and Minority Accrual Estimates 
35 
10.0 
EVALUATION CRITERIA 
36 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
36 
10.2 
IFI Checklist and Central Review 
36 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
36 

 
 
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11.1 
Purpose 
36 
11.2 
Determination of Reporting Requirements 
37 
11.4 
Routine Adverse Event Reporting 
38 
12.0 
RECORDS AND REPORTING 
38 
12.1 
CDUS 
38 
13.0 
PROSPECTIVE EVALUATION OF GALACTOMANNAN AND (1→3) BETA-D 
GLUCAN ASSAYS AS DIAGNOSTIC TOOLS FOR INVASIVE FUNGAL 
INFECTION IN CHILDREN WITH ACUTE MYELOID LEUKEMIA RECEIVING 
FUNGAL PROPHYLAXIS. 
39 
13.1 
Sample Collection and Testing Procedures (These studies are optional) 
39 
13.2 
Background 
42 
13.3 
Specific Aims 
45 
13.4 
Patient Accrual 
45 
13.5 
Gold Standards for IFI and IA Infections 
46 
13.6 
Methodology to Identify IFI and IA 
46 
13.7 
Factors resulting in False Positive Results 
47 
13.8 
Statistical Design 
47 
13.9 
Significance 
49 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
50 
14.1 
Single Nucleotide Polymorphisms (This study is optional) 
50 
15.0 
BANKING SPECIMENS 
50 
APPENDIX I: YOUTH INFORMATION SHEETS 
51 
APPENDIX II: EORTC/MSG CRITERIA 
53 
REFERENCES 
55 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM 
59 

 
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SEE SECTIONS 13 AND 14 FOR SPECIMEN SHIPPING ADDRESSES 

 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. The Certificate protects 
against the involuntary release of information about subjects collected during the course of our covered 
studies. The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings. However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances. For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not 
protect against mandatory disclosure by the researchers of information on suspected child abuse, 
reportable communicable diseases, and/or possible threat of harm to self or others. 
 
 
 
 
ABSTRACT 
Invasive fungal infections (IFI) have steadily increased over the past 2 decades in children with acute 
myeloid leukemia (AML). Over 50% of infectious-related deaths in this population are attributable to IFI. 
These dismal numbers are despite empiric therapy and treatment with the best available agents. The 
failure of these strategies to impact morbidity and mortality from IFI makes a strong case for the 
exploration of preventive strategies. This study will utilize a 2-arm, open-label randomized design to 
evaluate the efficacy of prophylaxis with caspofungin in comparison with fluconazole in children with de 
novo, relapsed or secondary AML. Study agent will begin following completion of each course of 
chemotherapy and continue through periods of neutropenia. This study also seeks to evaluate the 
usefulness of the Platelia EIA Aspergillus galactomannan (GM) assay as well as beta-D glucan testing in 
early diagnosis of IFI. ACCL0933 will also explore the relationship between proven or probable IFI and 
single nucleotide polymorphisms (SNP) of genes involved in immunity and develop predictive models of 
IFI that will be useful in the early identification of susceptible patients. 

 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization* 
FLUCONAZOLE ARM 
Age based dosing  
See Section 4.2 for details. 
ON STUDY 
*Protocol therapy must begin within 24-72 hours following the completion of the first course of systemic 
chemotherapy for current diagnosis. 
# Prophylaxis started within 24-72 hours following completion of each systemic chemotherapy course and 
continues until ANC > 100-500/µL following the nadir.  
^ Galactomannan and beta-D glucan testing twice weekly. See Section 13 for details.  
@ SNP- Single Nucleotide Polymorphisms. Collect sample at end of Course 1. See Section 14 for details. 
IFI –Invasive Fungal Infections (including Invasive Aspergillosis) 
HSCT – Hematopoietic Stem Cell Transplantation 
EVALUATIONS ^
Off Protocol 
Therapy 
SNP 
Analysis@ 
Protocol therapy ends when patient completes planned 
courses of chemotherapy. 
 
Patients who are taken off protocol therapy (but are not off 
study) must be followed for all infection endpoints until they 
meet the Off Study criteria in Section 8.2 or the 
Discontinuation from IFI Observation criteria in Section 8.3. 
First Course of Chemotherapy# 
Subsequent Courses of Chemotherapy# 
Diagnosis 
De novo, relapsed or secondary AML or treatment with 
institutional standard AML therapy in those without 
AML (for example, myelodysplastic syndrome, bone 
marrow blasts > 5% or biphenotypia) 
CASPOFUNGIN ARM 
70 mg/m2/day – Day 1 
50 mg/m2/day – Subsequently 
(maximum loading dose 70 mg/day) 

 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objective 
 
1.1.1 
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. 
 
1.2 
Secondary Objectives 
 
Clinical 
 
1.2.1 
To determine if prophylaxis with caspofungin will result in a lower incidence of proven or probable cases 
of invasive aspergillosis (IA) compared with fluconazole. 
 
1.2.2 
To determine if prophylaxis with caspofungin will result in improved survival compared to fluconazole. 
 
1.2.3 
To determine if prophylaxis with caspofungin will result in less empiric antifungal therapy compared to 
fluconazole. 
 
Biological 
 
1.2.4 
To determine the sensitivity, specificity, positive and negative predictive value of biweekly 
galactomannan (GM) and beta-D glucan testing in diagnosing IFI. 
 
1.2.5 
To test the association between single nucleotide polymorphisms (SNPs) in genes involved in innate 
immunity and proven or probable IFI. 
 
1.2.6 
To develop predictive models of IFI using SNP in genes involved in immunity and clinical covariates. 
 
 
2.0 
BACKGROUND 
 
2.1 
Overview and Rationale for Study 
This study is a 2-arm open-label randomized clinical trial to evaluate the efficacy of caspofungin 
prophylaxis compared with fluconazole prophylaxis. A total of approximately 550 subjects will be 
randomized (until accrual of at least 275 participants on each treatment arm) during periods of 
neutropenia associated with chemotherapy for the treatment of AML.  
 
The frequency and severity of IFI in immunocompromised patients has increased steadily over the past 
2 decades.1-3 The incidence of IFI as a cause of sepsis has more than tripled with 5,231 cases in 1979 
compared with 16,042 cases in 2000.4 In children with fungal sepsis, the case fatality rate has been 
estimated to be 13%.5 Among children with cancer, those undergoing hematopoietic stem cell 
transplantation (HSCT) and those receiving AML therapy are at highest risk for IFI. The most common 

 
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causes of IFI in children with cancer are Candida spp. and Aspergillus spp.  
 
Candida spp. are commensal organisms that normally reside on mucosal and skin surfaces. The portal of 
entry is typically the gut mucosa and less commonly the skin. Therefore, children undergoing intensive 
therapy for cancer that results in mucositis are at high risk for infection with Candida spp. Although 
mucosal candidal infections occur, candidemia is the most serious clinical syndrome caused by Candida 
spp. Its manifestations may include fever unresponsive to antibiotics, macronodular skin lesions, 
myalgias, and sepsis. Acute hematogenous dissemination of Candida to 1 or more organs can occur 
including the heart, lung, brain, eye, kidney, liver and spleen. Immunocompromised children are at higher 
risk for disseminated disease. Disseminated infections are considered to be more severe and require 
longer courses of antifungal therapy. The attributable mortality of invasive candidiasis in children has 
been reported to be 10%. These data suggest that 1 child would be saved for every 10 children in whom 
candidemia can be prevented.6  
 
Infections with Aspergillus spp. account for the vast majority of non-Candida IFI in children with cancer. 
Children undergoing AML therapy have the highest risk of IA outside the transplant setting. IA most 
commonly presents as pneumonia. Infiltrates are commonly wedge-shaped, pleural-based or nodular and 
visible on chest radiographs or CT scans. The infiltrates may initially be accompanied by a halo sign and 
later by a crescent sign. In children with uncontrolled infection, the infiltrates may be diffuse. Less 
commonly, sinusitis may also occur. Finally, Aspergillus can disseminate to the central nervous system. 
IA is associated with mortality rates in children of greater than 50%.1,7-11 
 
The burden of IFI in pediatric AML is considerable. CCG 2961 demonstrated that the incidence of IFI in 
children with AML was 13% per treatment phase. Approximately half the infections were caused by 
Aspergillus and the other half by Candida. Most importantly, 31% of infection-related deaths were 
associated with Aspergillus, and 25.9% of infectious deaths were associated with Candida.12 In order to 
impact on survival of children with AML, strategies to reduce IFI are urgently needed. In general, the 3 
types of strategies directed toward fungal infections are prophylaxis, empiric therapy, and treatment of 
IFI. The current rates of IFIs and attributable mortality due to IFI are primarily derived from the setting of 
empiric therapy and treatment with best available agents, and thus, these strategies currently are 
insufficient to make a major impact on fungal morbidity and mortality. Thus, strategies to prevent IFI 
should be the priority. Furthermore, IFIs likely impact on the ability to deliver anti-leukemic therapy and 
many IFI are never microbiologically documented, further strengthening the imperative to prevent IFI 
rather than relying upon empiric or treatment strategies alone. 
 
2.2 
Selection of Study Medication 
 
2.2.1  Choice of Fluconazole Prophylaxis as the Standard Arm 
A systematic review and meta-analysis of randomized, clinical trials demonstrated antifungal prophylaxis 
significantly decreased all-cause mortality in patients receiving chemotherapy.13 The conclusions from the 
systematic review and consensus guidelines from the Centers for Disease Control and Prevention, the 
Infectious Disease Society of America, the American Society for Blood and Marrow Transplantation, and 
the first European Conference on Infections in Leukemia all recommend antifungal prophylaxis for HSCT 
recipients.14,15 The systematic review concluded that antifungal prophylaxis “should probably be 
administered to high-risk leukemia patients.”13  
 
Fluconazole has been shown to be an effective antifungal agent for prophylaxis against IFI in high-risk 
patients in previous studies and antifungal prophylaxis with fluconazole reduces morbidity and mortality 
among allogeneic HSCT recipients.16 Fluconazole has also been used in other patient populations with 
neutropenia, although its effectiveness in these patients is less clear.17 However, fluconazole may not be 

 
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the best agent for patients with AML since it lacks activity against filamentous fungi (e.g. Aspergillus), 
which represent half the causes of IFI in children with AML.  
 
Nonetheless, the trial uses fluconazole as the standard prophylaxis arm because it is effective against 
Candida infections, and its use as prophylaxis is regarded appropriate by the above mentioned consensus 
guidelines. The first European Conference on Infections in Leukemia, published in 2007, recommended 
fluconazole as the preferred agent for anti-fungal prophylaxis.15  In addition, as highlighted by Wingard, it 
is not known whether the toxicity and cost of adding empiric mold coverage is superior to a strategy of 
fluconazole and aggressive monitoring and pre-emptive treatment for molds.18 
 
Furthermore, fluconazole was chosen as the comparator as it is the most commonly used agent for 
antifungal prophylaxis in pediatric AML in North America and according to a recent COG-wide survey, 
154/178 (86.5%) of institutions currently use either fluconazole or no prophylaxis in children with de 
novo AML.19   
 
Another possible agent which could have been chosen as the control arm is itraconazole. Itraconazole has 
a wider spectrum of activity than fluconazole, including activity against Aspergillus and has been shown 
to be more effective than fluconazole when used for prophylaxis in patients with neutropenia. However, 
the clinical usefulness of itraconazole is limited by poor tolerability and bioavailability of the oral 
formulations.  
 
2.2.2  Choice of Caspofungin Prophylaxis as the Intervention Arm 
Newer antifungal agents with a broader spectrum of activity that have been considered as study 
medications include the newer azoles (voriconazole, posaconazole) and the echinocandins (caspofungin, 
micafungin, anidulafungin). The following highlights why caspofungin was chosen as the intervention 
arm. 
 
2.2.2.1  Azole Antifungal Agents 
The broad-spectrum azoles, including voriconazole and posaconazole, have in vitro activity against a 
wide spectrum of fungi including Candida and Aspergillus.  
 
Voriconazole is Food and Drug Administration (FDA) approved for the treatment of aspergillosis and 
candidiasis. There are two studies that have compared voriconazole to fluconazole or itraconazole for 
prophylaxis. A randomized, double-blind trial of fluconazole vs. voriconazole for the prevention of IFI in 
600 HSCT patients was conducted.20  The primary endpoint was fungal free survival rate at 6 months and 
this survival was 75% in the fluconazole group and 78% in the voriconazole group (p=.72). Overall 
survival was 80% vs. 81% (p=.61), respectively. The incidence of fungal infection was not statistically 
different and was 10.6% in the fluconazole arm and 6.6% in the voriconazole arm (p=.11). Another study 
compared voriconazole vs. itraconazole in 114 adult high-risk leukemia patients.21 Two patients in the 
itraconazole group and no patients in the voriconazole group developed an IFI. However, the numbers 
were too small for a meaningful statistical comparison. Response to chemotherapy, overall mortality and 
survival were similar in both groups. Of particular significance, 15/49 (23%) of patients receiving 
voriconazole discontinued prophylaxis due to side effects compared to 4/49 (8%) of patients receiving 
itraconazole. All of these studies were conducted in adults. 
 
In addition to the prophylactic setting, it may also be useful to examine voriconazole in the empiric 
antifungal setting as it may shed insight into its efficacy. Voriconazole was compared to liposomal 
amphotericin B for empiric antifungal therapy in patients with neutropenia and persistent fever.22 This 
was a large, randomized trial that included over 800 patients. The overall success rates were 26% for 
voriconazole and 30.6% for liposomal amphotericin B (95% confidence interval for the difference, -10.6 
to 1.6). Thus, voriconazole failed the non-inferiority cut-off, suggesting that voriconazole may be inferior 

 
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to liposomal amphotericin B for empiric treatment of fever and neutropenia raising questions about its 
efficacy in patients with febrile neutropenia. 
 
 
The largest pediatric study of voriconazole was an open label, compassionate-use evaluation in 
58 children with proven or probable IFI refractory to or intolerant of conventional antifungal therapy.23 
Forty-five percent of the patients had a complete or partial response to therapy.  
 
Metabolism of voriconazole occurs in the liver via CYP450 enzyme family, including CYP2C9, 
CYP3A4, and CYP2C19 isoenzymes24 and therefore, the potential for drug interactions with voriconazole 
is high. The main side effects of voriconazole include visual disturbances, skin rashes, elevations in 
hepatic enzymes and rarely, severe, life-threatening hepatitis.24  
 
When evaluating studies of antifungal agents with anti-mold activity vs. fluconazole, there are three trials 
that showed improved survival and/or a lower rate of IFI when anti-mold agents were compared to 
fluconazole. Two of the studies used posaconazole and one trial used micafungin.25,26 In other words, 
there are no studies that have demonstrated that voriconazole is superior to fluconazole as prophylaxis 
against IFI. Therefore, the decision not to use voriconazole as the comparator in this trial was based on 
available data that show no significant advantage over fluconazole or itraconazole, the potential for 
toxicity, and the potential for drug interactions in children receiving AML chemotherapy. Furthermore, 
pharmacokinetics and appropriate dosing are less certain in children compared with adults, thus making 
voriconazole even less attractive in this population. 
 
Posaconazole is an attractive agent to consider as antifungal prophylaxis in the AML population. A 
randomized, multi-center study of posaconazole vs. fluconazole or itraconazole in patients with 
neutropenia associated with the treatment of AML or myelodysplastic syndrome found that posaconazole 
reduced the rate of IFI from 8% to 2% compared to fluconazole. However, children less than 13 years of 
age were excluded and the median age of study subjects was approximately 50 years of age.25 Its use is 
limited in children because of insufficient dosing information for young children. Furthermore, 
posaconazole has the same concerns regarding hepatotoxicity and drug interactions as exist for 
voriconazole. Finally, posaconazole can only be administered as an oral agent currently and children 
receiving AML therapy may not be able to comply with oral medication during the neutropenic period. 
Therefore, posaconazole is not an appropriate agent to use in children with AML at this time. 
 
The next COG Phase 3 AML trial will randomize subjects to receive or not receive bortezomib and there 
is considerable risk of drug interactions with concurrent administration of bortezomib and either 
voriconazole or posaconazole, thus further decreasing the feasibility of their use in pediatric AML.  
 
2.2.2.2 Echinocandin Antifungal Agents 
Echinocandins target cell wall biosynthesis of β-1, 3-glucan and exhibit in vitro activity against both 
Candida and Aspergillus species. There are 3 currently available echinocandins, namely micafungin, 
anidulofungin and caspofungin. 
 
Micafungin has been studied in children with cancer. A Phase I pediatric febrile neutropenia study found 
that doses up to 4 mg/kg/day IV were well tolerated with no side effects.27 A recent study of micafungin 
in combination with a second antifungal agent in pediatric and adult bone marrow recipients with IA 
revealed an overall response rate of 40%.28 The success rate in the pediatric patient population was similar 
to the adult patients. Pediatric patients were also enrolled in a recent micafungin prophylaxis study in 
patients undergoing HSCT.26 This study was a randomized, double-blind, multi-center study of 
882 patients, of which 10% were children younger than 16 years of age. Although the study did not have 
statistical power to specifically address efficacy in the pediatric subgroup, the magnitude and the direction 
of micafungin efficacy were similar in children and adults.26 Dosing in children under the age of 8 years 

 
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appears to yield a higher clearance of micafungin, resulting in the likely need for an increased dose in this 
age group. Despite the pharmacokinetic studies and its recent FDA approval in adults, there is no 
accepted dosage of micafungin in pediatric patients. 
 
Anidulafungin has the least data in pediatric patients. A Phase I/II dose escalation study of anidulafungin 
in children with persistent neutropenia showed that the drug was well tolerated in pediatric patients and 
can be dosed based on body weight. Pediatric patients receiving 0.75 or 1.5 mg/kg/day IV have 
pharmacokinetic properties similar to adults receiving 50-100 mg/kg/day, respectively.29 
 
Among the echinocandins, caspofungin is the most extensively studied agent in children. Caspofungin 
recently received FDA approval for use in children ≥ 3 months of age. There have been 5 pediatric 
caspofungin studies (3 pharmacokinetic and 2 safety/efficacy trials). A multicenter, prospective, open-
label study in 50 children with proven candidiasis or aspergillosis was recently completed.30 Caspofungin 
was well-tolerated. Fifty percent of children with IA and 81% of children with invasive candidiasis were 
successfully treated. These efficacy outcomes were consistent with previous adult studies focused on 
these infections. A randomized, double-blind, multicenter trial of caspofungin vs. liposomal amphotericin 
for empirical antifungal therapy of pediatric patients with persistent fever and neutropenia was also 
completed. Overall success rates were 41% for caspofungin vs. 28% for liposomal amphotericin; 
however, this difference did not reach statistical significance.31 Caspofungin demonstrated efficacy 
consistent with adult data for this indication. A comprehensive review of the safety of caspofungin across 
the 5 pediatric studies was performed. Of the 171 children receiving caspofungin, therapy was 
discontinued due to drug-related adverse events in 3 patients. Elevations in serum transaminases were 
seen in 8% of patients.32 The currently recommended pediatric dose of caspofungin in children is 
70 mg/m2/day IV on the first day of therapy followed by 50 mg/m2/day IV for subsequent days. The 
maximum daily loading dose is 70 mg. The maximum daily maintenance dose is 50 mg. 
 
Based on the available dosing data, safety data, and efficacy data regarding the echinocandins, 
caspofungin has been chosen as the best suited agent to take forward into studies of antifungal 
prophylaxis in pediatric AML patients because it is the only echinocandin approved for use in children as 
young as 3 months of age and because of extensive experience in children with cancer. Furthermore, there 
have been safety concerns raised recently regarding the use of micafungin in children from the European 
Medicines Agency.33 Finally, there is no approved dosing for anidulofungin in young children. 
 
2.3 
Rationale for Platelia EIA Aspergillus GM and Serum Beta-D Glucan Assays 
The diagnosis of IFI, especially IA, is often difficult because of the lack of specific clinical symptoms in 
high-risk patients and the invasiveness of standard diagnostic tests. Therefore much attention has been 
focused on developing non-invasive tests for diagnosing IFI. GM is a polysaccharide cell-wall component 
that is released by Aspergillus during growth. The Platelia EIA Aspergillus GM assay was approved by 
the FDA in 2003 for use in adult patients.34 Early large scale clinical testing included few children, but 
available data suggest that detection values for adult patients may not be extrapolated to children.35 
Furthermore, the utility of the GM assay in pediatric patients has not been rigorously studied in a 
prospective manner and therefore its true value as a diagnostic test in children is still unclear. Serum beta-
D glucan (found in all fungi except Cryptococcus species and Zygomycetes) can be detected using an 
approved diagnostic serum assay and has been found to have high specificity and high positive predictive 
values for the detection of IFI in adults.36 However, data on the performance of this assay in children are 
limited. Data suggests that combining GM testing with beta-D glucan testing would further improve the 
usefulness of the test; twice weekly testing having been suggested as practical to enable reasonably 
prompt diagnosis of IFI.37 See Section 13 for details on these optional ancillary studies.  

 
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2.4 
Rationale for Single Nucleotide Polymorphism (SNP) Aim 
In addition to early detection of fungal infections, there also is interest in identifying children particularly 
susceptible to these infections. There is considerable evidence that there is a genetic component to the 
susceptibility and outcome of infection in both normal and immunocompromised populations.38,39 For 
example, a study using a Danish adoption registry found that premature death from infection is much 
more heritable compared to premature death from cardiovascular disease or cancer.40 Redundancy in the 
immune system may be important for protection against serious infection and in the face of 
immunosuppression, defects in redundant pathways may be uncovered, leading to invasive bacterial or 
fungal infections.41,42 While defects in immunity may contribute to susceptibility to infection and 
outcome, excessive inflammation during infection may also contribute to septic shock and mortality.43 
Thus, variation in immunity and inflammatory genes likely plays a role in an individual’s susceptibility, 
response and prognosis related to infection. There is evidence specifically to link SNPs and the risk of 
fungal infections. For example, Choi and colleagues found that 2 polymorphisms in IL-4 were associated 
with chronic disseminated candidiasis in patients with acute leukemia.42 In addition, a polymorphism in 
DEFβ was associated with Candida carriage in type 1 diabetes.44 Based on these and other studies, we 
propose to test for associations between genetic variants in genes mediating innate immunity and IFI. 
 
 
3.0 
STUDY ENROLLMENT AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration  
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This number is 
obtained via the eRDE system once authorization for the release of protected health information (PHI) has 
been obtained. The COG patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help.  
 
In order for an institution to maintain COG membership requirements, every newly diagnosed patient needs 
to be offered participation in ACCRN07, Protocol for the Enrollment on the Official COG Registry, The 
Childhood Cancer Research Network (CCRN). 
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will 
be assigned only one BPC number per COG Patient ID. For additional information about the labeling of 
specimens please refer to the Pathology and/or Biology Guidelines in this protocol.  
 
3.1.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. Sites must 
submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory Office and allow 
3 business days for processing. The submission must include a fax coversheet (or optional CTSU IRB 
Transmittal Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may be 
submitted in lieu of the signed IRB approval letter. All CTSU forms can be located on the CTSU web 
page (https://www.ctsu.org). Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the RSS Tab.  
 
IRB/REB approval documents may be faxed (1-215-569-0206) Emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.  
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a “Time of 
Need” registration. For Time of Need registrations, in addition to marking your submissions as 
‘URGENT’ and faxing the regulatory documents, call the CTSU Regulatory Helpdesk at: 1-866-651-
CTSU. For general (non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923. 

 
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3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study 
enrollment is accomplished by going to the Enrollment application in the RDE system. If you have 
problems with enrollment, refer to online help in the Applications area of the COG website.  
 
 
3.1.4 
Timing 
Patients must be enrolled before protocol-directed antifungal prophylaxis begins. Treatment with non-
protocol directed antifungal prophylaxis with any agent is permitted prior to enrollment, but treatment 
with fluconazole or caspofungin (determined by randomization at enrollment) starts within 24-72 hours 
following completion of the first course of current chemotherapy. The date protocol-directed antifungal 
prophylaxis is projected to start must be no later than 5 calendar days after the date of study enrollment 
however, consent may be obtained earlier, and may occur at the same time consent is obtained for AML 
treatment. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated in the eligibility section below. 
 
3.1.5 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
  
3.1.6 
Randomization 
Randomization will take place at the time a patient is entered On Study via RDE. Patients will be assigned to 
either antifungal prophylaxis with caspofungin or antifungal prophylaxis with fluconazole. Randomization 
will be stratified into 2 groups: 1) de novo AML vs. 2) all other patients. 
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per 
COG policy 7.2). All clinical and laboratory data required for determining eligibility of a patient 
enrolled on this trial must be available in the patient's medical/research record which will serve as the 
source document for verification at the time of audit.  
 
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Patients must be ≥ 3 months and ≤ 30 years at the time of enrollment. 
 
3.2.2 
Diagnosis 
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). 
 
Please note: Patients with a history of prolonged antifungal therapy (example relapsed AML) are eligible. 
 
3.2.3 
Organ Function Requirements: 
 
3.2.3.1 Adequate renal function defined as: 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 

 
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- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR45 utilizing child length and stature data published 
by the CDC. 
 
3.2.3.2 Adequate liver function defined as: 
 
- 
Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
 
 
- 
SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age. 
 
 
EXCLUSION CRITERIA 
 
3.2.4 
Patients with the following diagnoses are not eligible:  
- 
acute promyelocytic leukemia (APL)  
- 
Down syndrome  
- 
juvenile myelomonocytic leukemia (JMML) 
 
3.2.5 
Patients with a documented history of IFI within the previous 30 days are not eligible. 
 
3.2.6 
Patients with a history of echinocandin or fluconazole hypersensitivity are not eligible. 
 
3.2.7 
Patients receiving treatment for an IFI are not eligible. 
 
3.2.8 
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. 
 
 
REGULATORY  
 
3.2.9 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.10 All institutional, FDA, and NCI requirements for human studies must be met. 

 
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4.0 
TREATMENT PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Overview of Treatment Plan 
 
This is a randomized clinical trial designed to assess the efficacy of caspofungin for preventing IFI 
(including IA) compared to fungal prophylaxis with fluconazole, the standard of therapy used in most 
COG institutions as prophylaxis in patients with AML and chemotherapy-induced neutropenia. 
 
Patients who consent to participate in ACCL0933 will be randomly assigned to antifungal prophylaxis 
with either fluconazole or caspofungin. Treatment with any anti-fungal prophylaxis after enrollment must 
be terminated prior to starting protocol-directed anti-fungal therapy. Protocol prophylaxis will be started 
within 24-72 hours following the last dose of systemic chemotherapy for each course. Administration of 
antifungal prophylaxis for each course will continue until (a) The absolute neutrophil count (ANC) is 
> 100-500/µL following the nadir; OR (b) Start of the next chemotherapy course; OR (c) Patient meets 
any off-protocol criteria (Section 8.1).  
 
If other systemic antifungal therapy is initiated for empiric therapy or treatment of suspected infection, 
then protocol prophylaxis should be held and assigned prophylaxis should resume when other systemic 
antifungal therapy is discontinued if this occurs prior to ANC recovery. 
 
Administration of assigned systematic antifungal prophylaxis continues with subsequent courses of 
chemotherapy until the patient meets any off-protocol criteria including proven or probable IFI according 
to institutional diagnosis. 
 
Fluconazole may be administered either intravenously (IV) or orally. Caspofungin is only available as an 
IV formulation. 
 
Note - For those institutions where patients are discharged prior to ANC recovery to 100-500/µL the 
following options exist:  
 
 
If the patient has been randomized to fluconazole they can continue this therapy orally at home 
until the ANC is >100-500/µL. 
 
If the patient is on caspofungin the parents and patient can decide to either remain in the hospital 
to continue caspofungin until the ANC is > 100-500/µL or be discharged home on daily IV 
caspofungin therapy until the ANC is > 100-500/µL. The latter may be associated with home 
healthcare costs that would not be funded by the study. It should be confirmed prior to discharge 
that the insurance company or other sources will cover such home healthcare costs.  
 
If the insurance company or other sources will not cover home healthcare costs not funded by the 
study, then the family can elect to pay for these services themselves or go home without 
continued caspofungin prophylaxis. In this circumstance, the treating physician should proceed 
with their standard clinical practices. 
 
See Section 6.2 for information regarding investigational vs. commercial drug supply following discharge 
home.  
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care. Minor unavoidable 
departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for 
surgery) for valid clinical, patient and family logistical, or facility,  procedure and/or anesthesia scheduling issues 
are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the protocol).  

 
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4.1.1. Randomization 
At the time of enrollment, patients will be randomly assigned to one of two treatment regimens: 
i)  Fluconazole Arm: This group will receive fluconazole, and represents the standard arm. 
ii)  Caspofungin Arm: This group will receive caspofungin and represents the experimental arm. 
 
Randomization will be stratified into 2 groups: 1) de novo AML vs. 2) all other patients. 
 
4.1.2 
Empirical Antifungal Therapy 
The persistence of fever for 5 days despite broad spectrum antibiotic therapy warrants the investigation of 
IFI and initiation of empiric antifungal therapy. Amphotericin B (lipid products) or voriconazole are 
recommended options based on their broad spectrum of antifungal activity. Assigned antifungal 
prophylaxis should be held during administration of these other systemic antifungal agents. 
 
4.1.3 
Concomitant Therapy Restrictions 
 
4.1.3.1 Fluconazole 
Some azoles, including fluconazole, have been associated with prolongation of the QT interval by 
electrocardiogram. Drugs known to prolong the QT interval should be used with caution or avoided with 
fluconazole. The administration of terfenadine with high dose fluconazole (≥ 400 mg adult dose) and 
cisapride with any dose of fluconazole is contraindicated. A list of drugs that prolong the QT interval can 
be found at http://www.azcert.org. 
 
Clinically or potentially significant drug interactions with fluconazole and the following agents have been 
observed: oral hypoglycemics (tolbutamide, glyburide, glipizide), coumarin-type anticoagulants (e.g., 
warfarin), phenytoin, cyclosporine, rifampin, theophylline, rifabutin, tacrolimus, short-acting 
benzodiazepines (more pronounced with oral fluconazole), and oral contraceptives. Since rifampin 
enhances the metabolism of concurrently administered fluconazole and the dose of fluconazole may need 
to be increased, the use of rifampin in this study should be avoided. Careful monitoring is required when 
fluconazole is administered with the other drugs.  
 
Coadministration of oral fluconazole with combination contraceptives has resulted in an overall mean 
increase in ethinyl estradiol and levonorgestrel levels. However, in some patients, levels of ethinyl 
estradiol and levonorgestrel decreased by up to 47% and 33%, respectively. While there is evidence that 
fluconazole can inhibit the metabolism of ethinyl estradiol and levonorgestrel, there is no evidence that 
fluconazole can induce the metabolism of these drugs. The clinical significance of the above effects is 
currently undetermined and may simply be a product of inter-individual variation in metabolism. 
 
Fluconazole inhibits several cytochrome P450 (CYP450) isoenzymes and may increase the serum level of 
drugs metabolized by CYP450 especially at high doses (> 200 mg adult dose). For a list of drugs 
metabolized by the CYP450 system see http://medicine.iupui.edu/flockhart.  
 
4.1.3.2 Caspofungin 
Coadministration of caspofungin with certain inducers of drug clearance and/or mixed inducer/inhibitors 
(e.g., efavirenz, nevirapine, phenytoin, rifampin, dexamethasone, and carbamazepine) may result in 
clinically important reductions in plasma caspofungin concentrations. Cyclosporine increases caspofungin 
area under the concentration curve (AUC) which results in a transient elevation of ALT/SGPT and 
AST/SGOT. Therefore, the use of these interacting drugs should be avoided if possible. 
 
For COG Supportive Care Guidelines see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 

 
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4.2 
Administration Schedule- FLUCONAZOLE ARM 
 
Patients randomized to this regimen will start prophylaxis within 24-72 hours following completion of 
each systemic chemotherapy course. Continue prophylaxis until: 
 
 
ANC > 100-500/µL following the nadir.  
OR 
 
The next chemotherapy course. 
OR 
 
Patient meets any of the off protocol therapy criteria (Section 8.1). 
 
If other systemic antifungal therapy is initiated for empiric therapy or treatment of suspected infection, 
then fluconazole prophylaxis should be held and fluconazole should resume when other systemic 
antifungal therapy is discontinued if this occurs prior to ANC recovery.  
 
Administration of assigned fluconazole prophylaxis continues with subsequent courses of chemotherapy 
until the patient meets any off-protocol criteria including proven or probable IFI according to institutional 
diagnosis. 
 
FLUCONAZOLE: by slow IV infusion over 1-2 hours* (or longer) OR by mouth. 
 
Once daily.  
Dose:  
Age ≥ 3 months to 17.99 years: 12 mg/kg/day once daily (maximum dose: 400 mg/day) 
Age ≥ 18 years to 30 years: 6 mg/kg/day once daily (maximum dose: 400 mg/day) 
 
*For IV: The rate of infusion should not exceed 200 mg/hour 
 
Oral fluconazole is available as 50, 100, 150, and 200 mg tablets and as an oral suspension at a 
concentration of 10 or 40 mg/mL. 
Rounding: When tablets are used, round the dose to the closest 50 mg. 
Round the suspension volume to the closest tenth of a mL. Round 0.05 mL up (e.g., round 3.15 mL to 
3.2 mL). 
 
Oral fluconazole can be taken at any time during the day with or without food. It should be administered 
at approximately the same time each day. If vomiting occurs within 30 minutes of taking the dose, the 
dose may be repeated once. If a dose is missed, it should be taken immediately and only if there are at 
least 12 hours until the next scheduled dose.  
 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS FOR TOXICITIES. For COG Supportive Care 
Guidelines see https://members.childrensoncologygroup.org/prot/reference_materials.asp 
 
The therapy delivery map (TDM) for fluconazole prophylaxis is on the next page.  
 
Following completion of prophylaxis in each course of chemotherapy, prophylaxis will restart at the end 
of the subsequent chemotherapy course as outlined above. 
 

 
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4.2.1. Fluconazole Treatment Arm. 
Patients randomized to fluconazole arm. 
      
  ____________________________ 
      Patient name or initials  
 
  ____________________________ 
DOB   
 
Prophylaxis with fluconazole begins within 24-72 hours following completion of each systemic chemotherapy course. Extensive 
administration details are in Section 4.2. This TDM is on One (1) page. 
 
 DRUG  
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
FLUCONAZOLE  
 
 
Slow IV infusion 
over 1-2 hours* 
(or longer) OR 
by mouth. 
 
 
≥ 3 months – 17.99 years: 
12 mg/kg/day 
(IV or enteral dose) 
Maximum dose: 
400 mg/day 
 
18 – 30 years: 
6 mg/kg/day 
(IV or enteral dose) 
Maximum dose: 
400 mg/day 
Once 
daily 
Start within 24-72 hours 
following completion of 
each systemic 
chemotherapy course. 
 
*For IV: The infusion rate 
should not exceed 
200 mg/hour. 
 
See Section 4.2 for oral 
drug administration. 
a. CBC, diff, plts, 
creatinine, SGPT, 
SGOT, bilirubin 
b. IFI Checklist (see 
Section 10.2) 
 
Optional:  
c. Galactomannan and 
beta-D glucan testing 
d. SNP 
 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
 
Enter Chemotherapy Course # Here___________ 
 
Ht_____cm 
    Wt____kg 
 
BSA____m2 
Date 
Due 
Date 
Given 
Day 
FLUCONAZOLE 
________mg 
Studies 
Comments (Include any held doses, 
or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
________mg 
 
a, c& 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End Date: _____________________ 
b, d% 
 
Continue prophylaxis until criteria in Section 4.2 are met. Following completion of prophylaxis in each course of 
chemotherapy, prophylaxis will restart at the end of the subsequent chemotherapy course as outlined in Section 4.2. 
& Collect twice weekly. See Section 13 for details. It is suggested that specimens be obtained on Mondays & Thursdays; specimens 
may be obtained ± 2 days from defined days as long as a minimum of 2 days separate each specimen collection. 
% Obtain at end of Course 1, optimally when the patient has ANC > 1000/µL and no circulating blasts. See Section 14 for details. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS FOR TOXICITIES and the COG website posted materials for 
Supportive Care Guidelines https://members.childrensoncologygroup.org/prot/reference_materials.asp 
 
 

 
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4.3 
Administration Schedule- CASPOFUNGIN ARM 
Patients randomized to this regimen will start prophylaxis within 24-72 hours following completion of 
each systemic chemotherapy course. Continue prophylaxis until: 
 
 
ANC > 100-500/µL following the nadir.  
OR 
 
The next chemotherapy course. 
OR 
 
Patient meets any of the off protocol therapy criteria (Section 8.1). 
 
If other systemic antifungal therapy is initiated for empiric therapy or treatment of suspected infection, 
then caspofungin prophylaxis should be held and caspofungin should resume when other systemic 
antifungal therapy is discontinued if this occurs prior to ANC recovery.  
 
Administration of assigned caspofungin prophylaxis continues with subsequent courses of chemotherapy 
until the patient meets any off-protocol criteria including proven or probable IFI according to institutional 
diagnosis. 
 
CASPOFUNGIN: by slow IV infusion over no less than 1 hour. 
 
Loading dose (LD): 70 mg/m2/day* - First day of therapy (Maximum dose: 70 mg/day). 
Maintenance dose (MD): 50 mg/m2/day* – Subsequent days (Maximum dose: 50 mg/day).  
 
*Use the Mosteller Formula for BSA calculation. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES.  
 
The therapy delivery map (TDM) for caspofungin prophylaxis for chemotherapy-induced neutropenia is 
on the next page.  
 
Following completion of prophylaxis in each course of chemotherapy, prophylaxis will restart at the end 
of the subsequent chemotherapy course as outlined above. 
 
 

 
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4.3.1 Caspofungin Treatment Arm 
Patients randomized to caspofungin arm. 
 
____________________________ 
       Patient name or initials  
 
____________________________ 
DOB  
 
Prophylaxis with caspofungin begins within 24-72 hours following completion of each systemic chemotherapy course. 
Extensive administration details are in Section 4.3. This TDM is on One (1) page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
CASPOFUNGIN 
IV over 1 hour 
70 mg/m2/day 
50 mg/m2/day 
 
1 
2 (and 
subsequently) 
Start within 24-72 hours 
following completion of each 
systemic chemotherapy 
course. 
 
Maximum Loading dose: 
70 mg/day 
 
Maximum Maintenance 
dose: 50 mg/day 
a. CBC, diff, plts, 
creatinine, SGPT, 
SGOT, bilirubin 
b. IFI Checklist (see 
Section 10.2) 
 
Optional: 
c. Galactomannan and 
beta-D glucan testing 
d. SNP 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
 
Enter Chemotherapy Course # Here___________ 
Ht_____cm 
Wt____kg 
BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
CASPOFUNGIN 
Day 1:_________mg; Day 2 and Subsequently: ________mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
LD:  __________mg 
a, c& 
 
 
 
2 
MD: __________mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End Date: _________________________ 
b, d% 
 
Continue prophylaxis until the criteria in Section 4.3 are met. Following completion of prophylaxis in each course of 
chemotherapy, prophylaxis will restart at the end of the subsequent chemotherapy course as outlined in Section 4.3. 
& twice weekly. See Section 13 for details. It is suggested that specimens be obtained on Mondays & Thursdays; specimens may 
be obtained ± 2 days from defined days as long as a minimum of 2 days separate each specimen collection. 
 
%Obtain at end of Course 1, optimally when the patient has ANC > 1000/µL and no circulating blasts. See Section 14 for details. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS FOR TOXICITIES and the COG website posted 
materials for Supportive Care Guidelines https://members.childrensoncologygroup.org/prot/reference_materials.asp 
 
 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Impaired Renal Function 
When estimating renal function for adjusting drug doses, use the Schwartz formula for patients < 18 years 
of age and the Cockcroft and Gault equation for patients ≥ 18 years of age.  
 
Fluconazole: 
Creatinine clearance 
(mL/min/1.73m2) 
Percent of dose 
Dose in mg/kg (max dose) 
≥ 3 months to 17.99 years: 
≥ 18 years to 30 years: 
> 50 
100% 
12 mg/kg (max 400 mg) 
6 mg/kg (max 400 mg) 
< 50 (no dialysis) 
50% 
6 mg/kg (max 200 mg) 
3 mg/kg (max 200 mg) 
Hemodialysis 
100% after each 
dialysis 
12 mg/kg (max 400 mg 
after each dialysis) 
6 mg/kg (max 400 mg 
after each dialysis) 
 
Note: When renal function improves to > 50 mL/min/1.73 m2, the dose can be increased to the full dose. 
 
Caspofungin: 
Adjustment of the dose is not needed in the setting of impaired renal function. Caspofungin is not 
dialyzable and supplementation is not required following hemodialysis. 
 
5.2 
Impaired Liver Function 
 
Fluconazole: 
Fluconazole should be held in patients who develop signs and symptoms consistent with liver disease or 
elevations in hepatic function tests as defined by an ALT or AST > 5 x ULN or serum bilirubin > 2 x 
ULN. 
 
Caspofungin: 
For all patients:  
Child – Pugh 
score46,47 
Percent of dose 
Dose in mg/kg (max dose) 
Mild (5-6) 
100% 
Loading dose: 70 mg/m2/dose (max 70 mg) 
Maintenance dose: 50 mg/m2/dose (max 50 mg) 
Moderate (7-9) 
Loading dose-100% 
Maintenance dose- 70% 
Loading dose: 70 mg/m2/dose (max 70 mg) 
Maintenance dose: 35 mg/m2/dose (max 35 mg) 
Severe (> 9) 
Hold 
Hold 
 
To calculate the Child-Pugh Score: 
Factor 
1 Point 
2 Points 
3 Points 
Total Bilirubin (mg/dL) 
< 2.0 
2.0-3.0 
> 3.0 
Albumin (g/dL) 
> 3.5 
2.8-3.5 
< 2.8 
INR 
< 1.7 
1.7-2.2 
> 2.2 
Ascites 
No Ascites 
Ascites, controlled 
Ascites, 
poorly controlled 
Encephalopathy 
No Encephalopathy 
Encephalopathy, 
controlled 
Encephalopathy,  
poorly controlled 
 
Caspofungin may be restarted or increased if liver function (and Child-Pugh score) improves. 

 
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6.0 
DRUG INFORMATION  
 
6.1 
FLUCONAZOLE (Diflucan)  
 
 
 
(04/16/14) 
 
Source and Pharmacology:  
Fluconazole is a triazole antifungal agent. It is structurally related to imidazole-derivative azole antifungal 
agents (e.g., clotrimazole, ketoconazole, miconazole) however, imidazoles have 2 nitrogens in the azole 
ring (imidazole ring) and fluconazole and other triazoles (e.g., itraconazole, terconazole) have 3 nitrogens 
in the ring (triazole ring). In addition, fluconazole contains a second triazole which makes it a bistriazole 
derivative and a halogenated phenyl ring. Replacement of the imidazole ring with a triazole ring 
apparently results in increased antifungal activity and an expanded antifungal spectrum of activity. 
Presence of the two triazole rings may contribute to fluconazole’s resistance to first-pass metabolism and 
the drug's low lipophilicity and protein binding. Presence of a halogenated phenyl ring increases 
antifungal activity and contributes to the aqueous solubility which make fluconazole suitable for IV 
formulation. 
 
Fluconazole is a highly selective inhibitor of the fungal cytochrome P-450 dependent lanosterol 14- 
alpha-demethylase. This enzyme converts lanosterol to ergosterol. The subsequent loss of normal sterols 
correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the 
fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole 
inhibition. 
 
Fluconazole is active against many fungi, including yeasts and dermatophytes. Fluconazole has been 
shown to be active against most strains of the following microorganisms both in vitro and in clinical 
infections: Candida (C) albicans, C glabrata (many strains are intermediately susceptible), C 
parapsilosis, C tropicalis, and Cryptococcus neoformans. Candida krusei is considered to be resistant to 
fluconazole. Resistance to fluconazole may arise from a modification in the quality or quantity of the 
target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target by efflux of fluconazole 
out of the cell, or some combination of these mechanisms.  
 
The pharmacokinetics of fluconazole are similar following IV or oral administration. In healthy adults 
receiving 50- or 100-mg doses of fluconazole given once daily by IV infusion over 30 minutes, serum 
concentrations of the drug 1 hour after dosing on the sixth or seventh day of therapy ranged from 2.14-
2.81 or 3.86-4.96 mcg/mL, respectively. In a multiple-dose study in children 5-15 years of age, IV 
administration of 2-, 4-, or 8-mg/kg doses of fluconazole resulted in mean peak plasma concentrations of 
5.5, 11.4, or 14.1 mcg/mL, respectively. Fluconazole is widely distributed into body tissues and fluids 
following oral or IV administration. In adult humans with normal renal function, concentrations of the 
drug in urine and skin may be 10 times higher than concurrent plasma concentrations. Concentrations in 

 
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saliva, sputum, nails, blister fluid, blister skin, and vaginal tissue are approximately equal to concurrent 
plasma concentrations. Fluconazole, unlike some azole-derivative antifungal agents (e.g., itraconazole, 
ketoconazole), distributes readily into the CSF following oral or IV administration. Another difference 
from other azole-derivative antifungals (e.g., itraconazole, ketoconazole, miconazole), is that fluconazole 
is only 11-12% bound to plasma proteins while the other azole derivatives are highly protein bound. 
 
The plasma elimination half-life of fluconazole in adults with normal renal function is approximately 
30 hours (range: 20-50 hours). The mean plasma half-life of fluconazole in children 5 to 15 years of age 
after multiple IV doses is at the range of 15-18 hours. In healthy adults, fluconazole is eliminated mainly 
by renal excretion with approximately 80% excreted in the urine as unchanged drug. Small amounts of 
the drug are excreted in feces. Metabolism accounts for only 11% of total drug excreted. The renal 
clearance rate in adults is 0.27 to 0.63 mL/min/kg and in children age 5 to 15 years it is 0.4 to 
0.66 mL/min/kg. 
 
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the 
electrocardiogram. Fluconazole should be administered with caution to patients with this potentially 
proarrhythmic condition. Clinically or potentially significant drug interactions between fluconazole and 
the following agents/classes have been observed: oral hypoglycemics (tolbutamide, glyburide, glipizide), 
coumarin-type anticoagulants (e.g., warfarin), phenytoin, cyclosporine, rifampin, theophylline, 
terfenadine, cisapride, astemizole, rifabutin, tacrolimus, short-acting benzodiazepines (more pronounced 
with oral fluconazole). Coadministration of oral fluconazole with combination contraceptives has resulted 
in an overall mean increase in ethinyl estradiol and levonorgestrel levels. However, in some patients 
levels of ethinyl estradiol and levonorgestrel decreased by up to 47% and 33%, respectively. The clinical 
significance of the above effects is currently undetermined and may simply be a product of interindividual 
variation in metabolism. 
Toxicity: 
 
Common 
Happens to 21-100 
subjects out of every 100 
Occasional 
Happens to 5-20 subjects 
out of every 100 
Rare 
Happens to < 5 subjects out of every 100 
Immediate: 
Within 1-2 
days of 
receiving 
drug 
 
Nausea, vomiting, diarrhea, 
abdominal pain, rash, 
pruritus. 
Anaphylaxis, allergic reaction, dyspnea, 
bloating, dyspepsia, taste perversion, QT 
prolongation, torsade de pointes, headache, 
dizziness, seizure. 
Prompt: 
Within 2-3 
weeks, prior 
to next 
course 
 
Elevated ALT/AST 
Stevens-Johnson syndrome and toxic 
epidermal necrolysis, hypokalemia, 
hypercholesterolemia, hypertriglyceridemia, 
leucopenia including neutropenia and 
agranulocytosis, eosinophilia, 
thrombocytopeniaL, hepatitis, cholestasis, 
fulminant liver failure  
Delayed: 
Any time 
later during 
therapy, 
excluding the 
above 
conditions 
 
 
Alopecia with prolonged used 
Unknown 
Frequency 
and Timing: 
Pregnancy Category C. There are no adequate and well controlled studies in pregnant women. There 
have been reports of multiple congenital abnormalities in infants whose mothers were being treated 
for 3 or more months with high dose (400-800 mg/day) of fluconazole. The relationship between 

 
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fluconazole use and these events is unclear. Fluconazole should be used in pregnancy only if the 
potential benefit justifies the possible risk to the fetus.  
(L) Toxicity may also occur later. 
 
Formulation and Stability: 
Fluconazole injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole in a sodium chloride 
or dextrose diluent. Each mL contains 2 mg of fluconazole and 9 mg of sodium chloride or 56 mg of 
dextrose. The pH ranges from 4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose 
diluent. Injection volumes of 100 mL and 200 mL are packaged in glass or in polyvinylchloride (PVC) 
bags. Specific storage requirements may vary among manufacturers. In general, fluconazole injection in 
glass bottles or PVC bags should be stored between 5-30C (41-86F) or between 5-25C (41-77F), 
respectively. Brief exposure to 40C (104F) does not adversely affect the product in the PVC container. 
Fluconazole solution should be protected from freezing. The overwrap moisture barrier should not be 
removed from the PVC bags until ready for use. The solution should not be used if it is cloudy or 
precipitated. 
 
Fluconazole is available as 50, 100, 150, or 200 mg tablets that may contain lactose. Fluconazole for oral 
suspension contains 350 mg or 1400 mg of fluconazole powder in bottles which may contain sucrose and 
sodium benzoate. The tablets and dry powder of fluconazole for oral suspension should be stored between 
68-77°F (20-25°C).  
 
CANADIAN SITES: 
Fluconazole injection is only available as 200 mg/100 mL. Oral fluconazole is available as 50 mg, 
100 mg 150 mg and 200 mg tablets. Fluconazole powder for oral suspension is only available as 350 mg 
of powder per bottle. Other product specifications are similar. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Injection: 
Fluconazole injection is provided as a 2 mg/mL solution in NS or D5W that is ready to infuse without 
further dilution. The infusion may be prepared according to standard operating procedures of the institution. 
For example, the calculated dose volume in NS or D5W may be is transferred to an evacuated PVC infusion 
bag or to an evacuated glass bottle. Since fluconazole solution contains no preservatives, and as with all 
parenteral drug products, aseptic technique must be used during the preparation of the dose. Institution 
guidelines should be followed for determining the expiration time of the infusion solution.  
 
Oral: 
To mix the oral suspension tap bottle until all the powder flows freely. To reconstitute, add 24 mL 
distilled water or Purified Water (USP) to the fluconazole 350 mg or 1400 mg powder in bottle and shake 
vigorously to suspend the powder. The concentration of the reconstituted suspension is 10 mg/mL for the 
350 mg bottle and 40 mg/mL for the 1400 mg bottle with a total volume of 35 mL of suspension per 
bottle. The reconstituted suspension should be stored between 86°F (30°C) and 41°F (5°C). Protect from 
freezing. Discard unused portion 2 weeks after reconstitution. Patients should be instructed to shake the 
oral suspension well before using. Oral fluconazole should be administered with or without food at 
approximately the same time each day and can be taken at any time during the day. 
 
Supplier: Commercially available from various manufacturers. See package insert for further information. 

 
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6.2 
CASPOFUNGIN (caspofungin acetate, Cancidas) 
 
 
(11/08/11) 
 
Source and Pharmacology:  
Caspofungin acetate, a semisynthetic lipopeptide synthesized from a fermentation product of Glarea 
lozoyensis, is an echinocandin antifungal agent. It inhibits the synthesis of beta (1, 3)-D-glucan, an 
essential component of filamentous fungal cell wall that is not present in mammalian cells. Caspofungin 
has been shown to be active both in vitro and in clinical infections against most strains of the following 
organisms: Aspergillus (A) fumigatus, A flavus, A terreus, Candida (C) albicans, C glabrata, 
C guilliermondii, C krusei, C parapsilosis, C tropicalis. Following an intravenous infusion, the plasma 
concentration of caspofungin declines in a polyphasic manner. A short alpha-phase that occurs 
immediately post-infusion is followed by a beta-phase (half-life of 9 to 11 hours) and an additional, 
longer half-life phase, gamma-phase (half-life of 40-50 hours). Caspofungin is extensively (about 97%) 
protein bound to albumin and is cleared mainly by distribution (rather than excretion or 
biotransformation). Caspofungin is slowly metabolized in the liver via hydrolysis and N-acetylation. 
Following a single intravenous dose, 35% of the parent drug and metabolites was excreted in feces and 
41% was excreted in the urine. After multiple doses of caspofungin 50 mg/day were given intravenously 
to adults, the total body clearance was 10.6 ± 3.8 mL/min. When a dose of 50 mg/m2/day was given 
intravenously to children and adolescents, the total body clearance was 12.6 ± 5.5 mL/min in adolescents 
(12 to 17 years of age), 6.4 ± 2.6 mL/min in children 2 to 11 years and 3.2 ± 0.4 mL/min in children 3 to 
23 months. 
 
Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for, and does not inhibit or 
induce, cytochrome P-450 isoenzymes in vitro. However, coadministration of caspofungin with certain 
inducers of drug clearance and/or mixed inducer/inhibitors (e.g., efavirenz, nevirapine, phenytoin, 
rifampin, dexamethasone, and carbamazepine) may result in clinically important reductions in plasma 
caspofungin concentrations. Cyclosporine increases caspofungin area under the curve (AUC) which 
results in a transient elevation of alanine transaminase (ALT) and aspartate transaminase (AST) and 
coadministration with tacrolimus may decrease tacrolimus AUC. 

 
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Toxicity: 
 
Common 
Happens to 21-100 
subjects out of every 
100 
Occasional 
Happens to 5-20 subjects 
out of every 100 
Rare 
Happens to < 5 subjects out of every 100 
Immediate: 
Within 1-2 
days of 
receiving drug 
Pyrexia, chills, diarrhea, 
rash, infusion reaction 
(systemic) 
Peripheral edema, phlebitis, 
nausea, vomiting, 
abdominal pain, cough, 
erythema, headache, 
hypotension 
Anaphylaxis, respiratory failure, infusion 
site pain/pruritus/swelling, urticaria, 
arrhythmia, atrial fibrillation, bradycardia, 
cardiac arrest, myocardial infarction, 
tachycardia, abdominal distension, upper 
abdominal pain, constipation, dyspepsia, 
asthenia, fatigue, anorexia, dizziness, 
somnolence, tremor, flushing, hypertension  
Prompt: 
Within 2-3 
weeks, prior to 
next course 
Hypokalemia 
Increase liver function tests 
(ALT/AST/Alkaline 
phosphatase), increase 
bilirubin, pneumonia 
Anemia, coagulopathy, febrile neutropenia, 
neutropenia, thrombocytopenia, mucosal 
inflammation, petechiae, hepatic failure, 
hepatomegaly, hepatotoxicity, hepatic 
necrosis, jaundice, bacteremia, sepsis, 
urinary tract infection hypomagnesemia, 
hypercalcemia, hyperglycemia, arthralgia, 
back pain, pain in extremity, convulsion, 
anxiety, confusional state, depression, 
insomnia, hematuria, renal failure, dyspnea, 
epistaxis, hypoxia, tachypnea, pancreatitis, 
erythema multiforme, Stevens-Johnson, 
skin exfoliation  
Unknown 
Frequency 
and Timing: 
U.S. Food and Drug Administration's Pregnancy Category: Category C. It is not known if 
caspofungin crosses the placenta in humans. There are no adequate and well-controlled studies 
with the use of caspofungin in pregnant women. 
In animal studies, caspofungin acetate has been shown to be embryotoxic. Abnormalities in rats, 
treated with caspofungin doses comparable to the human dose, included incomplete ossification 
of the skull and torso and increased incidence of cervical rib. In rabbits, incomplete ossifications 
of the talus/calcaneus were noted. In rats and rabbits caspofungin crossed the placenta and was 
evident in fetal plasma. 
 
Formulation and Stability: 
Caspofungin is available as a lyophilized white to off-white powder/cake as a single-use vial in two vial 
sizes (50 mg and 70 mg). Each vials contains an intentional overfill. The 50 mg vials contain 54.6 mg and 
the 70 mg vial contains 75.6mg. The 50mg vials also contain 39 mg of sucrose and 26 mg of mannitol. 
The 70 mg vials also contain 54 mg of sucrose and 36 mg of mannitol. The pH is adjusted during 
manufacturing with glacial acetic acid and sodium hydroxide. The lyophilized powder vials should be 
stored refrigerated at 2 to 8C (36 to 46F). 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Preparation instructions in this monograph apply only to the Merck USA product as supplied for 
this study. 
 
Prior to reconstitution, equilibrate the refrigerated vial to room temperature. Aseptically add 10.8 mL of 
0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with 
methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol to the 

 
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vial. Use diluents without benzyl alcohol for neonates and infants < 2 years of age or patients with 
hypersensitivity to benzyl alcohol.  
 
The concentration of the reconstituted solution depends on the vial size and is listed in the table below: 
 
CANCIDAS 
vial*  
Total Drug Content 
(including overfill)  
Reconstitution 
Volume to be added*  
Resulting 
Concentration 
following 
Reconstitution**  
50 mg  
54.6 mg  
10.8 mL  
5 mg/mL  
70 mg  
75.6 mg  
10.8 mL  
7 mg/mL  
*Preparation instructions apply only to the Merck USA product as provided in this study. 
**Note different concentrations following reconstitution of the product in the vial. 
 
The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained. 
Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and 
prior to infusion. Do not use hazy, precipitated, or discolored solutions. The reconstituted solution may be 
stored for up to 1 hour at ≤ 25°C (≤ 77°F). Since caspofungin vials are for single use only; the remaining 
solution should be discarded.  
 
Dilute the appropriate volume of reconstituted caspofungin in 0.9%, 0.45% or 0.225% Sodium Chloride 
Injection or Lactated Ringers Injection. The final concentration should not exceed 0.5 mg/mL. The 
stability of the diluted solution for administration is 24 hours if stored at ≤ 25°C (≤ 77°F) or 48 hours if 
stored refrigerated at 2 to 8°C (36 to 46°F). Since the infusion solution contains no preservatives and as 
with all parenteral drug products, aseptic technique must be used during the preparation of the infusion 
bag. Institution guidelines should be followed to determine the expiration time of the infusion solution. 
The expiration time should not exceed 24 hours at ≤ 25°C (≤ 77°F) and 48 hours refrigerated. 
 
Caspofungin is administered by slow intravenous infusion over no less than 1 hour. Do not mix or co-
infuse caspofungin with other medications, as there are no data available on the compatibility of 
caspofungin with other intravenous medications. DO NOT USE DILUENTS CONTAINING 
DEXTROSE since caspofungin is not stable in diluents containing dextrose. The infusion line should be 
flushed with 0.9% sodium chloride before and after drug administration. 
 
Supplier: Caspofungin will be supplied by the manufacturer Merck & Company, Inc., USA. The 
University of Pennsylvania School of Medicine will distribute the study medication to the study sites 
through their Investigational Drug Service Pharmacy. Drug ordering and drug destruction information can 
be found on the study website. Drug receiving and accountability records should be maintained and 
performed according to local institutional procedures.  
 
If local regulations do not allow for dispensing of investigational drug supply for home use, 
commercial drug supply may be used for patients at home. All hospitalized patients must receive 
drug from investigational inventory. 
 

 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations  
Obtain prior to start of phase unless otherwise indicated.  
 
STUDIES TO BE OBTAINED 
Baseline 
Course 1#  
Subsequent 
Courses#  
End of ACCL0933 
Therapy 
REQUIRED 
History 
X 
 
 
 
Physical Exam (Ht, Wt, BSA) 
X 
 
 
 
CBC, differential, platelets 
X 
X 
X 
X 
Creatinine, SGPT, SGOT, bilirubin 
X 
X 
X 
X 
IFI checklist 
 
X* 
X* 
X* 
OPTIONAL 
Sample for SNP Genotyping 
 
X% 
 
 
GM, BG Assays 
 
2x weekly@ 
2x weekly@ 
 
# Course 1 of fluconazole or caspofungin follows Course 1 of AML therapy. Subsequent Courses refers 
to protocol-directed antifungal prophylaxis, not AML therapy.  
*  Submit relevant IFI checklist documents via the Document Imaging System: (626) 447-2204 at the end 
of each course of protocol therapy. See Section 10.2 for further details. 
%  Obtain at end of Course 1, optimally when the patient has ANC > 1000/µL and no circulating blasts. 
@  Collect specimens twice weekly during the period of neutropenia (until ANC > 100-500/µL). See Section 
13.1 for specimen collection details. It is suggested that specimens be obtained on Mondays and 
Thursdays but other days are acceptable if more convenient. A minimum of 2 days should separate 
each specimen collection. All specimens must be collected in the specimen vials provided by 
MiraVista Laboratories in the shipped lab collection kits. Alternative specimen vials should never be 
used as they may contribute to false results.  
 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as indicated for good clinical care.  
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care. Minor unavoidable 
departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for 
surgery) for valid clinical, patient and family logistical, or facility, procedure and/or anesthesia scheduling issues 
are acceptable per COG administrative Policy 5.14 (except where explicitly prohibited within the protocol).  

 
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7.2 
Optional Studies  
 
7.2.1 
Galactomannan and (1→3) Beta-D Glucan Assays 
Two antifungal antigen assays (Platelia Aspergillus EIA and Fungitell Assay) will be performed during 
the period of neutropenia in order to identify IA only and all IFI respectively. 6 mL of peripheral blood 
will be collected in a gold top serum-separator tube (provided by MiraVista) twice weekly. See Section 13 
for sample collection, processing and shipping details. For each period of neutropenia, documentation of 
exposure or lack of exposure to each of the following will be performed: amoxicillin-clavulanate, 
piperacillin-tazobactam, and intravenous immunoglobulin. Documentation of infection with Pneumocystis 
jiroveci, Penicillium spp., Histoplasma capsulatum, Geotrichum spp., or Neosartoria spp. will occur through 
microbiology or pathology reporting and through routine adverse event reporting. See Section 11 for sample 
collection and shipping details. 
 
 
7.2.2 
SNP Analysis 
Genotyping will be conducted in order to determine genes mediating immune function. Patients enrolled 
on AAML1031 will require no additional sample collection to participate. For all other patients, 5 mL of 
peripheral blood will be collected in a purple top tube at the end of Course I, optimally when the patient has 
an ANC > 1000/µL (and with no circulating blasts). See Section 14 for sample collection and shipping 
details. 
 
7.3 
Follow-up 
See COG Late Effects Guidelines for recommended post treatment follow-up 
http://www.childrensoncologygroup.org/disc/LE/default.htm 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
8.1 
Criteria for Removal from Protocol Therapy 
 
a) Development of proven or probable IFI including IA according to institutional diagnosis. 
b) Patients who begin conditioning for HSCT. 
c) Begin a new chemotherapy regimen for AML that is refractory to, or relapsed with current AML 
chemotherapy. 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Recovery from neutropenia following completion of the final planned AML chemotherapy course .  
f) Physician determines it is in patient’s best interest. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study below. 
Follow-up data will be required unless consent was withdrawn. A patient that is placed on empiric fungal 
therapy for prolonged fever and neutropenia should NOT be removed from protocol therapy for subsequent 
AML chemotherapy courses unless one of the off protocol therapy criteria is met. 
 
8.2 
Off Study Criteria 
 
a) Death. 
b) Lost to follow-up. 
c) Withdrawal of consent for any further data submission. 
d) Second anniversary of study entry. 

 
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8.3 
Discontinuation from IFI Observation Criteria 
 
Patients who are taken off protocol therapy (but are not off study) must be followed for all infection 
endpoints until they meet the Discontinuation from IFI Observation Criteria (below) or until they 
meet the Off Study Criteria (See Section 8.2).  
 
a) Begin conditioning for HSCT. 
b) Begin a new chemotherapy regimen for AML that is refractory to, or relapsed with current AML 
chemotherapy. 
c) Two weeks after recovery from neutropenia following completion of the final planned AML 
chemotherapy course. 
 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Statistical Design 
This is a randomized open-label trial to determine if prophylaxis with caspofungin during periods of 
neutropenia following chemotherapy for AML is associated with a lower incidence of proven or probable IFI 
compared with fluconazole. Eligible AML patients at ages 3 months to 30 years will be randomized to 
receive daily prophylaxis with either caspofungin or fluconazole. Randomization will be stratified into 
2 groups: 1) de novo AML vs. 2) all other patients. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
Eligible subjects will have de novo, relapsed, or secondary AML, or any diagnosis being treated with 
institutional standard AML therapy (for example myelodysplastic syndrome, bone marrow blasts > 5% or 
biphenotypia). This protocol does not require concurrent enrollment on a COG therapeutic protocol. 
Patients treated per the upcoming de novo AML protocol, AAML1031 but not enrolled (for example, due 
to failure to meet AAML1031 eligibility criteria, refusal or other reasons) may enroll on ACCL0933. The 
de novo AML therapeutic protocol, AAML0531, accrued over 300 patients per year and the subsequent 
de novo AML protocol, AAML1031, is projected to accrue about 290 patients per year. The potential 
patient pool for ACCL0933 will be larger than AAML1031, and therefore, the accrual rate for this study 
is expected to be about 150 patients per year. Taking into account the initial delay in opening the study at 
institutions, the expected total accrual duration for 550 eligible patients is about 4 years. The maximum 
accrual, including ineligible enrollments, is 575 patients.  
 
 
9.3 
Statistical Analysis Methods 
 
9.3.1 
Study Endpoints 
 
Primary endpoint 
The primary endpoint is the development of proven or probable IFI defined according to criteria 
developed by the European Organization for Research and Treatment of Cancer/Mycoses Study Group 
(EORTC/MSG) (from which time to IFI will be computed).48  
 
Secondary Endpoints 
Endpoints for secondary objectives include: the development of proven or probable IA defined according 
to criteria developed by the EORTC/MSG (from which time to IA will be computed), death due to any 
cause (from which time to death will be computed), the need for empiric antifungal therapy defined as the 
institution of antifungal therapy while a study subject is receiving prophylaxis (from which the days of 
empirical antifungal therapy will be computed), results from GM and beta-D glucan assays for the 
diagnosis of IFI or IA alone, and results of the genotyping assays for SNP analysis.  
 
An exploratory endpoint will be the development of proven, probable or possible IFI. 

 
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9.3.2 
Central Committee Review 
In order to ensure consistent and accurate application of the EORTC/MSG guidelines across all study 
patients, a Central Review Committee including Pediatric Oncologists and Pediatric Infectious Disease 
Specialists will be assembled. Through consensus meetings, committee members will review all data 
pertinent to the EORTC/MSG guidelines and determine whether a patient sustained a possible, probable 
or proven IFI or IA infection during the study period. The following data for each study patient will be 
collected and available at the time of the review: pathology reports, all CT scan and MRI reports, fungal 
Gram stain and microbiology culture results, non-culture mycology testing results (i.e., Histoplasma urine 
antigens, cryptococcal CSF and serum antigens), ophthalmology exams, bronchoscopy reports, and 
dosing and duration of steroid exposures.  
 
All reviewers will be blinded to the patient’s antifungal exposures in order to limit any bias in 
determining the primary and secondary endpoints. 
 
9.3.3 
Sample size with power justification 
A total of approximately 550 eligible patients will be randomized to the 2 arms (at least 275 patients on 
each arm). Patients will be followed for infection outcome data until criteria in Section 8.3 has been met 
unless the patient is off study per Section 8.2 prior to meeting criteria in 8.3. 
 
Since the current AAML1031 proposal plans 4 courses of chemotherapy with about 1 month duration for 
each course, it implies that likely many study participants will be followed for IFI for about 5 months. 
The power calculation assumes an IFI incidence in the fluconazole group of 8% and an IFI incidence in 
the caspofungin treatment groups of 2% at 5 months. The hazard ratio is 0.24. We assume up to 10% of 
patients may have early termination of follow up on IFI due to change in AML therapy such as refractory 
disease, relapse, or death. It is estimated that up to 25% of patients treated on or per AAML1031 may go 
to SCT prior to finishing all 4 courses. Therefore, altogether up to 35% patients may not be followed until 
the end of 5 months for IFI. With at least 275 patients on each arm, a planned 5-month follow up on each 
patient and up to 35% patients being censored by 5 months, we have about 80% power to detect the 
expected difference in time-to-IFI curves between the 2 arms (8% vs. 2% at 5 months) in a log rank test 
with 2-sided alpha level of 0.05. In the calculation, both failure and censoring are assumed to follow an 
exponential distribution during the 5 months. The majority of the censoring events prior to 5 months are 
expected to be due to SCT which likely occur later in the 5 months, so the exponential censoring 
distribution might not be a very good approximation but should be conservative in power consideration.  
 
The assumed baseline incidence of IFI of 8% at 5 months is based on data reported in previous studies. 
CCG protocol 2961 found a 13% incidence of IFI. The rate of microbiologically documented sterile site 
fungal infections documented on AAML0531 is 12 ± 2% as of April 2010; not all of these would meet 
MSG/EORTC criteria as proven/probable IFIs. In the power calculation, the onset of IFI in both groups 
over the 5-month period is assumed to follow an exponential distribution and is 8% and 2% for 
fluconazole and caspofungin at 5 months respectively. Under such exponential models, the incidence of 
over 5 months is approximately even, about 1.6% per month for fluconazole and 0.4% per month for 
caspofungin.  
 
In this setting, we have a potential competing risk issue but its impact on estimating the risk for IFI 
should be minimal. We expect that majority of the censoring for IFI prior to the study completion are due 
to SCT or relapsed/refractory disease; the occurrence of such events are likely independent of the risk for 
IFI should the patient continue on the AML therapy, and can be considered true censoring events in the 
power consideration above. On the other hand, death prior to any other event constitutes a competing risk 
for IFI, but we expect such deaths to be rare and will not likely exceed 5% during the first 5 months; the 
impact that it has on estimating the risk of IFI by treating it as censored is minimal. Recently there have 
been some developments on sample size considerations under competing risk setting for either the 

 
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proportional cause-specific hazard model49 or proportional sub-distribution hazard model.50 However 
since the cumulative incidence of IFI under competing risk setting also involves the cause specific hazard 
of the competing risk, the interpretation of some of the planning parameters in these settings can be 
complicated and additional assumptions about the competing risk need to be made; it is also not yet well 
understood which model is better in different real settings. Given the fact that the true competing risk here 
is rare, we still use standard survival analyses for sample size considerations, but will perform competing 
risk analyses on the study data to ensure that it does not change the results of the comparison. 
 
9.3.4 Analysis Plans 
 
 
Descriptive Analyses 
Standard descriptive statistics will be used to describe subjects’ baseline characteristics and study 
outcome measures overall and within each treatment group. Summary statistics such as means, standard 
deviations, medians, and ranges will be produced for all measured variables. The balance of baseline 
measures across the treatment groups will be examined using appropriate two-sample tests. 
 
Analysis for Primary Objective and Secondary Clinical Objectives  
The primary analysis will be based on the principle of intention to treat (i.e., by the treatment assignment 
of patients at randomization, regardless of subsequent compliance with the assigned treatment). Most of 
the events that take patients off IFI follow up prematurely such as going to SCT, relapse/refractory 
disease, may be considered independent from the risk for IFI; therefore they may be considered as true 
censoring events. Death before any such censoring events is a competing risk for IFI; however since the 
chance of that happening will be rare, expected to be no more than 5%, the effect of competing risk by 
death as the first event should be minimal. Therefore, we will focus on standard survival analyses but will 
also perform competing risk analyses to check if the results change after we consider death as a 
competing risk. In standard survival analyses, patients who go off IFI follow up before developing IFI for 
any reason will be treated as being censored. We will use Kaplan-Meier analyses to evaluate time to any 
IFI and log rank test to assess if there is any benefit associated with caspofungin compared to fluconazole. 
For competing risk analyses, nonparametric estimate of the cumulative incidence function for IFI will 
then be calculated by treating death (if first event) or possibly death plus other events as competing risk 
for IFI; Gray’s test 51 will be used to compare the cumulative incidence function between the 2 arms.  
 
Similar standard survival analyses and competing risk analyses will be performed for secondary 
objectives 1-3 and the exploratory endpoint. For the secondary objective of time to development of 
invasive aspergillosis (IA), other IFI will also be considered a competing risk variable for IA in the 
competing risk analysis. For time to death (by any cause), only standard survival analyses will be 
performed. The total days of empiric antifungal therapy will also be compared between the 2 arms using 
t-test or Wilcoxon rank sum test. 
 
Analysis of GM and beta-D Glucan Assays 
Sensitivity, specificity, positive predictive value, and negative predictive value of the GM assay and beta-
D glucan assay will be determined using standard formulas and EORTC/MSG criteria as the gold 
standard. Please see Section 13.8 for additional statistical considerations for this secondary aim. 
 
SNP Analysis in Genes Involved in Immunity 
We will perform haplotype analysis using previously established methods for unrelated subjects.52,53 To 
deal with possible false positive or negative results, we will perform the following. First, in order to 
handle the concern of multiple testing, we will adjust the P value required for statistical significance by 
the false discovery rate, which is an approach to multiple testing that is a compromise between unadjusted 
tests of significance and more traditional, but too conservative Bonferonni adjustment.54 Second, to 
handle the potential for population stratification, all analyses will be performed with and without 
adjustment by ethnicity. We will use Kaplan-Meier analyses to evaluate time to any IFI, and determine 

 
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the impact of candidate gene SNPs using the log rank test. For the exploratory analysis on the relationship 
between IFI and the identified SNPs in the candidate genes, study participants will be grouped based on 
the genotype of specific SNP(s). If the primary analysis suggests no difference in IFI between 
caspofungin and fluconazole, standard log rank analysis will be used to compare the time to IFI between 
patient groups defined by the SNP(s); stratified log rank test adjusting for treatment arm will be 
considered if the data suggest a treatment difference on IFI between caspofungin and fluconazole. 
 
In developing a clinical prediction model for IFI, the outcome is time to IFI and the predictors can be 
demographic factors, clinical factors, co-morbid conditions, and SNPs. Standard survival analysis such as 
Cox model (or competing risk analyses modeling the cause-specific hazard or cumulative incidence 
function, if needed) will be used to build predictive models. Unlike an explanatory model, inclusion of 
variables into the predictive model will depend only on its ability to improve the prediction of the 
outcome and does not necessarily have to be based on biologic plausibility (although plausibility could 
make a prediction rule more accessible to clinicians). On the other hand, a clinically useful predictive 
model also needs to be practical in that the variables must be available in most clinical settings. We will 
take into account these factors in developing the predictive models, and internal cross-validation 
techniques will be considered in assessing the models. 
 
9.3.5 
Interim Monitoring 
Study data will be reviewed by DSMC twice a year during the first 2 years of study activation, and once a 
year thereafter upon their approval if the study goes smoothly. We plan two formal interim efficacy 
analyses comparing treatment outcomes between the 2 arms, after approximately one third and two thirds 
of the patients have completed study treatment and IFI observation. The endpoints for the interim 
analyses include time to the following individual event: IFI, invasive aspergillosis, death. Log rank test 
will be the primary method for these interim analyses; monitoring boundary for the primary endpoint on 
IFI will be based on Lan-Demet’s method with spending function αt.2,55 Competing risk analyses such as 
estimating the cumulative incidence of the event and Gray’s test for IFI or IA will be performed as well to 
check that corresponding competing risk analyses do not suggest a different conclusion than the standard 
survival analyses.  
 
Informal interim safety analyses will also be performed at each DSMC review on the observed adverse 
events between the 2 arms. This analysis will include all patients who receive at least one dose of study 
medication. The proportion of patients experiencing any grade 4 or higher non-hematological adverse 
event will be compared between the 2 groups using chi-square tests. For this monitoring, each test will be 
at two-sided level of 0.05 without adjustment for multiple testing, to ensure us being alerted by any 
potential difference in adverse events between the 2 arms. If a significant difference between the 2 arms is 
found (p<0.05), the study committee will examine the adverse event profiles for safety considerations and 
decide if any action needs to be taken. 

 
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9.4 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
  Total 
Hispanic or Latino 
58 
52 
110 
Not Hispanic or Latino 
226 
239 
465 
Ethnic Category: Total of all 
subjects 
284 
291 
*575 
Racial Category 
 
American Indian or Alaskan Native 
2 
1 
3 
Asian 
17 
14 
31 
Black or African American 
39 
34 
73 
Native Hawaiian or other Pacific 
Islander 
0 
1 
1 
White 
226 
241 
467 
Racial Category: Total of all 
subjects 
284 
291 
*575 
 
 
 
 
* These totals must agree. 
 
This distribution was derived from AAML0531 and AAML00P2. 
 

 
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10.0 
EVALUATION CRITERIA  
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4 of the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the CTCAE version 4 can be downloaded from the NCI website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Additionally, toxicities are 
to be reported on the appropriate case report forms. 
 
10.2 
IFI Checklist and Central Review 
Institutions will be provided with case report forms to complete which will help to identify whether patients had IFI 
(IFI checklist). Biopsy and imaging reports are requested rather than report interpretation in order to minimize the 
work load for sites. An independent data review committee including infectious disease and oncology 
experts who are unaware of treatment assignments will review and classify all cases of proven/probable 
IFI by EORTC/MSG.48  
 
 
The following materials in the IFI checklist will be submitted (via the Document Imaging System:  
(626) 447-2204) at the end of each course of protocol therapy, only if they were performed to investigate 
an IFI according to local physician discretion: 
 
Pathology reports (including autopsy reports),  
 
CT scan and MRI reports,  
 
Fungal Gram stain and microbiology culture results (including both positive and negative results),  
 
Non-culture mycology testing results (i.e. Histoplasma urine antigens, cryptococcal CSF and 
serum antigens),  
 
Ophthalmology exams (even if evidence of fungi not seen), and 
 
Bronchoscopy reports (even if evidence of fungi not seen).  
 
In addition, dosing and duration of steroid exposure will be collected and entered via eRDE. All reviewers 
will be blinded to the patient’s antifungal exposures in order to limit any bias in determining the primary 
and secondary endpoints.  
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents.  
 

 
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11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of the adverse 
event including the grade (severity); 2) the relationship to the study therapy (attribution); and 3) the prior 
experience (expectedness) of the adverse event. 
  
Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source. In some cases an agent obtained commercially may be used for indications not included in the 
package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even in 
these cases, the agent is still considered to be a commercial agent and the procedures described below 
should be followed. 
 
Determine the prior experience Expected events are those that have been previously identified as resulting 
from administration of the agent. An adverse event is considered unexpected, for reporting purposes only, 
when either the type of event or the severity of the event is not listed in:  
 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group posted on 
the COG website; or 
 
the drug package insert. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment with 
investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial neoplasm is not 
considered a secondary malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via CTEP-AERS. Three 
options are available to describe the event:  
 
Leukemia secondary to oncology chemotherapy   
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy 
 
11.3 
Reporting of Adverse Events for Commercial Agents - via CTEP-AERS 
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited Reporting System), 
accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used in this study 
are listed in the front of this protocol immediately following the Study Committee roster.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE reporting 
and are located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All appropriate treatment 
areas should have access to a copy of the CTCAE. 
 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who have NOT 
received any doses of an investigational agent on this study. 
 

 
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CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy 
With a Commercial Agent or Within 30 Days1 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution. Any death that occurs more 
than 30 days after the last dose of treatment with a commercial agent which 
can be attributed (possibly, probably, or definitely) to the agent and is not 
due to cancer recurrence must be reported via CTEP-AERS 
 
11.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on the COG case 
report forms and do not affect the requirements for CTEP-AERS reporting. 
 
The NCI defines both routine and expedited AE reporting. Routine reporting is accomplished via the 
Adverse Event (AE) Case Report Form (CRF) within the study database. For this study, routine reporting 
will include all toxicities reported via CTEP-AERS and all Grade 4 and higher non-hematological 
Adverse Events. 
 
 
 
12.0 
RECORDS AND REPORTING 
 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will 
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and 
October 31. This is not a responsibility of institutions participating in this trial. 
 

 
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13.0 
PROSPECTIVE EVALUATION OF GALACTOMANNAN AND (1→3) BETA-D 
GLUCAN ASSAYS AS DIAGNOSTIC TOOLS FOR INVASIVE FUNGAL INFECTION IN 
CHILDREN WITH ACUTE MYELOID LEUKEMIA RECEIVING FUNGAL PROPHYLAXIS. 
 
13.1 
Sample Collection and Testing Procedures (These studies are optional) 
 
13.1.1  Sample submission 
At the time of enrollment, if a new patient has consented to the optional galactomannan and beta-D 
glucan study, a sample collection kit will be automatically express delivered to the treating institution. If 
the kit is not received within 48 hours of enrollment, please contact Patti Connolly at MiraVista (317-856-
2681 x451) as soon as possible to prevent any further delays. The kit contains special vials that are 
mandatory for specimen collection. Alternative specimen vials should never be used as they may 
contribute to false results.  
 
13.1.2 Sample Collection  
Whole blood samples will be collected twice weekly during the period of neutropenia (until ANC > 100-
500/µL). It is suggested that specimens be obtained on Mondays and Thursdays but other days are 
acceptable if more convenient. A minimum of 2 days should separate each specimen collection.  
 
In order to perform both assays on a single specimen (Platelia™ Aspergillus EIA and Fungitell® beta-D 
glucan assay), collect 5 mL of whole blood in a gold top serum-separator tube (provided by MiraVista) 
and label with the site number, COG ID number, and date (labels will be provided with the sample 
shipping kit). Although the above volume of blood testing will likely represent a small fraction of the 
blood testing performed during the period of 1 week, it may result in an important increase in certain 
patients (i.e., smaller children or anemic children). Therefore, we have set the following maximum limits 
per kilogram for blood draws related to this ancillary study: 3 mL of blood/kg body weight in an 8 week 
period. 
 
13.1.3 Specimen processing  
Each specimen should be processed as follows prior to shipping: 
1. Allow the blood to clot for 30-60 minutes at room temperature. 
2. Centrifuge the specimen for 15 minutes at 1,000 – 1,300 x g. 
3. Remove the serum from the clot and place it into the provided polypropylene storage tube 
and label the tube. 
4. A total minimum volume of 2 mL of serum is required to run the Platelia™ Aspergillus EIA 
and Fungitell® beta-D glucan assay. 
 
 
13.1.4 Storing specimens 
1. Specimens should be frozen at -70°C the day of collection after following the above 
processing steps. 
2. Specimens can be stored at -70°C until shipment. Specimens stored at -70°C may be stored 
indefinitely. 
 

 
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13.1.5 Shipping of specimens: 
Each center will use shipping kits provided by MiraVista Diagnostics. These kits contain Styrofoam lined 
boxes, sealing tape, labels, and a cold pack. The boxes are designed to hold 10 frozen serum specimens. 
In order to optimize efficiency, a box should not be sent until 10 specimens have been collected.  
 
 
Requisitions: 
1. Complete an ACCL0933 GM & BG Requisition Form for each specimen sent for testing. 
All areas of the requisition form must be completed. 
 
Packaging: 
1. Assure all specimen labels and packaging labels are correct and legible. Please use 
the labels provided in the kits as they are designed to withstand specimen freezing 
and thawing without disruption of the written patient identification information. A 
Sharpie marker is most effective for writing on these labels. 
2. Place the labeled vials containing the patient serum into a biohazard plastic bag along 
with absorbent material such as gauze or paper towel and seal. Use the biohazard 
plastic bags provided in the kit.  
3. Ship specimens in the boxes provided along with the cold pack that should be frozen.  
4. Open the box and remove the Styrofoam liner lid and the sealing tape. 
5. Place the frozen cold pack into the liner. The frozen cold pack will ensure specimen 
integrity during overnight shipment. 
6. Place the biohazard plastic bag containing the requisition forms and specimens 
directly on top of the frozen cold pack. 
7. Replace the Styrofoam liner lid. 
8. Complete an ACCL0933 GM & BG Requisition Form for each specimen and place 
them on top of the liner before sealing the box. 
9. Wet the sealing tape provided in the kit and seal the cardboard box. 
10. If the specimen tube labels and requisition forms do not match when received at 
MiraVista Diagnostics, a call will be made to the study site on the day of receipt. 
 
Shipping Instructions: 
1. Ship packages to the following address: 
 
MiraVista Diagnostics 
4705 Decatur Blvd. 
Indianapolis, IN  46241 
317-856-2681 
 
2. Use the FedEx website (www.fedex.com) to learn the current guidelines for the shipping 
of human body fluids and generating shipping labels. 
3. Generate a label via the FedEx website and schedule a pick up (use the MiraVista FedEx 
account provided). 
4. Affix the FedEx label to the top of the box. 
5. Ship all packages Priority Overnight via FedEx to arrive at MiraVista Diagnostics by 
10:30 AM the next morning. 
6. Do not ship on a Friday, Saturday, or the day before a holiday. MiraVista is closed each 
weekend and on holidays. 

 
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13.1.6 Testing of specimens: 
1. Testing of serum specimens for this study will be performed in batches. 
a. Negative results are final. 
b. Positive results are retested on the next work day for confirmation. 
2. Testing will not occur under the following conditions: 
a. The specimen has been stored under unacceptable storage times and/or temperatures. 
b. The specimen has been shipped under unacceptable time and/or temperature 
conditions.  
c. The specimen volume is less than needed to complete the testing process.  
d. The specimen cannot be pipetted due to viscosity. 
e. The specimen is hemolyzed or icteric for Fungitell®. 
f. The specimen is of a type other than serum separated off the clot. 
3. Platelia™ Aspergillus EIA results are reported as a GM index. 
4. Fungitell® beta-D glucan assay results are reported as pg/mL. 
 
 
13.1.7 MiraVista Contact Information 
 
Technical Assistance: Patti Connolly  
317-856-2681 x451 
 
Medical Director: 
Joseph Wheat, M.D. 
317-856-2681 x452 
 
13.1.8 Galactomannan and Beta-D glucan Assays 
Testing will be performed by technicians blinded to each patient’s clinical information. Test results will 
not be made available to treating physicians since the utility of these tests is not yet established in 
children and because we will not be conducting testing in real time. Thus, results will not be utilized 
for clinical decision-making. 
 
To our knowledge BG testing is not routinely performed at many pediatric centers but may be performed 
at some of the COG sites while GM testing is currently performed at a number of pediatric centers. 
Regardless of the number of institutions offering such testing options, we anticipate that such testing will 
be ordered by a subset of treating physicians. The local BG and GM results will not be included in our 
final analysis of the 2 biomarker assays’ operating characteristics. However, these results may effect a 
change from fungal prophylaxis to preemptive or empiric therapy and may encourage or discourage more 
comprehensive efforts to diagnose a proven or probable IFI in any given patient. This in turn may falsely 
influence our evaluation of the 2 biomarker assays’ operating characteristics. For each patient we will 
identify whether local BG or GM testing has been performed and, via a sensitivity analysis, explore 
whether such a practice influences the operating characteristics. The plans for this sensitivity analysis are 
described in more detail in Section 13.8.4 below.  
 
The Platelia Aspergillus EIA study is reported as a GM index. We will use the FDA-approved threshold 
of ≥ 0.5 GM index on a single test sample as our criteria for a positive test result. The Fungitell Assay is 
reported in pg per mL of patient’s serum. The manufacturer recommendation for a single positive 
Fungitell assay result of > 80 pg/mL will be used to define a positive test. 

 
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13.2 
Background 
 
13.2.1 Changing approach to antifungal therapy in pediatric AML patients 
Various strategies for starting antifungal therapy in patients with cancer exist and include56 : 
 
1. Prophylaxis: Initiation of antifungal therapy in asymptomatic patients without any evidence 
of IFI, during periods of high risk such as during prolonged neutropenia resulting from 
chemotherapy or bone marrow transplant. 
2. Empirical antifungal therapy: Initiation or modification of antifungal therapy after persistence 
of fever in the setting of neutropenia and broad-spectrum antibiotics. 
3. Preemptive therapy: Use of radiographic and/or specific biomarkers to identify and treat 
suspected IFI prior to overt clinical presentation. 
4. Therapy for proven, probable or presumed IFI: Therapy initiated for the treatment of proven 
or probable IFI based on EORTC/MSG criteria or based on clinical presumption of IFI. 
 
The significant morbidity and mortality associated with IFI among patients with AML has led many 
clinicians to adopt a strategy that includes antifungal prophylaxis during periods of neutropenia.19 
Retrospective evaluation of neutropenic children receiving fungal prophylaxis with fluconazole or 
micafungin suggested a reduction in the risk for IFI.57,58 The ideal antifungal agent for such prophylaxis in 
children is not known and will be addressed in the primary aim of this study. Regardless of the specific 
antifungal agent, it is likely that prophylaxis will be successful and be integrated as the standard of care 
for all future pediatric AML therapy. Despite a reduction in IFI, prophylaxis will not eliminate all such 
infections. In patients with breakthrough infections on prophylactic therapy, early suspicion for IFI and 
modification of antifungal therapy will still be paramount to improving patient outcomes. 
 
Unfortunately, the current approach for risk stratification of IFI (persistence of fever for > 5 days on 
broad spectrum antibiotics) may be less than ideal in populations at high risk for IFI.56 The clinical 
presentation at the start of an IFI can range from completely asymptomatic, to fever without localizing 
signs or symptoms, to clinical sepsis. This is illustrated by a randomized trial of empiric caspofungin vs. 
liposomal amphotericin B. Patients were excluded from this study if they had a current documented IFI. 
Despite this, 4.9% of subjects were ultimately identified as having proven or probable IFI at baseline prior 
to initiating the antifungal treatment.26 Therefore, relying on traditional methods to guide empiric 
antifungal modifications would result in over-treating some patients with low likelihood of IFI and a 
failure to modify therapy in other patients that have an underlying IFI. A preemptive therapeutic approach 
that utilizes screening diagnostic studies to identify patients likely to have an IFI at the earliest possible 
point may be more rational and successful.  
 
13.2.2  
Traditional diagnostic studies to identify patients with suspected IFI 
Traditional diagnostic modalities for IFI are limited to radiologic imaging and blood or tissue culture 
techniques. Radiologic studies may show visceral involvement but an invasive biopsy procedure is 
necessary to differentiate between a fungal or non-fungal infectious process. Although blood cultures may 
be used to isolate Candida spp. during candidemia, they are not helpful in the setting of invasive 
candidiasis without fungemia. Furthermore, traditional blood cultures are not typically successful at 
isolating mold infections such as Aspergillus. Cultures of tissue specimens can be definitive but require 
invasive techniques for sample procurement.  

 
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13.2.3  
Galactomannan and Beta-D Glucan Assays 
Alternative non-invasive approaches involve serial evaluation of a patient’s serum for the presence of 
galactomannan (GM) or beta-D glucan (BG). The former is present in Aspergillus spp. while the latter is 
present in a vast majority of pathogenic fungi.59,60 Two validated FDA approved antigen detection assays, 
The Platelia Aspergillus EIA and the Fungitell Assay, currently exist for the detection of GM and BG, 
respectively. 
 
13.2.3.1 
The Platelia Aspergillus EIA and Fungitell Assay in Adults 
The Platelia Aspergillus EIA is a commercially available kit from Bio-Rad Laboratories that utilizes an 
EB-A2 monoclonal antibody and sandwich technique for detection of GM. In 2003, the assay received 
FDA approval for use in adults after it was prospectively validated in a cohort of immunosuppressed 
patients.61 This cohort included patients aged 16 years or older with various leukemias, lymphomas or 
those undergoing stem cell transplants. Twice a week testing was performed in 362 separate 
hospitalizations. Criteria for proven or probable invasive aspergillosis (IA) developed by the 
EORTC/MSG were used as the gold standard. This testing strategy resulted in 72.9% sensitivity, 94.7% 
specificity, 61.3% positive predictive value (PPV), and 96.8% negative predictive value (NPV) for 
detection of IA. Detection of GM preceded the time of definitive IA diagnosis in 96% of the proven IA 
cases by a median of 17 days. Two separate meta-analyses have since been performed which support the 
usefulness of GM screening in adults.34,62  
 
The Fungitell Assay (formerly Glucatell) is a commercially available kit from the Associates of Cape 
Cod, Inc. for the identification of BG in the serum of patients with IFI. This assay received FDA approval 
in May of 2004 to assist in the diagnosis of IFI. The operating characteristics of the assay have been 
elucidated in multiple adult cohorts. The first included adult patients with newly diagnosed AML or 
myelodysplastic syndrome undergoing initial Induction chemotherapy and receiving fungal prophylaxis 
with either caspofungin or itraconazole.63 The Fungitell Assay was performed in 283 patients twice a 
week for the duration of neutropenia resulting in sensitivity, specificity, PPV and NPV for diagnosing 
proven or probable IFI of 100%, 90%, 43%, and 100%, respectively. More importantly, a positive 
Fungitell Assay result was identified at a median of 10 days prior to the clinical diagnosis of IFI in this 
cohort. 
 
The second study evaluated 95 adult patients with fever and neutropenia down to 16 years of age. Thirty-
eight patients with proven, probable or possible IFI were identified. The resultant sensitivity, specificity, 
PPV and NPV were 97.4%, 28.6%, 55.2%, and 92.3% respectively. The specificity reported was reduced 
as compared to results from the prior publication as they included possible as well as probable and proven 
cases of IFI. Positive Fungitell Assay results preceded clinical diagnosis of IFI by a median of 5 days.64  
 
13.2.3.2 
The Platelia Aspergillus EIA and Fungitell Assay in Children 
Multiple cohort studies have reported the operating characteristics of GM assay testing in pediatric 
patients undergoing therapy for acute leukemias or bone marrow transplantation35,65-67 (see Table 1). A 
number of these studies documented a 100% sensitivity of the GM assay including the study with the 
largest pediatric patient population.66One study with fewer total patients did not reveal high sensitivity for 
GM assay testing but this study was limited as it only included one identified case of IA.35 None of these 
studies included patients on routine antifungal prophylaxis and thus the results cannot be extrapolated to 
our patient population.  
 
Only one study evaluating BG levels in children has been performed. This study was limited to healthy 
children and revealed elevated baseline levels of BG in a subset of the patients.68 To date, the Fungitell 
Assay testing has never been performed in immunocompromised pediatric patients. 

 
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Table 1. Operating characteristics of Galactomannan testing for diagnosis of proven or probable 
aspergillosis in pediatric patients 
Author, Year 
Total # 
patients 
in study 
Proven or 
probable 
aspergillosis 
Sensitivity 
Specificity 
TP 
FP 
TN 
FN 
Steinbach, 2007  
64 
1 
0% 
87% 
0 
8 
55 
1 
Hovi, 2007  
89 
1 
100% 
93% 
1 
6 
82 
0 
Sulaihan, 2001  
347 
9 
100% 
89.9% 
9 
34 
304 
0 
Rohrlich, 1996  
37 
10 
100% 
92.6% 
10 
2 
25 
0 
 
13.2.4 Gaps in knowledge 
The Platelia Aspergillus EIA and the Fungitell Assay have each shown reassuring operating 
characteristics in adults making these biomarkers an attractive option for screening for IFI in children. 
More importantly, the 2 diagnostic tests afford the possibility of identifying an IFI days to weeks before 
the clinical diagnosis is made. However, it is not reasonable to extrapolate results from these adult studies 
to children. There is an absence of data regarding the operating characteristics of either biomarker in large 
homogeneous cohorts of children with leukemia.  
 
Additionally, no data exist on either biomarker in a cohort of pediatric patients receiving antifungal 
prophylaxis. The use of prophylactic anti-fungal therapy will likely reduce the incidence of IFI or 
suppress actual IFI and thus potentially alter the predictive values of these biomarkers. As noted above, 
the use of prophylactic therapy will likely become standard of care and therefore it is imperative to define 
the operating characteristics of these biomarkers in such a population. 
 
Lastly, it may be optimal to consider the results of each biomarker in combination as opposed to 
evaluating the impact of each study independently. The simultaneous interpretation of both Platelia 
Aspergillus EIA and the Fungitell Assay for the identification of IFI in children has never been 
evaluated. It is plausible that interpreting the 2 biomarkers in combination would improve the sensitivity 
of detecting an IFI. 
 
13.2.5 Summary 
Currently, the decision to start empiric antifungal therapy in pediatric patients with neutropenia in the 
setting of AML is based on the persistence of fever despite a number of days of broad spectrum 
antibiotics. This approach is rudimentary and likely not particularly sensitive for the presence of an IFI. 
Maartens et al,69 identified afebrile and asymptomatic adults with IFI, emphasizing the need for better 
diagnostic studies and abandoning the use of persistent or new fever as the only trigger for antifungal 
modification. The availability of the Platelia Aspergillus EIA and the Fungitell Assay offer an opportunity 
to more accurately stratify pediatric patients for their risk for breakthrough IFI while on antifungal 
prophylaxis. Adult trial data for both of these assays are encouraging as they are almost always correct 
when the results are negative (i.e., high NPV) and maintain a reasonable sensitivity for presence of IFI 
(i.e., high sensitivity). Certainly, they may be at risk for false positive results (i.e., low PPV) which could 
result in unnecessarily treating patients without an IFI. Despite this potential for overtreatment it is still 
likely more desirable to have such results guide empiric antifungal decisions as opposed to the limited 
current practice of persistent fever and neutropenia.  
 
However, before we can employ these biomarker assays as guides for initiating or escalating to empiric 
antifungal therapy in children we must better define their operating characteristics in the same population. 
The parent study cohort provides a one time opportunity to evaluate the operating characteristics of both 
of these tests in the setting of 2 different antifungal prophylaxis agents in a homogeneous cohort of 
pediatric AML patients. The choice of which antifungal agent to use for future trials will likely be 

 
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determined by the results of this study. Knowledge of the operating characteristics of each biomarker 
interpreted separately and in combination under these study conditions is necessary to inform their 
potential utility as integral markers to guide empiric antifungal choices for future AML patients. 
 
 
13.3 
Specific Aims 
 
Primary Aim: 
i) 
To define the operating characteristics of 2 fungal antigen assays, Platelia Aspergillus EIA and 
Fungitell Assay for the identification of IA only and all IFI among pediatric AML patients 
receiving antifungal prophylaxis. This primary aim will have 3 sub-aims: 
 
a) 
Define the test characteristics using a combination of the results from the Platelia Aspergillus EIA 
and Fungitell Assay for identifying IA only and all IFI. 
Hypothesis: A positive Platelia Aspergillus EIA or positive Fungitell Assay will be more 
sensitive at identifying patients with IA only or with IFI while on antifungal prophylaxis as 
compared to either test alone. 
b) 
Define the test characteristics of the Fungitell Assay for identifying all IFI. 
Hypothesis: A single positive Fungitell Assay will have > 90% sensitivity in identifying all IFI in 
pediatric AML patients on antifungal prophylaxis. 
c) 
Define the test characteristics of Platelia Aspergillus EIA for identifying IA only. 
Hypothesis: A single positive Platelia Aspergillus EIA will have > 90% sensitivity in identifying 
IA only in pediatric AML patients on antifungal prophylaxis. 
 
13.4 
Patient Accrual  
All patients enrolled on ACCL0933 will be offered the chance to participate in the anti-fungal screening 
study. We anticipate that at least 80% of the patients in the parent trial will enroll in this ancillary study 
resulting in an estimated 440 patients at baseline. Those who consent will undergo Platelia Aspergillus 
EIA and Fungitell Assay testing. Blood sampling will be conducted twice weekly during anti-fungal 
prophylaxis treatment after each course of chemotherapy.  
 
Each patient will have the potential for multiple courses of chemotherapy with each course having 
variable durations of neutropenia. Based on data from the AAML0531 trial, we have estimated the 
number of patients progressing from the first course of chemotherapy through the fourth course of therapy 
as well as duration of neutropenia for each course (see Table 2). Given a planned frequency of biomarker 
testing of twice per week, estimates of the number of Platelia Aspergillus EIA and Fungitell Assays 
performed during each chemotherapy course are provided (see Table 2).  
 
Table 2. Estimated number of Platelia Aspergillus EIA and Fungitell Assay performed per course. 
Chemotherapy 
course 
Estimated Duration of 
neutropenia* (days) 
# of testing time 
points for 1 patient 
during neutropenia! 
Platelia EIA 
Fungitell 
Assay 
I (n=440) 
20 
6 
2640 
2640 
II (n=380) 
18 
5 
1900 
1900 
III (n=337) 
17 
5 
1685 
1685 
IV (n=216) 
28 
8 
1728 
1728 
Total 
- 
- 
7953 
7953 
*Based on median duration of neutropenia for each course from AAML0531 trial 
! Based on a plan for 2 tests per week during neutropenic period 

 
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13.5 
Gold Standards for IFI and IA Infections 
The criteria established by the EORTC/MSG for proven or probable IFI and proven or probable IA will 
be used as the gold standard.48 These definitions have been used as the primary endpoints for prior studies 
validating Platelia Aspergillus EIA and the Fungitell Assay. 
 
13.6 
Methodology to Identify IFI and IA 
The EORTC/MSG guidelines incorporate clinical, microbiologic, histopathologic, and radiographic data 
for classification of proven or probable IFI or IA. Therefore, in order to establish these diagnoses, the 
following data will be obtained (according to the IFI checklist (Section 10.2): pathology reports 
(including autopsy reports), CT scan and MRI reports, fungal gram stain and microbiology culture results, 
non-culture mycology testing results (i.e. histoplasma urine antigens, cryptococcal CSF and serum 
antigens), ophthalmology exams, and bronchoscopy reports. An independent data review committee 
including infectious disease and oncology experts who are unaware of treatment assignments will review 
and classify all cases of fungal infection according to the consensus criteria of the EORTC/MSG. 
 
13.6.1 Justification of Methodologic Choices  
 
13.6.1.1 Justification for Chosen Thresholds for Platelia Aspergillus EIA and Fungitell Assay 
IFI outcomes are often devastating, thus it would be desirable to optimize sensitivity at the potential 
expense of specificity. Furthermore, a highly sensitive test will likely result in a high negative predictive 
value. Clinicians caring for patients with positive tests would then have a heightened concern for IFI 
while a negative test result would reassure them that no further modifications to antifungal therapy are 
necessary at that time. It was with these intentions that the following threshold values were chosen to 
conclude negative and positive results for each biomarker. 
 
The level of ≥ 0.5 GM index for Platelia Aspergillus EIA will be the established threshold to determine a 
positive result. This is the level that was established for FDA approval during testing in adults. The 
operating characteristics of this test have been evaluated in pediatric and adult patients using various 
cutoffs ranging from 0.5 to 1.5 as well as using single and consecutive positive results. Increasing the 
threshold level and requiring multiple consecutive positive results often reduced the sensitivity while 
optimizing specificity. As noted above, our goal is to optimize sensitivity and negative predictive value, at 
the risk of lower specificity and positive predictive value. Therefore, the lower threshold of ≥ 0.5 on a 
single test was chosen. 
 
The Fungitell Assay threshold result of ≥ 80 pg/mL was chosen based on manufacturer recommendations 
and available data. For two adult studies that evaluated this test, the cut-off for a positive test was lowered 
to > 60 pg/mL.63,64 Lowering of the manufacturer threshold in these two studies resulted in high 
sensitivity which would be consistent with the goals of our study. However, analysis of BG levels in 120 
healthy children revealed that 22% of them had BG levels greater than 60 pg/mL.68 Although this level 
would optimize sensitivity, the likelihood for false positivity is too high. There were still 15% of healthy 
children in this study that had a level of ≥ 80 pg/mL. This suggests that even at a level of ≥ 80 pg/mL, 
sensitivity of this assay in children would be preserved. Therefore, the manufacturer threshold of 
≥ 80 pg/mL was chosen. For both biomarker assays, a post hoc analysis of various cutoffs as well as 
assessment of sequential positive testing will be performed in an attempt to identify the most ideal cut-off 
for future use of this assay as an integral biomarker (please see statistical analysis below). 
 
13.6.1.2 Justification for IFI Gold Standard 
We have chosen to use EORTC/MSG defined proven or probable IA or IFI (Appendix II) as the gold 
standard. The ideal gold standard to compare to each biomarker would be a positive culture of a fungal 
organism from blood or infected tissue. However, there are significant challenges to establish the 
presence of fungal infection with isolation of the etiologic organism. Certain molds such as Aspergillus 

 
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do not grow routinely in blood cultures, the ability to obtain tissue for culture can be impacted by the size 
and location of a visceral lesion, and the clinical status of a patient may preclude invasive procedures to 
obtain cultures. Therefore, an alternate endpoint to identify all patients who truly have IFI is necessary. 
This issue has been addressed by the EORTC/MSG. This group of experts initially created criteria based 
on clinical, radiographic and culture data to define possible, probable and proven IFI in 2002 and revised 
these criteria in 2009.48,70 These criteria have served as the primary endpoint for major trials of antifungal 
drug efficacy, in strategy trials, for formulating clinical practice guidelines, as well as for undertaking 
epidemiologic studies. Consistent use of these criteria as the primary endpoint will allow for comparison 
of the resultant data to prior and future studies. 
 
13.7 
Factors resulting in False Positive Results 
A number of medications, medical interventions, and infections have been suggested as possible causes of 
false positive results for BG and GM testing.59,60,71 Table 3 lists the potential causes of false positive 
results reported in the literature. It is anticipated that patients being treated for AML will have reason to 
be exposed to a number of these medications, infusions and/or medical interventions. Additionally, 
Pneumocystis jiroveci infection is also considered a cause of a “false positive” BG test. Technically this is 
not a true false positive as the Fungitell Assay is detecting BG from the cell wall of Pneumocystis jiroveci 
as it would for other fungal infections. However, in this instance it is considered a false positive as the 
treatment of choice for this infection is trimethoprim-sulfamethoxazole as opposed to a typical anti-fungal 
agent. A sensitivity analysis (as described in Section 13.8.4 below) will be performed to investigate the 
impact of these false positive rates on the operating characteristics of the 2 biomarkers. 
 
 
Table 3. Potential factors resulting in false positive testing for (1→3) beta-D glucan and GM assays 
 
 
 
 
13.8 
Statistical Design 
 
13.8.1 Sample Size and Estimated Event Rates 
The parent trial comparing prophylaxis with caspofungin to fluconazole in newly diagnosed AML 
patients anticipates enrollment of at least 275 patients for each arm with a total cohort of approximately 
550 patients. As noted above we anticipate that at least 80% of the patients enrolled in the parent trial will 
also be enrolled in this ancillary study. This will result in 220 patients from each study arm. Consent for 
testing will be included as a part of the parent trial enrollment, thus significantly limiting the need for 
additional resources to complete this biomarker study.  
Factor 
(1→3) Beta-D Glucan Assay 
Galactomannan EIA Assays 
Medications 
Amoxicillin-clavulanate 
 
*Piperacillin-Tazobactam  
*Amoxicillin-clavulanate 
Infusions 
 
*Intravenous immune globulin 
*Cellulose filters for IV infusion 
*Albumin 
*Plasmalyte (electrolyte infusion) 
*Intravenous solution with sodium 
gluconate 
Medical interventions 
*Hemodialysis with cellulose filter 
*Gauze packing on serosal surfaces 
 
*Enteral feeding with soybean 
proteins 
Other infections 
*Pneumocystis jiroveci 
*Penicillium spp. 
*Histoplasma capsulatum 
*Geotrichum 
*Neosartoria 

 
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The estimated number of probable or proven IFI events for final analyses will be different for both 
proposed biomarkers as they account for different types of fungal infections and the incidence for each 
will vary by study arm. The Fungitell Assay has the potential to identify most pathogenic fungi and thus a 
majority of the probable or proven IFIs will be considered as true events (excluding IFIs form 
Zygomycetes and Cryptococci). The Platelia Aspergillus EIA is specific for Aspergillus and thus only 
probable or proven IA will be considered as true events for that analysis.  
 
Based on Section 9.3.3 of the parent trial the estimated incidence of IFI for patients in the fluconazole 
group is 8% and 2% in the caspofungin arm. Assuming the enrollment of 220 patients in each study arm, 
there would 18 IFI events in the fluconazole group and 4 IFI events in the caspofungin group. Based on 
data from the CCG 2961 AML trial, one-third of microbiologically proven fungal infection were the 
result of Aspergillus. Therefore, it is estimated that 6 of the 18 IFI events in the fluconazole group will be 
IA and between 1 and 2 of the IFI events in the caspofungin group will be IA.  
 
13.8.2 Sensitivity, Specificity, PPV, and NPV 
The validity of a biomarker is based on whether the study appropriately categorizes patients with and 
without the illness in question (sensitivity and specificity). Alternatively the validity of a test can be 
measured by how well the test results predict the presence or absence of the disease (PPV and NPV). 
Collectively, sensitivity, specificity, PPV, and NPV are often referred to as the test’s operating 
characteristics with the sensitivity and NPV being the most clinically relevant parameters for this study. 
Each component of the operating characteristics will be calculated based first on the entire cohort. As 
indicated in the sample size estimates above the incidence of IFI will vary between the two study arms. It 
is well documented that variations in the incidence/prevalence of a disease will impact the operating 
characteristics of a diagnostic test specifically for the PPV and NPV. Therefore, each assay’s sensitivity, 
specificity, PPV and NPV will also be calculated separately for each study arm.  
 
The operating characteristics for both the Platelia Aspergillus EIA and the Fungitell Assay will be 
computed at the patient level for each of the sub-aims as follows: 
 
a) 
Outcome of IA only or all IFI defined as a single positive test for either the Platelia Aspergillus 
EIA or the Fungitell Assay as compared to the EORTC/MSG criteria for proven or probable IA 
only or all IFI. 
 
b) 
Outcome of IA only defined as a single positive test for Platelia Aspergillus EIA only as 
compared to the EORTC/MSG criteria for proven or probable IA only. 
 
c) 
Outcome of all IFI defined as a single positive test for the Fungitell Assay as compared to the 
EORTC/MSG criteria for all proven or probable IFI. 
  
Sensitivity, specificity, PPV and NPV and their accompanying 95% confidence intervals will be 
calculated using STATA statistical software version 11.0 (College Station, TX). As noted above, these 
parameters will first be calculated for the entire cohort and then for each study arm separately. The latter 
analyses are important as the incidence of IFI may vary by study arm thus impacting the interpretation of 
the assay results. A patient with multiple episodes of IFI will only be included in the analyses as a single 
IFI. 
 
13.8.3 Receiver Operator Characteristics Curve  
In addition to understanding the operating characteristics of a diagnostic test at a single defined threshold, 
it is also important to understand how variations in the test’s threshold can alter the test’s operating 
characteristics. The receiver operating characteristics (ROC) curve is a useful approach to illustrate how 
these operating characteristics will change as the threshold changes. Therefore, a receiver-operating-

 
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characteristics (ROC) curve will be generated with a series of sensitivities and specificities derived from 
various cutoff values. For the Platelia Aspergillus EIA cutoffs of > 0.5, 1.0, 1.5 and 2.0 will be used. For 
the Fungitell Assay cutoffs of ≥ 40, ≥ 60, ≥ 80, and ≥ 100 pg/mL will be used to create the ROC. The 
ROC curve will be displayed graphically (sensitivity vs. 1-specificity) and evaluated numerically 
(c-statistic). The c-statistic (also referred to as the area under the curve (AUC)) varies from 0.5 to 1.0 and 
is a measure of the test’s ability to discriminate between patients with and without the gold standard 
diagnosis.72 A c-statistic of 0.5 is possible by chance alone while a perfectly discriminating test will result 
in a c-statistic of 1.0. 
 
Additionally, the ROC curves will be used in an exploratory analysis to identify the threshold for each 
biomarker assay that optimizes the diagnostic test’s sensitivity while maintaining a reasonable specificity. 
The identified thresholds will be used to categorize each patient as “likely to have IFI or IA” and “not 
likely to have IFI or IA”. Once these 2 sub-groups are defined we will calculate the incidence rates of IFI 
or IA for each sub-group and compare them. Because the anticipated incidence for IFI and IA may be 
variable between the two study arms (those receiving fluconazole and those receiving caspofungin) this 
approach will have to be done at the level of each study arm. The incidence rates will be compared 
statistically using Pearson’s Chi-square analysis. 
 
Finally, to further explore the ideal utility and interpretation of each biomarker, serial testing results will 
be explored. For this analysis the Platelia Aspergillus EIA will be considered positive when a patient has 
2 consecutive tests > 0.5 GM index and the Fungitell Assay will be considered positive when a patient has 
2 consecutive test results ≥ 80 pg/mL. Operating characteristics and ROC curves will be constructed in a 
similar manner as discussed above. 
 
13.8.4 Sensitivity Analysis 
Sensitivity analyses will be explored for reasoning expressed in both Sections 13.1 and 13.7 above. The 
first sensitivity analysis will attempt to identify the direction and magnitude of the bias resulting from the 
availability of clinical BG and GM testing outside of the ancillary study. Such testing has the potential to 
change the treating clinician’s approach for diagnosing an IFI. It is possible that these test results could 
result in more or less investigation (i.e., radiologic imaging) to identify an IFI which could ultimately 
impact on the incidence of identified IFI. Therefore, in addition to calculating the operating characteristics 
for all patients enrolled as described in Section 13.8.2 above, the same operating characteristics will be 
calculated after excluding all patients that had at least 1 biomarker test result available to the treating 
clinician.  
 
The second sensitivity analysis will be performed to explore the impact of the various factors described in 
Section 13.7 that may contribute to a positive result for either biomarker. False positive results would 
impact the final interpretation of sensitivity and PPV for each of the assays. However, it is also possible 
that one of the factors listed in Table 3 is present in a patient that truly has an IFI. Therefore, we plan to 
still include all patients in the primary analysis for calculation of each assays’ operating characteristics. In 
this sensitivity analysis, we will eliminate all patients with a positive test that correlates in time with at 
least 1 of the factors listed in Table 3.  
 
13.9 
Significance 
Fungal infections continue to be major contributors to morbidity and mortality in children receiving 
chemotherapy for AML. Although antifungal prophylaxis in these patients will reduce the frequency of 
IFI, it will not eliminate the risk of these devastating infections. Early diagnosis and therapeutic 
modifications are paramount to improving patient outcomes. The Platelia Aspergillus EIA and the 
Fungitell Assay are potential diagnostic tools that could improve the time to diagnosis of IFIs. More 
definitive data regarding the operating characteristics of these 2 biomarkers interpreted simultaneously 
and separately in the setting of a large pediatric cohort receiving fungal prophylaxis are necessary. 

 
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Evaluating the biomarkers first as integrated tests will provide valuable information regarding the utility 
of each test so that they can be utilized as integral markers in future pediatric cancer trials. Finally, 
specimens from this study will be stored for potential future investigation. This will allow for the 
possibility of evaluating future versions of these or other biomarker assays for the identification of IFI in 
this cohort. 
 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
 
14.1 
Single Nucleotide Polymorphisms (This study is optional) 
 
Genotypes of interest in genes mediating immune function will be determined by review of experimental 
data from AAML0531 and review of the literature. Genotyping will be conducted as part of 1R01 
CA133881 and analysis will be performed on the Taqman Open Array Platform according to the 
manufacturer’s instructions.  
 
14.1.1 Sample Collection 
Patients Enrolled on AAML1031: 
All samples for ACCL0933 will be obtained from the AML Reference Laboratory from samples submitted 
on patients enrolled on AAML1031. Thus, no additional sample collection beyond AAML1031 sample 
collection will occur for patients enrolled on the AAML1031 trial.  
 
All Other Patients: 
For patients not enrolled on AAML1031, 5 mL of peripheral blood should be collected in a purple top tube at 
the end of Course I, when the patient has an ANC > 1000/µL (and with no circulating blasts).  
 
14.1.2 Labeling:  
Label the tubes with the patient’s COG ID number, protocol ID number, BPC #, date and time of 
collection.  
 
14.1.3 Shipping:  
Ship sample at room temperature, 2nd day delivery, using the COG courier account 
(https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf). 
The 
laboratory 
is 
unable to accept Saturday deliveries. Include a COG Specimen Transmittal Form with shipment. 
 
The SNP sample (for patients not enrolled on AAML1031) should be shipped to the address below.  
 
Richard Aplenc, MD, PhD 
Pediatric Oncology 
4018 CTRB 
3501 Civic Center Blvd 
Philadelphia, PA  19104-4318 
Phone: (267) 426-7252 
Fax: (267) 425-0113 
E-mail: Aplenc@email.chop.edu 
 
Please contact Dr. Richard Aplenc for any questions regarding sample acquisition. 
 
15.0 
BANKING SPECIMENS 
 
If the patient consents, leftover blood samples (from the studies described in Section 13 and 14) will be 
banked for future research studies. 
 

 
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APPENDIX I: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ACCL0933 
(for children from 7 through 12 years of age) 
 
A Research Study Comparing 2 Drugs Used To Prevent Serious Fungal Infections In Children With 
Acute Myeloid Leukemia. 
 
1. We have been talking with you about your likelihood of getting Invasive Fungal Infections. 
Invasive Fungal Infections are infections which occur in people whose natural infection-fighting 
ability (also called immunity) have been reduced. The strong cancer fighting drugs (called 
chemotherapy) used to treat your acute myeloid leukemia (AML) reduce your immunity and 
make you likely to get invasive fungal infections. 
 
2. We are asking you to take part in a research study because you are at risk of invasive fungal 
infections. A research study is when doctors work together to try out new ways to help people 
who are sick. In this study, we are trying to find better ways to prevent invasive fungal infections 
in children on treatment for AML. 
 
3. Children who are part of this study will be given medicines that help prevent invasive fungal 
infections. These drugs are called antifungal agents. In this study, one group of children will get 
the usual antifungal drug called fluconazole. The other group will get a newer antifungal agent 
called caspofungin. Your doctor will tell you which group you are in. We do not know if the 
newer antifungal agent will be better than the usual treatment. That is why we are doing this 
study.  
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is a better 
chance of avoiding invasive fungal infections during your treatment for AML, but we don’t know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” There is a risk that you will have bad effects from the newer antifungal agent 
or that it will not be better at preventing you from getting invasive fungal infections during your 
treatment for AML. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood for some special tests. We want to see 
if 2 new blood tests can help doctors detect fungal infections as early as possible, and better than 
the usual tests used. We also want extra blood samples for another special blood test that looks at 
your genes for an abnormality that may make an individual more likely to get invasive fungal 
infections. Samples for these tests would be taken when other standard blood tests are being 
performed, so there would be no extra procedures. You can still take part in this study even if you 
don't allow us to collect the extra blood samples for research.  
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY ACCL0933 
(for teens from 13 through 17 years of age) 
 
A Research Study Comparing 2 Drugs Used To Prevent Serious Fungal Infections In Children and 
Adolescents With Acute Myeloid Leukemia. 
 
1. We have been talking with you about your likelihood of getting Invasive Fungal Infections. 
Invasive Fungal Infections are infections which occur in people whose natural infection-fighting 
ability (also called immunity) have been reduced. The strong cancer fighting drugs (called 
chemotherapy) used to treat your acute myeloid leukemia (AML) reduce your immunity and 
make you likely to get invasive fungal infections. 
 
2. We are asking you to take part in a research study because you are at risk of invasive fungal 
infections. A research study is when doctors work together to try out new ways to help people 
who are sick. In this study, we are trying to find better ways to prevent invasive fungal infections 
in children on treatment for AML. 
 
3. Children who are part of this study will be given medicines that help prevent invasive fungal 
infections. These drugs are called antifungal agents. Children and adolescents that are part of this 
study will be placed into 1 of 2 treatment groups by a process called randomization. 
Randomization means that the study treatment groups are assigned by chance, and is like flipping 
a coin, only it is done by a computer. In this study, one group of children will get the usual 
antifungal drug called fluconazole. The other group will get a newer antifungal agent called 
caspofungin. Your doctor will tell you which group you are in. We do not know if the newer 
antifungal agent will be better than the usual treatment at preventing invasive fungal infections. 
That is why we are doing this study.  
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is a better 
chance of avoiding invasive fungal infections during your treatment for AML, but we don’t know 
for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” There is a risk that you will have bad effects from the newer antifungal agent 
or that it will not be better at preventing you from getting invasive fungal infections during your 
treatment for AML. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood for some special tests. We want to see 
if 2 new blood tests can help doctors detect fungal infections as early as possible, and better than 
the usual tests used. These new tests are called beta-D glucan and galactomannan assays. We also 
want extra blood samples for another special blood test that looks at your genes for an 
abnormality that may make an individual more likely to get invasive fungal infections. This is 
called single nucleotide polymorphism (SNP) analysis. Samples for these tests would be taken 
when other standard blood tests are being performed, so there would be no extra procedures. You 
can still take part in this study even if you don't allow us to collect the extra blood samples for 
research.  

 
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APPENDIX II: EORTC/MSG CRITERIA 
 
 
Criteria for proven invasive fungal disease except for endemic mycoses48 
 
Analysis and specimen 
Moldsa 
Yeastsa 
Microscopic analysis: sterile material 
Histopathologic, cytopathologic, or direct microscopic examinationb 
of a specimen obtained by needle aspiration or biopsy in which 
hyphae or melanized yeast-like forms are seen accompanied by 
evidence of associated tissue damage 
Histopathologic, cytopathologic, or direct microscopic examinationb 
of a specimen obtained by needle aspiration or biopsy from a 
normally sterile site (other than mucous membranes) showing yeast 
cells—for example, Cryptococcus species indicated by encapsulated 
budding yeasts or Candida species showing pseudohyphae or true 
hyphaec 
Culture 
 
 
Sterile material 
Recovery of a mold or “black yeast” by culture of a specimen 
obtained by a sterile procedure from a normally sterile and clinically 
or radiologically abnormal site consistent with an infectious disease 
process, excluding bronchoalveolar lavage fluid, a cranial sinus 
cavity specimen, and urine 
Recovery of a yeast by culture of a sample obtained by a sterile 
procedure (including a freshly placed [!24 h ago] drain) from a 
normally sterile site showing a clinical or radiological abnormality 
consistent with an infectious disease process  
Blood 
Blood culture that yields a moldd (e.g., Fusarium species) in the 
context of a compatible infectious disease process 
Blood culture that yields yeast (e.g., Cryptococcus or Candida 
species) or yeast-like fungi (e.g., Trichosporon species) 
Serological analysis: CSF 
Not applicable 
Cryptococcal antigen in CSF indicates disseminated cryptococcosis 
 
a  If culture is available, append the identification at the genus or species level from the culture results. 
b  Tissue and cells submitted for histopathologic or cytopathologic studies should be stained by Grocott-Gomorri methenamine silver stain or by periodic acid Schiff stain, to facilitate inspection of 
fungal structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should be stained with a fluorescent dye (e.g., calcofluor or blankophor). 
c  Candida, Trichosporon, and yeast-like Geotrichum species and Blastoschizomyces capitatus may also form pseudohyphae or true hyphae. 
d  Recovery of Aspergillus species from blood cultures invariably represents contamination 

 
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Criteria for probable invasive fungal disease except for endemic mycoses48 
 
Host factorsa  
Recent history of neutropenia (< 0.5 X 109 neutrophils/L [< 500 neutrophils/mm3] for >10 days) temporally related to the onset 
of fungal disease  
Receipt of an allogeneic stem cell transplant  
Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a mean minimum 
dose of 0.3 mg/kg/day of prednisone equivalent for > 3 weeks  
Treatment with other recognized T cell immunosuppressants, such as cyclosporine, TNF- blockers, specific monoclonal 
antibodies (such as alemtuzumab), or nucleoside analogues during the past 90 days  
Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined immunodeficiency)  
Clinical criteriab  
Lower respiratory tract fungal diseasec  
The presence of 1 of the following 3 signs on CT:  
Dense, well-circumscribed lesions(s) with or without a halo sign  
Air-crescent sign  
Cavity  
Tracheobronchitis  
Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis  
Sinonasal infection  
Imaging showing sinusitis plus at least 1 of the following 3 signs:  
Acute localized pain (including pain radiating to the eye)  
Nasal ulcer with black eschar  
Extension from the paranasal sinus across bony barriers, including into the orbit  
CNS infection  
1 of the following 2 signs:  
Focal lesions on imaging  
Meningeal enhancement on MRI or CT  
Disseminated candidiasisd  
At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks:  
Small, target-like abscesses (bull’s-eye lesions) in liver or spleen  
Progressive retinal exudates on ophthalmologic examination  
Mycological criteria  
Direct test (cytology, direct microscopy, or culture)  
Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following:  
Presence of fungal elements indicating a mold  
Recovery by culture of a mold (e.g., Aspergillus, Fusarium, Zygomycetes, or Scedosporium species)  
Indirect tests (detection of antigen or cell-wall constituents)e  
Aspergillosis  
Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF  
Invasive fungal disease other than cryptococcosis and zygomycoses  
-D-glucan detected in serum  
 
NOTE. Probable IFD requires the presence of a host factor, a clinical criterion, and a mycological criterion. Cases that meet the criteria for a host 
factor and a clinical criterion but for which mycological criteria are absent are considered possible IFD.  
a Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to invasive fungal diseases can 
be recognized. They are intended primarily to apply to patients given treatment for malignant disease and to recipients of allogeneic 
hematopoietic stem cell and solid-organ transplants. These host factors are also applicable to patients who receive corticosteroids and other T cell 
suppressants as well as to patients with primary immunodeficiencies.  
b Must be consistent with the mycological findings, if any, and must be temporally related to current episode.  
cEvery reasonable attempt should be made to exclude an alternative etiology.  
d The presence of signs and symptoms consistent with sepsis syndrome indicates acute disseminated disease, whereas their absence denotes 
chronic disseminated disease.  
e These tests are primarily applicable to aspergillosis and candidiasis and are not useful in diagnosing infections due to Cryptococcus species 
or Zygomycetes (e.g., Rhizopus, Mucor, or Absidia species). Detection of nucleic acid is not included, because there are as yet no validated or 
standardized methods.  

 
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Herbrecht R, Letscher-Bru V, Oprea C, et al: Aspergillus galactomannan detection in the 
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Marty FM, Lowry CM, Lempitski SJ, et al: Reactivity of (1-->3)-beta-d-glucan assay with 
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Clin Chem 54:17-23, 2008 
 
 
 
 

 
 
 
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SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM 
 
ACCL0933 
A Randomized Open-Label Trial of Caspofungin versus Fluconazole to Prevent Invasive 
Fungal Infections in Children Undergoing Chemotherapy for Acute Myeloid Leukemia (AML) 
 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required. When we say “you” 
in this consent form, we mean you or your child; “we” means the doctors and other staff. 
 
Why am I being invited to take part in this study? 
 
You are being asked to take part in this research study because you are getting treatment with 
strong cancer fighting drugs (called chemotherapy) for AML, and therefore at risk of getting an 
invasive fungal infection. 
 
Invasive fungal infections are infections caused by organisms called fungi that enter the blood 
stream and spread to different organs in the body. Chemotherapy used to treat AML severely 
reduces the body’s natural infection fighting ability. In patients who died from infections while 
receiving treatment for AML, an invasive fungal infection was the cause in more than half of the 
cases. Preventing invasive fungal infections due to chemotherapy is therefore very important for 
the treatment success of people with AML. 
 
This study is called a clinical trial. A clinical trial is a research study involving treatment of a 
disease in human patients. This study is organized by Children’s Oncology Group (COG). COG 
is an international research group that conducts clinical trials for children with cancer. More than 
200 hospitals in North America, Australia, New Zealand, and Europe are members of COG. 
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard preventive treatment for invasive fungal infections and 
this clinical trial.  
 
Please take your time to make your decision. You may want to discuss it with your friends and 
family. We encourage parents to include their child in the discussion and decision to the extent 
that the child is able to understand and take part. 
 
This model informed consent form has been reviewed by the DCT/NCI and is the official consent 
document for this study. Institutions should use the sections of this document which are in bold type 
in their entirety. Editorial changes to these sections may be made as long as they do not change 
information or intent. If the local IRB insists on making deletions or more substantive modifications 
to any of the sections in bold type, they must be justified in writing by the investigator at the time of 
the institutional audit.  

 
 
 
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What is the current standard of treatment for this disease? 
 
The current standard preventive treatment for people who are at risk of invasive fungal 
infections due to chemotherapy treatment for cancers like AML is the use of fungi fighting drugs 
(called antifungal therapy). The current standard antifungal drug used is called fluconazole. 
 
Why is this study being done? 
 
Current standard antifungal therapy with fluconazole (also called Diflucan) has been shown to 
be effective in preventing invasive fungal infections in people with AML; especially those caused 
by the fungi Candida. However, previous studies have shown that it does not fully prevent 
infections caused by some types of fungi called filamentous fungi. Aspergillus is a type of 
filamentous fungi.  
 
In this study, researchers want to find out if using a newer antifungal drug called caspofungin 
(also called Cancidas) will be better than the current standard antifungal drug fluconazole at 
preventing invasive fungal infections when given to people with AML after receiving 
chemotherapy treatment.  
 
The drug caspofungin was chosen because this class of medication has been shown to be 
effective in the prevention of various fungal infections, including Candida and Aspergillus, in a 
study of both adults and children. Caspofungin is an antifungal drug that has been approved by 
the Food and Drug Administration (FDA) for use in children as well as adults.  
 
The use of caspofungin to prevent invasive fungal infections is experimental. 
 
The overall goal of this study is to: 
 
 
Compare the effects, good and/or bad, of 2 antifungal drugs: caspofungin and 
fluconazole on people getting treatment for AML, who are at risk of getting 
invasive fungal infections, to find out which is better. In this study, you will get 
either caspofungin or fluconazole. You will not get both. 
 
What will happen on this study that is research? 
 
Before you take part in this study, you will first get cancer treatment for AML that includes the 
use of chemotherapy. Taking part in this study will not change the cancer treatment plan you 
get. 
 
Treatment on this study involves antifungal drugs used to prevent invasive fungal infections. In 
this study you will get 1 of 2 treatment plans. The 2 treatment arms are called: 
 
 
Fluconazole Arm – Current standard treatment; patients will get therapy with fluconazole. 
 
Caspofungin Arm – Experimental treatment; patients will get therapy with caspofungin. 
 
Random Assignment  
You will receive 1 of 2 different treatment plans. The treatment plan that you receive is decided 
by a process called randomization. Randomization means that the treatment is assigned based 
on chance. It is a lot like flipping a coin, except that it is done by computer. You and your doctor 
will not pick which treatment you get. You will have an equal chance of being on either the 
caspofungin arm or the fluconazole arm. The randomization process is described in the COG 
Family Handbook for Children with Cancer. 

 
 
 
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Subjects (people who agree to be part of this study) will have started treatment for AML. At the 
end of the first course of chemotherapy, some subjects will be randomized to receive 
fluconazole while others will get caspofungin. For the remainder of your AML chemotherapy, 
you will continue to get either caspofungin or fluconazole at the end of each chemotherapy 
course to prevent you from developing an invasive fungal infection.  
 
 
Diagram of Treatment 
 
This chart shows the treatments on the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan Tables 
Preventive treatment that is standard for invasive fungal infections as well as standard tests and 
procedures are described in Attachment #1. The following drug therapies relate to the 
experimental comparison of the treatment groups in this study. 
 
Various methods are used to give drugs: 
 
IV - Drug is given using a needle or tubing inserted into a vein. Drugs can be given rapidly 
over a few minutes (“push”) or slowly over minutes or hours (“infusion”). 
 
PO- Drug is given by tablet or liquid swallowed through the mouth. 
 
Treatment for participants who are on Fluconazole Arm - Standard Treatment 
Drug 
How the drug will be given  
Days 
Fluconazole 
IV Infusion over 1- 2 hours (or 
longer) or PO 
 
Start at the end of each chemotherapy 
course & continue until blood cells recover 
or the next chemotherapy course begins.  
 
Treatment for participants who are on Caspofungin Arm – Experimental Treatment 
Drug 
How the drug will be given  
Days 
Caspofungin 
IV Infusion over 1 hour 
(Dose on first day is different from 
dose given in the days that follow) 
Start at the end of each chemotherapy 
course & continue until blood cells recover 
or the next chemotherapy course begins. 
 
Subjects randomized 
Fluconazole arm 
Caspofungin after each 
course of AML therapy 
Fluconazole after each 
course of AML therapy 
Caspofungin arm 

 
 
 
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Research Study Procedures 
If you have a fungal infection while you are on this study, copies of some of the scans or reports 
of the tests that identify the infection will be sent to a central review center as part of COG 
quality control. 
 
Optional Research Study Tests 
We would like to do the following tests because you are a part of this study. These tests are not 
part of standard care and you do not need to take part in these tests to be on this study. The 
results of these tests will not be returned to you and no treatment decisions will be based on the 
results. The results of these tests will not be a part of your medical record. If you provide 
specimens to the researchers, there are no plans for you to profit from any new products 
developed from research done on your specimens. 
 
At the end of this consent, there are questions for you to indicate if you want to take part in 
these optional research tests.  
 
Platelia EIA Aspergillus Galactomannan (GM) Assay and Serum Beta–D-Glucan Testing - 
Biomarker Studies 
Researchers would like to see if they can identify certain biomarkers in the blood. Biomarkers 
are substances in the blood produced from the fungal organisms that cause invasive fungal 
infections. The biomarkers that will be measured in your blood are called galactomannan and 
beta-D-glucan. Findings from this research will help researchers know more about fungal 
infections, as well how to diagnose and treat them better. 
 
If you agree, about a teaspoon of blood will be taken from you twice a week while you are 
receiving antifungal treatment. This will be drawn from your central line when other standard lab 
tests are being collected. 
 
Single Nucleotide Polymorphisms (SNP) Analysis – Genetic Study 
Researchers would like to look for genetic changes that may put subjects at an increased risk of 
invasive fungal infections. This test is called single nucleotide polymorphism (SNP) analysis. 
Information learned from this study may be useful in the future for identifying patients that are 
more likely to have invasive fungal infections. 
 
[For subjects not enrolled on AAML1031]: 
If you agree, about a teaspoon of blood will be collected for SNP analysis. The sample will be 
collected after the first course of chemotherapy when other routine blood tests are performed.  
 
[For subjects enrolled on AAML1031]: 
Since you are being treated on the AML clinical trial AAML1031, a blood sample will be sent to a 
COG laboratory after the first course of chemotherapy. If you agree, this sample can also be 
used for the SNP analysis and no extra blood will be collected. 
 
Future Studies: 
If you agree, we would like to store (bank) any leftover blood for future studies. The research 
that may be done with the samples is not designed to help you during your present treatment. It 
might help people who have cancer and other diseases in the future.  
 
Research on the banked specimens is very unlikely to discover results that are important to 
your current or future health. However, if it does, COG will try to contact your doctor about what 
the research tests might mean. Only the doctor will be notified and the information will not 

 
 
 
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become part of your medical record. Your doctor will decide whether to discuss the results with 
you. Your doctor may recommend repeat testing, meeting with a genetic counselor, or no further 
action. 
 
What side effects or risks can I expect from being in the study? 
 
Treatment Risks 
You may have side effects while on this study. All people taking part in this study will be 
carefully monitored for side effects. Side effects may be mild or very serious; and you 
may be given care to lessen side effects. Many side effects go away soon after you stop 
taking the drug causing the side effects, but in some cases, may last longer or never go 
away. 
 
The risks of the individual drug given as standard treatment are listed in Attachment #2.  
 
Reproductive risks: Women should not become pregnant and men should not father a 
baby while on this study because the drug(s) in this study can be bad for an unborn 
baby. If you or your partner can get pregnant, it is important for you to use birth control 
or not have sex while on this study. Check with your study doctor about what kind of 
birth control methods to use and how long to use them. Some birth control methods 
might not be approved for use in this study. Women should not breastfeed a baby while 
on this study. Also check with your doctor about how long you should not breastfeed 
after you stop the study treatment(s). 
 
Risks of Study 
Several studies have shown that even though fluconazole is effective in preventing 
fungal infections caused by Candida, it is not quite as effective at preventing fungal 
infections caused by filamentous fungi like Aspergillus. Infections with Aspergillus are 
usually very severe, and have been shown to cause more infection-related deaths than 
infections with Candida. 
 
The use of caspofungin may cause more complications than the use of fluconazole.  
 
The caspofungin treatment that is being studied could be less effective than the current 
standard treatment with fluconazole. 
 
In addition to the risks described above, there may be unknown risks, or risks that we did 
not anticipate, associated with being in this study. 
 
Risks and side effects reported or expected with caspofungin include: 
Likely 
May happen in 21 to 100 subjects 
out of every 100. 
Less Likely 
May happen in 20 or less than 20 
subjects out of every 100. 
Rare but serious 
 
Fever (high 
temperature) 
 
Chills 
 
Rash 
 
Diarrhea 
 
Reaction that can 
occur during or 
following infusion of 
 
Fluid build-up in the tissues 
of the arms and legs 
 
Pain and inflammation in the 
vein through which the drug 
was given 
 
Nausea 
 
Vomiting 
 
Pain in the abdomen (belly) 
 Allergic reaction which can 
be life-threatening and 
potentially fatal. This 
reaction requires immediate 
medical treatment.  It may 
include fever, chills and skin 
rash. Less commonly 
wheezing, shortness of 
breath, swelling of the 

 
 
 
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the drug.  The reaction 
may include fever, 
chills, reddening of the 
face with feelings of 
warmth, rash, low or 
high blood pressure, 
fast heartbeat, fast 
breathing, and 
difficulty breathing  
 
Low level of potassium 
in the blood which may 
cause weakness, 
tiredness, muscle 
cramps, constipation, 
and abnormal heart 
beat and may require 
that you take extra 
potassium by mouth or 
through the vein  
 
 
Cough 
 
Redness of the skin 
 
Headache 
 
Low blood pressure 
 
Increase in the blood of 
certain enzymes or bilirubin 
(a substance that comes from 
the liver breaking down 
waste products) which could 
indicate liver irritation or 
damage  
 
Infection in the lung 
(pneumonia)  
 
Pain, fluid build-up and 
itching at the injection site 
 
Itching 
 
Fast or slow heart beat 
 
High blood pressure 
 
Bloating of the abdomen 
(belly) 
 
Constipation 
 
Acid or upset stomach 
(heartburn) 
 
Loss of desire to eat or 
appetite 
 
A feeling of weakness and/or 
tiredness 
 
Sleepiness 
 
Dizziness 
 
Tremor (shakiness usually of 
the hands) 
 
Reddening of the face with 
feelings of warmth 
 
Fewer white blood cells, red 
blood cells and platelets in 
the blood  
o a low number of white 
blood cells can make it 
easier to get infections 
o a low number of red blood 
cells can make you feel 
tired and weak 
o a low number of platelets 
causes you to bruise and 
bleed more easily 
 
Fever with a low white blood 
cell count which could 
indicate infection and may 
require hospitalization and 
treatment with antibiotics 
 
Abnormal clotting of the 
blood  
 
Inflammation of mucosal 
tissues like the lining of the 
throat, drop in blood 
pressure, and rapid heart 
rate may occur. 
 A life-threatening condition 
in which the level of oxygen 
in the blood becomes too 
low or the level of carbon 
dioxide in the blood 
becomes too high. 
 Abnormal electrical 
conduction within the heart 
which could cause irregular 
heart beat, could cause the 
heart to stop beating and 
could be life-threatening 
 Heart attack 
 Damage to the liver which 
can lead to inflammation 
and/or scarring which could 
lead to a yellow appearance 
to the skin, and fluid 
collection in the abdomen 
(belly) which makes it look 
larger 
 The liver rapidly loses its 
ability to function. This may 
cause many complications, 
including excessive bleeding 
and increasing pressure in 
the brain, requires 
hospitalization and may be 
life-threatening 
 Severe blood infections 
which will need to be treated 
and may be life-threatening 
 Convulsion (seizures) 
 Severe kidney damage 
(which may be permanent) 
 Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes and which may 
be life-threatening 
 

 
 
 
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mouth 
 
Tiny reddish or purplish 
spots containing blood that 
appears in skin or mucous 
membrane as a result of 
localized bleeding 
 
Abnormal low levels of 
magnesium in the body 
which may require that you 
take extra magnesium by 
mouth or vein 
 
High levels of sugar or 
calcium in the blood that may 
require treatment 
 
Pain in the joints, back and/or 
arms and legs 
 
Anxiety 
 
Confusional state 
 
Depression 
 
Difficulty sleeping or falling 
asleep 
 
Shortness of breath  
 
Low levels of oxygen in the 
blood which may make you 
feel short of breath 
 
 A fast rate of respiration that 
may cause pain in the chest 
 
Nose bleed 
 
Inflammation of the pancreas 
(an organ in the abdomen 
which makes insulin and 
certain digestive chemicals).   
This may cause pain in the 
abdomen (belly) which can 
be severe and may increase 
the blood sugar. 
 
Enlarged liver 
 
The skin and the whites of 
the eyes appears yellow as a 
result of too much bilirubin (a 
substance that comes from 
the liver breaking down 
waste products) in the blood 
 
Blood in the urine which may 
indicate kidney (or bladder) 
damage 
 
Infection in the bladder or 
kidney 
 
Red bumpy rash which may 
become severe 
 
Although caspofungin has the potential risks noted above, it may be better at preventing 
invasive fungal infections caused by Aspergillus as compared to fluconazole, but the benefit of 
caspofungin is uncertain.  

 
 
 
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For the optional studies, the greatest risk to you is the release of information from your health 
records. We will do our best to make sure that your personal information will be kept private. 
The chance that this information will be given to someone else is very small. 
 
 
Are there benefits to taking part in the study? 
 
We hope that this study will help you personally, but we do not know if it will.  
 
Potential benefits to you could include a better chance of preventing invasive fungal infections 
during treatment for AML. 
 
We expect that the information learned from this study will benefit other patients in the future. 
 
What other options are there? 
 
Instead of being in this study, you have these options: 
 
 
Current standard therapy even if you do not take part in the study. Standard therapy 
is described on page 1. It is the Fluconazole Arm of this study. 
 
 
Receiving no prevention against fungal infections. 
 
 
Taking part in another study 
 
Please talk to your doctor about these and other options. 
 
How many people will take part in the study? 
 
The total number of people enrolled on this study is expected to be 575. 
 
How long is the study? 
 
Subjects in this clinical trial are expected to receive treatment on this study for durations that will 
be determined by the length of your chemotherapy. After treatment, you will have follow-up 
examinations and medical tests. 
 
We would like to continue to find out about your health for 2 years after you start this study.  
 
You can stop taking part in the study at any time. However, if you decide to stop participating in 
the study, we encourage you to talk to the study doctor and your regular doctor first. They will 
help you stop safely.  
 
Your doctor or the study doctor may decide to take you off this study: 
 
if he/she believes that it is in your best interest 
 
if your disease comes back during treatment 
 
if you experience side effects from the treatment that are considered too severe 
 
if new information becomes available that shows that another treatment would be better for 
you 

 
 
 
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What about privacy? 
 
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Your personal information may be 
given out if required by law. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
 
The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is included in Attachment #3. 
 
Organizations that may look at and/or copy your research or medical records for research, 
quality assurance and data analysis include groups such as: 
 
 
The Children's Oncology Group 
 
The Representatives of the National Cancer Institute (NCI), Food and Drug  
Administration (FDA), and other U.S. and international governmental regulatory 
agencies involved in overseeing research 
 
The Institutional Review Board of this hospital 
 
The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute 
 
The drug company that makes caspofungin or their designated reviewers. 
 
What are the costs? 
 
Taking part in this study may lead to added costs to you or your insurance company. There 
are no plans for the study to pay for medical treatment. Please ask about any expected added 
costs or insurance problems. Staff will be able to assist you with this. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. However by signing this form, you are not giving up any legal rights to 
seek to obtain compensation for injury. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
The drug company that makes caspofungin is supplying the drug at no charge for subjects on 
this study. Therefore, if you are randomized to the caspofungin arm, you or your insurance 
company will not be charged for the caspofungin. The drug company does not cover the cost of 
getting the caspofungin ready and giving it to you, so you or your insurance company may have 
to pay for this. 
 
Caspofungin is given IV only. Therefore some hospitals may want to keep you admitted during 
the period you are receiving caspofungin, while others may discharge you to continue 
caspofungin at home. There may be additional costs to you or your insurance company if you 
are discharged from the hospital to continue to have the drug given at home. This may include 
the cost of caspofungin if given at home. If your insurance company or other hospital sources 
will not cover this additional cost and you cannot cover it yourself, you may stop taking 
caspofungin and use whatever your hospital usually uses to prevent fungal infections.  

 
 
 
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Fluconazole is a standard antifungal drug, and would most likely be given to you if you did not 
take part in the study. Therefore, if you are randomized to the fluconazole arm, you or your 
insurance company will be charged for the fluconazole. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout. You can print a copy of 
the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Funding support 
 
If you choose to enroll on this study, this institution will receive some money from the Children’s 
Oncology Group to do the research. There are no plans to pay you for taking part in this study.  
 
The optional tests are not part of standard care. The cost of performing these tests will be free 
of charge. There will be no cost to you or your insurance company. 
 
This study includes providing specimens to the researcher. There are no plans for you to profit 
from any new product developed from research done on your specimens.  
 
 
What are my rights as a participant? 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not 
to be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled. You will still receive medical care. 
 
You can decide to stop being in the study at any time. Leaving the study will not result in any 
penalty or loss of benefits to which you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies COG if 
changes must be made to the study. Members of COG meet twice a year to discuss results of 
treatment and to plan new treatments.  
 
During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years from now since all people on the 
study need to have completed treatment.  
 
Whom do I call if I have questions or problems? 
 
For questions about the study or if you have a research related problem or if you think you have 
been injured in this study, you may contact Dr. XXXX or your doctor at XXXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX IRB Administrator at XXXX. 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX. 

 
 
 
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Where can I get more information? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor 
can 
get 
you 
this 
Handbook, 
or 
you 
can 
get 
it 
at 
http://www.childrensoncologygroup.org/familyhandbook. 
 
Visit the NCI's Web site at http://www.cancer.gov. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237).  
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/ 
 
A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as 
required by U.S. Law. This web site will not include information that can identify you. At 
most, the web site will include a summary of the results. You can search this web site at 
any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
Specimens for optional research tests 
This section of the informed consent is about samples for the optional research tests (biomarker 
and SNP studies). 
 
The choice to let us use specimens for research is up to you. No matter what you decide to do, 
it will not affect your care. You can still be a part of the main study even if you say ‘No’ to taking 
part in any of these optional research studies. 
 
If you decide now that your specimens can be used for research and banking you can change 
your mind at any time. Just contact us and let us know that you do not want us to use your 
specimens. Then any specimens that we have will be destroyed.  
 
If you want to learn more about tissue research with banked specimens, the NCI website has an 
information sheet called "Providing Your Tissue For Research: What You Need To Know.” This 
sheet can be found at: http://www.cancer.gov/clinicaltrials/resources/providingtissue. 
 
Please read the information below and think about your choices. After making your decisions, 
check “Yes” or “No”, then add your initials and the date after your answer. If you have any 
questions, please talk to your doctor or nurse, or call our research review board at the IRB’s 
phone number included in this consent. 
 
1. I agree to the collection of extra blood samples for the research studies about biomarkers in 
the blood that may show fungal infections as early as possible. 
 
 
Yes_____ 
No_____ 
 
________ / _______ 
 
 
 
 
 
 
   Initials         Date 
 

 
 
 
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[For Subjects Enrolled on AAML1031] 
2. I agree that a blood sample (currently in a COG laboratory) may be used to look at genetic 
risk factors for fungal infections.  
 
 
Yes_____ 
No_____ 
 
________ / _______ 
 
 
 
 
 
 
   Initials         Date 
 
[For Subjects NOT Enrolled on AAML1031] 
2.  I agree to the collection of extra blood for SNP analysis that will look at genetic risk factors 
for fungal infections.  
 
 
Yes_____ 
No_____ 
 
________ / _______ 
 
 
 
 
 
 
   Initials         Date 
 
3. If some blood is left over after the studies above are completed, I agree that it may be kept 
(banked) for future research to learn about, prevent, or treat cancer.    
 
Yes_____ 
No_____ 
 
 
________ / _______ 
 
 
 
 
 
 
   Initials         Date 
 
4. If some blood is left over after the studies above are completed, I agree that it may be kept 
(banked) for use in research to learn about, prevent or treat other health problems (for example: 
diabetes, Alzheimer's disease, or heart disease). 
 
Yes_____  
No_____  
 
 
________ / _______ 
   Initials         Date 
 
SIGNATURE 
I have been given a copy of all _____ pages of this form. The form includes three (3) 
attachments. 
 
I have reviewed the information and have had my questions answered.  
 
I agree to take part in this study (ACCL0933) 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
IRB# 
IRB Approved: 
 
 

 
 
 
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Attachment #1 
Treatment and Procedures Common to all Patients at Risk of IFI 
 
Method for Giving Drugs 
 
IV - Drug is given using a needle or tubing inserted into a vein. Drugs can be given rapidly 
over a few minutes (“push”) or slowly over minutes or hours (“infusion”). 
 
PO- Drug is given by tablet or liquid swallowed through the mouth. 
 
Central Line 
Your doctor may recommend that you get a special kind of IV called a “central line.” This is a 
kind of IV placed into a big vein in your chest that can stay in for a long time. The risks 
associated with central lines will be explained to you and all of your questions will be answered. 
If you are to have a central line inserted, you will be given a separate informed consent 
document to read and sign for this procedure. A description of the types of central lines is in the 
COG Family Handbook for Children with Cancer.  
 
Therapy for Patient on Fluconazole Treatment Plan (Standard Treatment Arm) 
The purpose of fluconazole therapy is to prevent the development of invasive fungal infections 
following treatment with chemotherapy for AML. 
 
Drug 
How the drug will be 
given  
Days 
Fluconazole 
IV infusion over 1-2 hours 
(or longer) or PO 
Once a day* 
*Start at the end of each chemotherapy course & continue until blood cells recover or the next 
chemotherapy course begins. 
 
Standard Tests and Procedures 
The following tests and procedures are part of regular cancer care and may be done even if you 
do not join the study. 
 
History and physical exam. 
 
Frequent labs to monitor blood counts and blood chemistries. 
 
Urine tests to measure how the kidneys are functioning. 
 
Pregnancy test for females of childbearing age before treatment begins. 

 
 
 
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Attachment #2 
Risks of Drugs Used to Prevent Invasive Fungal Infections 
 
Risks and side effects related to fluconazole include: 
Likely 
May happen in 21 to 100 
subjects out of every 100 
Less Likely 
May happen in 20 or less than 20 subjects out of 
every 100 
Rare but serious 
 
 
Allergic reaction 
 
Shortness of breath 
 
Nausea and/or vomiting 
 
Bloating 
 
Acid or upset stomach (heartburn) 
 
Change in taste 
 
Diarrhea 
 
Abdominal pain 
 
Headache 
 
Dizziness (rare) 
 
Skin rash 
 
Itching 
 
Low level of potassium in the blood 
which may cause weakness, 
tiredness, muscle cramps, 
constipation, and abnormal heart 
beat and may require that you take 
extra potassium by mouth or 
through the vein 
 
Increase of triglycerides and 
cholesterol in the blood which could 
lead to heart problems later in life 
 
A rare but severe lowering of the 
white blood cell count which can 
make you very susceptible to 
infections which could be life- 
threatening  
 
An increase in the blood of a type of 
white blood cell called an 
eosinophil. These are sometimes 
associated with allergic reactions. 
 
A low number of platelets causes 
you to bruise and bleed more easily 
 
Increase in the blood of certain 
enzymes which could indicate liver 
irritation or damage 
 
A condition in which the flow of bile 
from the liver is blocked and may 
cause itching, dark colored urine, 
light colored feces, and yellow eyes 
or skin 
 
Hair loss with prolonged 
fluconazole use 
 
Severe allergic 
reaction which can be 
life-threatening with 
shortness of breath, 
low blood pressure, 
rapid heart rate, chills 
and fever 
 
A heart rhythm 
disorder that can 
cause fast, chaotic 
heartbeats. The rapid 
heartbeats may lead to 
fainting and in some 
cases, your heart's 
rhythm may beat so 
erratically that it can 
be life-threatening 
 
Severe rashes which 
can result in loss of 
skin and damage to 
mucous membranes 
and which may be life-
threatening 
 
Seizures (convulsions) 
 
Damage to the liver 
which can lead to 
inflammation and/or 
scarring which could 
lead to a yellow 
appearance to the 
skin, and fluid 
collection in the 
abdomen (belly) which 
makes it look larger 
 
The liver rapidly loses 
its ability to function. 
This may cause many 
complications, 
including excessive 
bleeding and 
increasing pressure in 
the brain, requires 
hospitalization and 
may be life-
threatening 
 

 
 
 
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Attachment #3 
Certificate of Confidentiality 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. The Certificate 
protects against the involuntary release of information about subjects collected during the 
course of our covered studies. The researchers involved in the studies cannot be forced to 
disclose the identity or any information collected in the study in any legal proceedings at the 
federal, state, or local level, regardless of whether they are criminal, administrative, or legislative 
proceedings. However, the subject or the researcher may choose to voluntarily disclose the 
protected information under certain circumstances. For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against 
that voluntary disclosure. Furthermore, federal agencies may review our records under limited 
circumstances, such as a DHHS request for information for an audit or program evaluation or an 
FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff of 
information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others.