Clinical trial NCT01503515
Conditions: Fungal Infection Hematopoietic and Lymphoid Cell Neoplasm
Sponsor: Children's Oncology Group
Start date: 2013-03-21; Completion date: 2021-09-30
Enrollment: 292 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies how well caspofungin acetate works compared to fluconazole or voriconazole in preventing fungal infections in patients following donor stem cell transplant. Caspofungin acetate, fluconazole, and voriconazole may be effective in preventing fungal infections in patients following donor stem cell transplant. It is not yet known whether caspofungin acetate is more effective than fluconazole or voriconazole in preventing fungal infections in patients following donor stem cell transplant.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if caspofungin (caspofungin acetate) is associated with a lower incidence of proven/probable invasive fungal infections (IFI) during the first 42 days following allogeneic hematopoietic cell transplantation (HCT) at high-risk for IFI compared with azole (fluconazole or voriconazole) prophylaxis.

EXPLORATORY OBJECTIVES:

I. To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 100 days following high-risk allogeneic HCT compared with azole (fluconazole or voriconazole) prophylaxis. (Exploratory) II. To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 and 100 days following high-risk allogeneic HCT compared with fluconazole prophylaxis. (Exploratory) III. To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 and 100 days following high-risk allogeneic HCT compared with voriconazole prophylaxis. (Exploratory) IV. To determine if caspofungin is associated with a superior fungal-free survival (FFS) (time to death or proven/probable IFI) at 42 and 100 days following high-risk allogeneic HCT compared with azole prophylaxis. (Exploratory) V. To describe the effect that caspofungin and azoles have on the incidence and severity of acute graft-versus-host disease (GVHD). (Exploratory) VI. To define the test characteristics of weekly Fungitell assay testing for identifying IFI in pediatric hematopoietic stem cell transplantation (HSCT) recipients receiving antifungal prophylaxis during the post-transplant neutropenic period. (Exploratory) VII. To create a deoxyribonucleic acid (DNA) specimen bank in anticipation of the development of biology correlative studies exploring the relationship between IFI and single nucleotide polymorphisms (SNPs) of genes involved in immunity. (Exploratory)

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive caspofungin acetate intravenously (IV) over 1 hour once daily (QD) beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression.

ARM II: Patients receive fluconazole IV over 1-2 hours QD or orally (PO) QD; or voriconazole IV over 1-2 hours QD or PO twice daily (BID) beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression.

After completion of study treatment, patients are followed up until day 100.

Arms: arm 1: Patients receive caspofungin acetate IV over 1 hour once daily (QD) beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression. arm 2: Patients receive fluconazole IV over 1-2 hours QD or PO QD; or voriconazole IV over 1-2 hours QD or PO BID beginning within 24 hours of allogeneic HSCT (day -1 or 0) and continuing until day 42 in the absence of invasive fungal infections or disease progression.
Interventions: intervention 1: Caspofungin Acetate intervention 2: Fluconazole intervention 3: Laboratory Biomarker Analysis intervention 4: Voriconazole
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV or PO intervention 3: Optional correlative studies intervention 4: Given IV or PO

Protocol documents:
Prot_SAP_ICF_000.pdf: 
ACCL1131
Activated:  03/11/13 
Closed:       11/08/16
Version Date: 11/16/15 
Amendment:  #2A 
CHILDREN’S ONCOLOGY GROUP 
ACCL1131 
A Phase III Open-Label Trial of Caspofungin vs. Azole Prophylaxis for Patients at High-Risk for 
Invasive Fungal Infections (IFI) Following Allogeneic Hematopoietic Cell Transplantation (HCT) 
A Phase III Study 
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. 
 
 
 
 
 
   
   
 
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ACCL1131  
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 
Exploratory Objectives 
8 
2.0 
BACKGROUND 
9 
2.1 
Rationale for Selected Approach and Trial Design 
9 
2.2  
Trial Importance 
10 
2.3 
Selection of Study Medication 
11 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
15 
3.1 
Study Enrollment 
15 
3.2 
Patient Eligibility Criteria 
16 
4.0 
TREATMENT PLAN 
18 
4.1 
Overview of Treatment Plan 
18 
4.2 
Administration Schedule: AZOLE ARM 
21 
4.3 
Administration Schedule: CASPOFUNGIN ARM 
26 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
28 
5.1 
Impaired Renal Function 
28 
5.2 
Impaired Liver Function 
28 
5.3 
Other Toxicities 
29 
6.0 
DRUG INFORMATION 
30 
6.1 
CASPOFUNGIN (caspofungin acetate, Cancidas)   (01/25/13) 
30 
6.2 
FLUCONAZOLE (Diflucan)     (08/12/11) 
33 
6.3 
VORICONIZOLE (Vfend)       (06/24/11) 
36 
7.0 
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
39 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
39 
7.2 
Optional Studies 
40 
7.3 
Follow-up 
40 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
40 
8.1 
Criteria for Removal from Protocol Therapy 
40 
8.2 
Off Study Criteria 
40 
9.0 
STATISTICAL CONSIDERATIONS 
41 
9.1 
Statistical Design 
41 
9.2 
Patient Accrual and Expected Duration of Trial 
41 
9.3 
Statistical Analysis Methods 
41 
9.4 
Gender and Minority Accrual Estimates 
46 
10.0 
EVALUATION CRITERIA 
47 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
47 
10.2 
IFI Checklist: Submission & Central Review 
47 
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ACCL1131  
10.3 
Acute GVHD 
47 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
48 
11.1 
Purpose 
48 
11.2 
Determination of Reporting Requirements 
48 
11.3 
Reporting of Adverse Events for Commercial Agents - via CTEP-AERS 
48 
11.4 
Routine Adverse Event Reporting 
49 
12.0 
RECORDS AND REPORTING 
49 
12.1 
CDUS 
49 
13.0 
PROSPECTIVE EVALUATION OF (1→3) BETA-D GLUCAN ASSAY AS A 
DIAGNOSTIC TOOL FOR INVASIVE FUNGAL INFECTION IN CHILDREN 
UNDERGOING ALLOGENEIC HCT RECEIVING FUNGAL PROPHYLAXIS. (FOR 
PATIENTS THAT CONSENT ONLY) 
50 
13.1 
Background 
50 
13.2 
Specific Aims and Hypotheses 
51 
13.3 
Study Design 
51 
13.4 
Patient Accrual 
52 
13.5  
Sample Collection and Testing Procedures (This section is optional) 
52 
13.6  
Gold Standards for IFI Infections 
54 
13.7  
Justification of Methodologic Choices 
55 
13.8  
Factors Resulting in False Positive Results 
55 
13.9  
Statistical Design 
56 
13.10 Significance 
58 
14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS FOR PATIENTS THAT 
CONSENT ONLY 
59 
14.1 
Single Nucleotide Polymorphisms 
59 
15.0 
BANKING SPECIMENS 
59 
APPENDIX I:  YOUTH INFORMATION SHEETS 
60 
APPENDIX II: EORTC/MSG CRITERIA 
62 
APPENDIX III: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR 
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT 
VERSUS HOST DISEASE (GVHD) 
64 
REFERENCES 
74 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM –FOR 
INSTITUTIONS WITH STANDARD USE OF FLUCONAZOLE 
79 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM –FOR 
INSTITUTIONS WITH STANDARD USE OF VORICONAZOLE 
94 
 
 
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ACCL1131  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
AGENTS  
 
Fluconazole                                        IND Exempt 
 
Voriconazole                                      IND Exempt 
 
Caspofungin (supplied by Merck)     IND Exempt 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTIONS 13 FOR SPECIMEN SHIPPING ADDRESSES 
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The Children's Cancer 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 your 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) are a significant cause of morbidity and mortality in patients undergoing 
allogeneic hematopoietic cell transplant (HCT). 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 an azole in children 
undergoing allogeneic HCT from an unrelated or mismatched related donor. The study agent will begin 
following at the time of transplant and continue through Day +42 or hospital discharge. This study also 
seeks to evaluate the usefulness of the Fungitell beta-D glucan Assay in early diagnosis of IFI. ACCL1131 
will also explore the relationship between proven or probable IFI and single nucleotide polymorphisms 
(SNP) of genes involved in immunity. 
  
 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
ENTRY 
Protocol therapy ends on HCT Day +42 or Day of 
Hospital Discharge (whichever is sooner). 
Randomization 
Protocol therapy must begin within 24 hours of HCT (Day 0) 
Voriconazole: 
Age & weight based dosing. 
See Section 4.2.3 for details.  
 
CASPOFUNGIN ARM 
70 mg/m2/day - Day 1 
50 mg/m2/day – Subsequently 
Fluconazole: 
Age based dosing. 
See Section 4.2.1 for details  
AZOLE ANTIFUNGAL ARM 
(Center Choice) 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objective 
 
1.1.1  
To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 days 
following allogeneic HCT at high-risk for IFI compared with azole (fluconazole or voriconazole) prophylaxis. 
 
1.2 
Exploratory Objectives 
 
Clinical 
 
1.2.1 
 
To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 
100 days following high-risk allogeneic HCT compared with azole (fluconazole or voriconazole) prophylaxis. 
 
1.2.2 
 
To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 and 
100 days following high-risk allogeneic HCT compared with fluconazole prophylaxis. 
 
1.2.3 
 
To determine if caspofungin is associated with a lower incidence of proven/probable IFI during the first 42 and 
100 days following high-risk allogeneic HCT compared with voriconazole prophylaxis. 
 
1.2.4 
 
To determine if caspofungin is associated with a superior fungal-free survival (FFS) (time to death or 
proven/probable IFI) at 42 and 100 days following high-risk allogeneic HCT compared with azole prophylaxis. 
 
1.2.5 
 
To describe the effect that caspofungin and azoles have on the incidence and severity of acute graft-versus-host 
disease (GVHD). 
 
Biological 
 
1.2.6 
 
To define the test characteristics of weekly Fungitell Assay testing for identifying IFI in pediatric HSCT 
recipients receiving antifungal prophylaxis during the post-transplant neutropenic period. 
 
1.2.7 
 
To create a DNA specimen bank in anticipation of the development of biology correlative studies exploring 
the relationship between IFI and single nucleotide polymorphisms (SNPs) of genes involved in immunity. 
 
 
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2.0 
BACKGROUND 
 
2.1 
Rationale for Selected Approach and Trial Design  
Almost all centers use anti-fungal prophylaxis for allogeneic HCT recipients, but no standard class of agents 
has emerged. A formal survey of the 80 COG HCT Centers shows that the majority of centers utilize 
fluconazole, although some centers have adopted voriconazole or an echinocandin, despite a paucity of data to 
support this practice (details below). Fluconazole is the trial-proven gold standard due to good tolerability and 
reasonable coverage of many Candida spp.1,2 However the emergence of fluconazole-resistant Candida, plus 
the risk of Aspergillus spp. (not covered by fluconazole) in high-risk patients, makes the identification of a 
superior agent a priority. While voriconazole does have excellent anti-Aspergillus activity, it has failed to show 
superiority to fluconazole post HCT,3 possibly due to erratic drug levels,4-6 a problem especially apparent in 
young children.7-9 In addition, voriconazole has multiple drug interactions with post-HCT immunosuppression 
medications.6,10-12 The echinocandins have significant activity against almost all Candida spp., the most 
common organisms encountered in the first month post-HCT, and there appears to be little concern for 
emerging resistance.13 In addition, echinocandins have some anti-Aspergillus activity, an excellent safety 
profile, few drug interactions, and an IV formulation (important for children with post-HCT mucositis and an 
inability to tolerate or absorb oral medications). The one randomized trial of an echinocandin for post-HCT 
prophylaxis showed promise at decreasing the need for empiric anti-fungal agents, but enrolled few pediatric 
patients and many low-risk patients, making it difficult to definitely determine the utility of echinocandins in 
high-risk pediatric HCT patients.14  
 
The recently published ASBMT Supportive Care Guidelines recommend fluconazole for standard-risk patients 
and consideration of micafungin for adult patients at high risk for mold infection, but no alternative agent is 
recommended for pediatric patients, because no data exists for this population.15 In addition, micafungin is not 
FDA-approved for use in children, has no accepted dose for children less than 2 years of age, and carries an 
EMEA black-box warning in Europe about animal studies showing a risk of developing liver tumors after 
prolonged administration.16 Therefore, this study is designed to definitively determine if caspofungin, an FDA-
approved agent for children over 3 months of age, is effective at preventing IFI infections. Given the safety of 
caspofungin, its excellent anti-Candida properties, and potential ability to suppress Aspergillus, we hypothesize 
that caspofungin will be superior to standard azole prophylaxis at preventing IFI post-HCT in patients at high 
risk for developing IFI. As IFI represent a significant source of post-HCT morbidity and mortality, reduction 
of IFIs should translate to improved post-HCT survival.  
 
The study has been designed as an open-label comparison of an echinocandin (caspofungin) vs. an azole (local 
center determination of fluconazole or voriconazole). This open-label randomized trial will test the 
effectiveness of our intervention in a setting that will mirror usual clinical practice and thus, this more pragmatic 
design can better inform decision-making.17,18 Because of this approach, the lack of blinding is not a weakness. 
There are other major feasibility issues with the use of these agents that favor the open-label approach. In an 
allogeneic HCT population, echinocandins and azoles (esp. voriconazole) have significant and dramatic 
differences relative to their interactions with concomitant medications. This is most important and relevant for 
the calcineurin inhibitors (CIs; cyclosporine and tacrolimus) and sirolimus. Caspofungin has no apparent effect 
on the levels of CIs.10 On the other hand, fluconazole is an inhibitor of several CYP enzymes and therefore 
causes an approximate 16-21% increase in the levels of CIs.11 Furthermore, voriconazole is a major inhibitor 
of CYP2C9, which causes significant interactions with these crucial transplant medications. The FDA label 
reports that concomitant use of voriconazole can cause a 1.7 to 3-fold increase in cyclosporine or tacrolimus 
levels, and recommends that the dosing of cyclosporine be decreased by 50% and the dosing of tacrolimus be 
decreased by 66% of the normal dose. A recent study demonstrated in a cohort of 27 adult BMT patients 
receiving voriconazole, 100% of patients required multiple tacrolimus dose reductions to achieve a safe target 
level.6 Furthermore, the use of voriconazole with sirolimus is officially contraindicated, and when its use has 
been reported, investigators have recommended dropping the levels of sirolimus to 90% of original dosing at 
the time of initiation of voriconazole.12 Given these drug-drug interactions, it is not safe and likely not possible 
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to conduct the trial in a truly blinded fashion. One potential limitation of an open label trial is the potential for 
observer bias in outcome determination. In this study, the primary outcome will be determined through a 
blinded review committee. This will minimize the possibility of observer bias, and has been successfully 
utilized in other anti-fungal prophylaxis trials in which a double-blind design was not feasible.19,20 Similarly, in 
non-transplant patients, multiple highly influential trials of extended-spectrum azoles have utilized a non-
blinded approach.21-23 Furthermore, open-label trials have another inherent advantage to double-blinded trials, 
which is that treating physicians may be uncomfortable not knowing what medications their patients are 
receiving. This can potentially lead to both decreased trial participation and to unanticipated confounders. This 
can be seen in the trial by Wingard et al. in which 7.8% of the fluconazole arm and 11.5% of the voriconazole 
arm received simultaneous off-study use of other mold-active agents.3 We would not expect this type of 
confounding behavior in an open-label trial.  
 
There are no data to support the concept that certain underlying conditions may confer a lower risk for IFI 
due to the presence of a relatively intact immune system prior to transplant. A recent publication by Hol et 
al. demonstrated that in 209 pediatric patients undergoing allogeneic HSCT, there was no difference in IFI 
rate based on the underlying condition (p = 0.967).24 This suggests that it is the transplant process itself, 
with the accompanying disruption in both innate and adaptive immunity, which is the primary risk factor 
for development of an IFI. Most reports do not distinguish the rates of IFI between various donor types. One 
series of retrospective data (primarily in adults) showed that the risk of IFI at 1 year in alternate donors was 
~2% higher than seen in matched-siblings.50 However, in the most recent pediatric-specific paper by Hol et al., 
there was a non-significant difference in IFI rate between MSD (9.3%) vs. MUD (10.5%) vs. UCB (14.3%) (p 
= 0.3). Given the similar IFI risk across donor sources, all allogeneic donor types will be considered eligible 
for enrollment on this trial. There will be no limitations to trial enrollment based on race or gender as there is 
no data to support differences in the incidence or outcomes of IFIs due to race or gender. 
 
 
2.2  
Trial Importance 
The profound immunosuppression that occurs while undergoing HCT places patients at high risk for infectious 
complications.25 Although bacteria represent the most common infection following HCT, IFI account for a 
significant amount of post-transplant mortality. The 1-year incidence of IFI in the pediatric HCT population 
has been reported to be as high as 13-20%, with 58-83% mortality.26-29 The most commonly identified invasive 
fungal organisms following HCT are Candida spp. and Aspergillus spp. Candida spp. are most commonly 
encountered during the neutropenic period in the first several weeks following HCT, while Aspergillus spp. 
have a bimodal distribution, with a first peak at a median of 16 days and the second at a median of 96 days 
post-allogeneic HCT.25,30 Different centers have reported slightly different incidences of developing an IFI early 
post HCT, ranging from 8.7% (first 28 days)26, to 4.1% (first 30 days)27, to 6.5% (first 40 days, Aspergillus 
only).28 Patients that are considered to be high-risk for developing an IFI following allogeneic HCT are those 
who undergo transplant from either an unrelated donor (including umbilical cord blood) or a partially-matched 
related donor, for treatment of a malignancy, bone marrow failure syndrome, or congenital 
immunodeficiency.15,28,29 Guidelines have been developed by the European Organization for Research and 
Treatment of Cancer and Mycoses Study Group (EORTC/MSG) to standardize the definitions of proven, 
probable, and possible IFI.31 
 
Based upon the above data, most centers employ an anti-fungal strategy that includes prophylaxis for allogeneic 
HCT recipients. However, no standard class of agent has emerged. Furthermore, given the different spectrum 
of organisms in the acute neutropenic phase and the later post-engraftment phase, it is very possible that the 
optimal agent may differ depending on time following stem cell infusion. This proposal is focused on the acute 
neutropenic phase.  
 
A positive study outcome will result in less IFI in patients undergoing alternative donor allogeneic HCT. 
Because IFI represents a major source of morbidity and mortality, this would improve overall outcomes and 
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subsequently allow expanded access of patients to alternative donor HCT, a potentially curative approach for 
children with high-risk leukemia. 
 
In addition, the diagnosis of IFI 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 noninvasive tests for diagnosing IFI. Serum beta-D glucan (found in all fungi except Crytpococcus 
spp. and Zygomycetes) can be detected using an approved diagnostic serum assay (the Fungitell Assay) and 
has been found to have high specificity and high positive predictive values for the detection of IFI in adults.32 
However, data on the performance of this assay in children are limited. A positive result of this aspect of the 
trial will allow earlier treatment of IFI in the future, and early treatment has been associated with superior 
resolution rates. In addition to early detection of fungal infections, there also is interest in identifying patients 
particularly susceptible to IFIs so that they can receive early targeted interventions. There is considerable 
evidence that there is a genetic component to the susceptibility and outcome of infection in both normal and 
immunocompromised populations. A recent study suggests an association between the donor TLR4 haplotype 
S4 and the risk of invasive aspergillosis (IA) among recipients of HCTs from unrelated donors.33  Another study 
reports that polymorphisms in the chemokine ligand 10 are associated with developing IA after allogeneic 
HCT.34 Other studies have demonstrated that polymorphisms in plasminogen or dectin-1 may also contribute 
to the development of IA post-HCT.35,36  
 
One of the biologic aim of the trial will be to create a DNA specimen bank to be used in future attempts to 
identify, in a homogenously treated cohort, those patients at the genetic level that have the highest risk for the 
development of an IFI, which in the future may allow for enhanced prophylaxis efforts in these patients, while 
allowing less stringent prophylaxis (with less toxicity) for patients at low genetic risk for IFI development. 
 
 
2.3 
Selection of Study Medication 
 
2.3.1 Prophylactic Fluconazole is Superior to Placebo in Allogeneic HCT Patients 
Based on two pivotal trials, the most common agent used for primary prophylaxis for IFI in children is 
fluconazole, despite the fact that fluconazole has no activity against Aspergillus spp. The first trial was 
performed by Goodman et al., who conducted a double-blind, randomized, multicenter trial in which patients 
greater than 12 years of age receiving autologous or allogeneic HCTs were randomly assigned to receive 
prophylactic fluconazole (400 mg daily) versus placebo from the start of the conditioning regimen until one of 
the following: the absolute neutrophil count (ANC) recovered >1000/µL, toxicity was suspected, or a systemic 
fungal infection was suspected or proven.1 Systemic fungal infections occurred in 15.8% patients who received 
placebo as compared with 2.8% who received fluconazole (P < .001). There was no significant difference in 
overall mortality between the groups. 
 
Slavin et al. also performed a randomized, double-blind, placebo-controlled trial and assessed the efficacy and 
toxicity of 400 mg/day fluconazole in preventing fungal infections during the first 75 days after autologous or 
allogeneic marrow transplantation in patients greater than 12 years of age.2 During prophylaxis, systemic fungal 
infections occurred in 7% of 152 fluconazole-treated patients compared with 18% of 148 placebo-treated 
patients (P = .004). The probability of survival was improved in fluconazole recipients, in whom 20% expired 
up to Day 110 after transplantation compared with 35% mortality in placebo recipients (P = .004). Fluconazole 
also appeared to protect from severe GVHD of the gut, possibly from decreased intestinal antigenic 
stimulation.29 
 
The dosing of fluconazole used on prior prophylaxis trials that have included patients under the age of 12 years 
have been either 6 mg/kg/day3 or 8 mg/kg/day.14 The pediatric fluconazole dose which is equivalent to the 
dose recommended for adults in the source guideline (400 mg/day) ranges from 6-12 mg/kg/day depending 
on patient age and weight.37-41 This is based on pharmacokinetic studies in children showing that children 
less than 15 years of age have a higher volume of distribution and faster elimination rate compared to 
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adults.37,38,40 From a safety standpoint, fluconazole is believed to be safe and well tolerated in doses up to 
12 mg/kg/day.39 This dose range is higher than the ASBMT recommendation of 3-6 mg/kg/day.15 However, 
we feel that the higher dose is justified given the available information outlined above and the adequate 
safety data. The dose of 12 mg/kg/day also unifies our approach with that of COG ACCL0933.  
 
2.3.2 Prophylaxis with Amphotericin or Extended Spectrum Azoles in Allogeneic HCT Patients 
Because fluconazole does not possess anti-Aspergillus activity, several trials have compared it to mold-active 
agents. Wolff et al. randomized patients undergoing allogeneic or autologous marrow or peripheral stem cell 
transplantation to receive fluconazole (400 mg/day PO or IV) or amphotericin B (0.2 mg/kg/day IV) beginning 
1 day prior to stem cell transplantation and continuing until recovery of ANC > 500/μl.42 Amphotericin B was 
significantly more toxic than fluconazole. Proven fungal infections occurred in 9.1% and 14.3% of related 
allogeneic marrow recipients receiving fluconazole or amphotericin B, respectively. Given the lack of 
significant benefit and the higher adverse event rate, low-dose amphotericin B has failed to supplant 
fluconazole as standard-of-care prophylaxis. 
 
Extended-spectrum azoles such as itraconazole do possess anti-Aspergillus activity. Marr et al. performed a 
randomized trial of 304 patients receiving allogeneic stem cell transplant to receive either fluconazole 
(400 mg/day) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or 200 mg IV daily) for 180 days after 
transplantation, or until 4 weeks after discontinuation of GVHD therapy.19 More patients in the itraconazole 
arm developed hepatotoxicity, and more patients were discontinued from itraconazole because of toxicities or 
gastrointestinal intolerance (36% vs. 16%, P < .001). Fewer patients in the itraconazole arm developed IFI 
while on study drug (fluconazole 15% vs. itraconazole 7%, P = .03); however there was no difference in overall 
or fungal-free survival. Because of its poor tolerability, itraconazole prophylaxis has generally been abandoned.  
 
A multi-center, randomized, double-blind trial was performed in 600 patients to compare fluconazole (400 mg 
daily in adults) versus voriconazole (200 mg twice daily in adults) for the prevention of IFIs in standard risk 
allogeneic HCT patients receiving full-intensity conditioning regimens.3 The cumulative rates of proven, 
probable and presumptive IFI were similar in the two arms: 11.2% for fluconazole and 7.3% for voriconazole 
at 6 months (P = .12) and 13.7% and 12.7% at 12 months (P = .59), respectively. Event-free and overall survival 
rates also were similar in both arms at 6 and 12 months. Rates of expected or unexpected severe adverse events 
and rates of premature study drug withdrawal were similar in both arms. Therefore, there did not appear to be 
a significant benefit of voriconazole compared with fluconazole as primary prophylaxis against IFI following 
HCT, although its use has been adopted by many centers. Possible reasons cited by others as to why 
voriconazole did not appear to be superior to fluconazole include: 1) that a significant fraction of patients treated 
with standard dosing of voriconazole may have had sub-therapeutic levels5; and 2) that voriconazole is possibly 
an inferior anti-Candida drug than fluconazole, with primarily fungistatic effects.43 
 
There is currently no accepted dosing schema for voriconazole in children less than 2 years of age, where 
clearance is expected to be even higher than in children between 2 and 12 years of age.8 Because of this, centers 
that choose to utilize voriconazole as their comparator arm will not be able to enroll patients between the ages 
of 3 months to 2 years. The dosing of older children will be based on the most recent pharmacokinetic data 
available.44 
 
2.3.3 Echinocandins as Prophylaxis in Allogeneic HCT 
Echinocandins are a novel class of antifungal agents that target β-(1,3)-D-glucan synthase and interrupt 
biosynthesis of the glucan polymers that make up fungal cell walls. Because mammalian cells do not possess 
cell walls, echinocandin administration to human patients has resulted in minimal toxicity. Echinocandins 
possess fungicidal activity against Candida spp. (including Candida krusei and Candida glabrata, which 
possess significant degrees of fluconazole resistance) and Pneumocystis jirovecii, as well as fungistatic activity 
against Aspergillus spp. The echinocandins may be superior to fluconazole45 or amphotericin B46 for treatment 
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of invasive candidiasis which, when combined with their anti-Aspergillus activity and excellent safety profile, 
makes them an attractive class of agent to use in the early post-HCT period.  
 
Van Burik et al. conducted a randomized, double-blind, multi-institutional Phase III trial involving 882 adult 
and pediatric patients undergoing autologous or allogeneic HCT, and compared 50 mg of micafungin (1 mg/kg 
for patients weighing < 50 kg) versus 400 mg of fluconazole (8 mg/kg for patients weighing < 50 kg) 
administered once per day.14 Success was defined as the absence of suspected, proven, or probable IFI through 
the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after 
treatment. Micafungin was extremely well-tolerated (discontinuation of study drug because of an adverse 
event: 4.2% in micafungin arm versus 7.2% in fluconazole arm). The overall efficacy of micafungin was 
superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HCT (80.0% in the 
micafungin arm vs. 73.5% in the fluconazole arm; P = .03). This trial was the first antifungal agent to 
demonstrate superior efficacy and tolerability compared to fluconazole. However, the number of pediatric 
subjects enrolled was small (n = 84). Also, micafungin was most effective at preventing the need for empiric 
antifungal therapy, which is a less clinically important endpoint, and did not reduce the incidence of proven or 
probable IFI. The lack of impact on IFIs may have been because the incidence of breakthrough IFIs in both 
groups was very low, likely due to the inclusion of low-risk patients (46% autologous HCT recipients) and very 
few patients undergoing umbilical cord blood transplant (n = 30), a population of significant interest to pediatric 
transplant physicians. A retrospective evaluation of 123 adult allogeneic HCT recipients who received 
caspofungin 35-50 mg/day for up to 100 days after transplantation as primary antifungal prophylaxis 
demonstrated that 7.3% developed breakthrough IFI in the first 100 days post-HCT. No caspofungin-related 
adverse events were reported.47 The major disadvantages to echinocandin use are cost and that it is only 
available in parental form. Thus, it is more difficult to administer once the patient has recovered from the 
neutropenic period and is ready for discharge from inpatient hospitalization.  
 
2.3.4 Summary of the Two Azole Control Design 
On January 26, 2011 (4 months after initial publication of the voriconazole trial by Wingard et al.3), we initiated 
a survey of the 80 COG Transplant Centers in North America and Australia/New Zealand in order to determine 
local standard-of-care anti-fungal prophylaxis for patients undergoing alternative donor (unrelated or 
mismatched related) HCT. The response rate was 80%, similar to the 83% seen in a survey of COG centers 
regarding anti-infective prophylaxis in patients with AML.48 We found that for patients undergoing unrelated 
donor HCT (including umbilical cord blood), 56% of centers continue to use fluconazole, while 28% of centers 
have adopted voriconazole, 11% of centers utilize an echinocandin, and 5% administer a lipid formulation of 
amphotericin B. The data were very similar for patients undergoing mismatch related donor HCT (57%, 27%, 
8%, and 8%, respectively). These results indicate that the profound lack of data for this patient population has 
led to a clinical situation where there is no clear universal agent of choice. Despite the fact that some centers 
have already adopted an echinocandin as the prophylaxis of choice, fully 89% of respondents indicated that 
they would be willing to participate in a trial of an echinocandin vs. an azole (center choice of fluconazole or 
voriconazole), as we have proposed for this trial. Even if all of the non-responding centers refused to participate, 
this would still be 71% of COG Transplant Centers. Finally, centers willing to participate were asked which 
azole they would choose as the comparator, and interestingly the pediatric HCT community was split almost 
evenly between fluconazole (54%) and voriconazole (46%), further justifying our two-azole design.  
 
Therefore, our study is designed so that the local institutions will be allowed to choose what their standard-of-
care anti-fungal prophylactic azole is for the study population in question. This practical study design reflects 
the real-world situation in which different agents have been adopted by individual centers on the basis of 
insufficient data. Furthermore, this design mirrors the Phase III trial in which posaconazole was compared to 
either fluconazole or itraconazole (two agents with different spectrums of activity) in non-transplant patients 
with neutropenia.22 In other words, that highly influential study used a similar strategy of comparing 
posaconazole against agents with and without mold activity in order to optimize acceptability of the trial. 
 
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For patients undergoing allogeneic HCT, fluconazole’s spectrum of activity is limited primarily to Candida 
spp. It has been demonstrated in two pivotal trials to be superior to placebo, but no patients under the age of 12 
years were included in either trial.1,2 Therefore, while fluconazole has been adopted as the “gold standard” for 
prophylaxis, for young children this is not based on any data. Voriconazole has the attractive feature of 
possessing activity against Aspergillus spp., as well as certain fluconazole-resistant strains of Candida, 
however, with the small trade-off that it is potentially less effective than fluconazole against fluconazole-
susceptible strains of Candida, where it is fungistatic, rather than fungicidal.43 More importantly, the 
pharmacokinetics of voriconazole are not simple. In adults and children over the age of 12 years (the subjects 
of most trials to date), voriconazole has non-linear properties with relatively well-established dosing regimens. 
Even in adults however, recent studies have called into question the “standard” dosing, and have proposed 
dosing based on serum drug levels due to ~25% of patients found to have extremely low voriconazole 
levels.4,5,49 Part of this variability may be due to polymorphisms of the gene encoding for CYP2C19, which can 
result in an increase or decrease in voriconazole metabolism.5 In children, the situation is even more 
problematic due to linear kinetics. In children between the ages of 2 and 12 years, the optimal dose may be 7 
mg/kg twice daily,7,9 while in children < 2 years of age, it may be as high as 8.5 mg/kg/dose twice daily.8 
However, none of these opinions regarding dosing and drug level monitoring have been universally-accepted, 
leading to a potential wide range of different treatment strategies and outcomes. Nevertheless, because of the 
advantage of voriconazole against Aspergillus spp., its use has been adopted for primary prophylaxis at many 
institutions, despite a paucity of data to support this practice. 
 
In the only head-to-head prospective trial of fluconazole vs. voriconazole, although there was a trend towards 
less IFI in the voriconazole arm, the difference was not statistically significant (P = .12).3 Furthermore, while 
patients over two years of age were eligible for this trial, in reality the number of pediatric patients enrolled 
was very small (n = 51), and in fact, no patient under the age of 9 years was given fluconazole. Therefore, the 
best trial to date has not been able to demonstrate that there is a difference between using fluconazole or 
voriconazole for IFI prophylaxis, despite the theoretical reasons why they might be different. Consequently, 
this is the rationale for the comparator being either fluconazole or voriconazole. Also, no trial to date has proven 
what the optimal agent is for children, especially those less than 12 years of age. 
 
Because of this lack of convincing data to support one azole over the other, when designing this trial, it was 
felt that forcing the local institutions to adopt one agent as their standard-of-care would likely lead to a 
significant degree of non-participation. This potential conflict was confirmed during informal polling of leading 
pediatric transplant physicians both on the COG Stem Cell Transplant Steering Committee and at the open 
sessions of the last several COG National Meetings. In contrast, the study design that we have proposed clearly 
has widespread support in the pediatric HCT community (89% of respondents indicating that they wished to 
participate in the trial). As noted above, this potential issue has been dealt with before in other trials, such as 
the non-blinded randomized comparison of posaconazole to the institutional choice of fluconazole or 
itraconazole, which led to its wide acceptance by the community.22  
 
 
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3.0 
STUDY ENROLLMENT PROCEDURES 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. 
 
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. The date protocol-
directed antifungal prophylaxis is projected to start must be no later than five (5) calendar days after the 
date of study enrollment.  
 
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. 
 
 
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3.1.5 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study. 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 an azole (fluconazole or 
voriconazole). Randomization will be stratified by:  
• 
Center choice of azole: fluconazole vs. voriconazole. 
• 
Age: ≥ 12 years vs. < 12 years 
• 
Type of transplant: Umbilical cord blood (UCB) donor vs. Non-UCB donor with ex vivo T-cell-
depletion vs. Non-UCB donor with standard pharmacologic GVHD prophylaxis. 
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per 
COG policy posted 5/11/01). 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.  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older 
than seven (7) days at the start of therapy. Laboratory tests need not be repeated if therapy starts 
within seven (7) days of obtaining labs to assess eligibility. If a post-enrollment lab value is outside 
the limits of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: bilirubin, ALT (SGPT) 
and serum creatinine. If the recheck is outside the limits of eligibility, the patient may not receive 
protocol therapy and will be considered off protocol therapy. See Section 7.1 for required studies to 
be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
3.2.1 
Age 
For centers that will use fluconazole as the antifungal comparator:  
Age ≥ 3 months and < 21 years.  
 
For centers that will use voriconazole as the antifungal comparator:  
Age ≥ 2 years and < 21 years.  
 
3.2.2 
Diagnosis 
- The patient must be undergoing allogeneic HCT from any donor (including matched related) with any 
stem cell source for any underlying condition. 
 
 
3.2.3 
Performance Level 
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2. Use Karnofsky for 
patients > 16 years of age and Lansky for patients ≤ 16 years of age.  
See https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard Sections for 
Protocols. 
 
3.2.4 
Organ Function Requirements 
 
3.2.4.1 Adequate Renal Function Defined As: 
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− 
Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
− 
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 GFR50 utilizing child length and stature data published by the CDC. 
 
 
3.2.4.2 Adequate Liver Function Defined As: 
- Total bilirubin < 2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert‘s Syndrome, 
and  
- SGOT (AST) or SGPT (ALT) < 5X upper limit of normal (ULN) for age. 
EXCLUSION CRITERIA 
3.2.5 
Within 90 days of enrollment:  
• 
Patients with a proven or probable invasive mold infection are not eligible.  
• 
Patients with an incompletely treated invasive yeast infection are not eligible.  
 
Patients with an elevated galactomannan level (≥ 0.5 Index) within 30 days prior to time of 
enrollment (if performed) must have a full evaluation for invasive aspergillosis (including a 
negative chest CT scan) during that time period to be eligible for enrollment.  
 
3.2.6 
Patients receiving treatment for an IFI are not eligible. 
 
3.2.7 
Patients with a history of echinocandin or azole hypersensitivity are not eligible. 
 
3.2.8 
Female patients of childbearing potential are not eligible unless a negative pregnancy test result has 
been obtained.  
 
3.2.9 
Sexually active patients of reproductive potential are not eligible unless they have agreed to use an 
effective contraceptive method for the duration of their study participation.  
 
3.2.10 Lactating females are not eligible unless they have agreed not to breastfeed their infants. 
 
REGULATORY  
 
3.2. 11 All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2. 12  All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
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4.0 
TREATMENT PLAN 
 
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). 
 
4.1 
Overview of Treatment Plan 
 
This is a randomized open-label clinical trial designed to assess the efficacy of caspofungin for preventing 
IFI (including IA) compared to antifungal prophylaxis with an azole (fluconazole or voriconazole), the 
standard therapies used in most COG institutions as prophylaxis in patients undergoing HCT. 
 
At the time of enrollment, the enrolling center will declare whether the comparator arm will be fluconazole 
or voriconazole based upon that institution’s standard of care and the choice of comparator should remain 
constant for the duration of the study. 
 
Patients who consent to participate in ACCL1131 will be randomly assigned to antifungal prophylaxis with 
either an azole or caspofungin. Treatment with any antifungal prophylaxis initiated prior to enrollment must 
be terminated prior to starting protocol-directed antifungal therapy. Protocol prophylaxis will be started 
within 24 hours of transplant (Day 0). Administration of antifungal prophylaxis will continue until (a) HCT 
Day +42; OR (b) Day of Hospital Discharge; OR (c) Patient meets any off-protocol criteria (Section 8.1). 
Following discontinuation of study medications, institutions may revert to local standard of care for post-
engraftment antifungal prophylaxis. 
 
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 Day +42, Day of Hospital Discharge, or at the time 
a patient is taken off-protocol therapy (see Section 8.1). 
 
Fluconazole and voriconazole may be administered either intravenously (IV) or orally. Caspofungin is only 
available as an IV formulation. 
 
4.1.1 
Randomization 
At the time of enrollment, patients will be randomly assigned to one of two treatment regimens: 
 
i) Azole Arm: This group will receive fluconazole or voriconazole, and represents the standard arm. 
 
ii) Caspofungin Arm: This group will receive caspofungin and represents the experimental arm. 
 
Randomization will be stratified into groups based on: 
i)    Center choice of azole: 1) fluconazole vs. 2) voriconazole. 
ii) Age: 1) ≥12 years vs. 2) < 12 years 
iii) Type of transplant: 1) Umbilical cord blood (UCB) donor vs. 2) Non-UCB donor with ex vivo 
T-cell-depletion vs. 3) Non-UCB donor with standard pharmacologic GVHD prophylaxis. 
 
 
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4.1.2 
Empirical Antifungal Therapy 
The persistence of fever for 3 to 5 days despite broad spectrum antibiotic therapy warrants the investigation 
for IFIs and initiation of empiric antifungal therapy.51 Amphotericin B (lipid products) is a reasonable 
option based on its broad spectrum of activity as empiric antifungal therapy in all treatment arms. The type, 
dose, and duration of non-assigned antifungal agent usage will be tracked. 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. Careful monitoring of calcineurin inhibitor levels is highly 
recommended on this protocol. 
 
Co-administration 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 Voriconazole 
Some azoles, including voriconazole, 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 
voriconazole. The administration of terfenadine and cisapride with any dose of voriconazole 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 voriconazole and the following agents have been 
observed: oral hypoglycemics (tolbutamide, glyburide, glipizide), coumarin-type anticoagulants (e.g., 
warfarin), phenytoin, cyclosporine, rifampin, theophylline, tacrolimus, short-acting benzodiazepines, and 
oral contraceptives. Since rifabutin enhances the metabolism of concurrently administered voriconazole 
and the dose of voriconazole may need to be increased, the use of rifabutin in this study should be avoided. 
Careful monitoring is required when voriconazole is administered with the other drugs. Currently, the co-
administration of voriconazole and sirolimus is contraindicated due to significant elevation in sirolimus 
levels. It is also to be expected that the co-administration of voriconazole and a calcineurin inhibitor 
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(cyclosporine or tacrolimus) will result in a 1.7 to 3 fold increase in cyclosporine or tacrolimus levels. The 
FDA label recommends that the dosing of cyclosporine be decreased by 50%, and the dosing of tacrolimus be 
decreased by 66%, of the normal dose when given with voriconazole. Careful monitoring of calcineurin 
inhibitor levels is highly recommended on this protocol.  
 
Voriconazole inhibits several cytochrome P450 (CYP450) isoenzymes and may increase the serum level of 
drugs metabolized by CYP450. For a list of drugs metabolized by the CYP450 system see 
http://medicine.iupui.edu/flockhart.  
 
4.1.3.3 Caspofungin 
Co-administration 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. Therefore, the use of these interacting 
drugs should be avoided if possible.  
 
Cyclosporine increases the caspofungin area under the concentration curve (AUC) which may result in a 
transient elevation of ALT/SGPT and AST/SGOT. Liver function tests should be closely monitored in 
patients receiving caspofungin and cyclosporine. Patients who develop abnormal liver function tests should 
be monitored and the risk/benefit of continuing concomitant therapy should be evaluated. The manufacturer 
of caspofungin recommends that concomitant use with cyclosporine should only occur in those patients for 
whom the potential benefit outweighs the potential risk. Centers comfortable with the use of tacrolimus for 
GVHD prophylaxis may consider utilizing this agent in place of cyclosporine. 
 
For COG Supportive Care Guidelines see: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
 
 
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4.2 
Administration Schedule: AZOLE ARM 
 
4.2.1 
FLUCONAZOLE COMPARATOR 
 
Patients randomized to this regimen will start prophylaxis within 24 hours of transplant (Day 0). Continue 
prophylaxis until the occurrence of any of the following, whichever is sooner: 
 
• 
Day +42 
OR 
• 
Day of Hospital Discharge 
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 Day +42, Day of Hospital Discharge, or patient off protocol.  
 
Following completion of study prophylaxis, institutions may revert to local standard of care for post-
engraftment anti-fungal prophylaxis. 
 
FLUCONAZOLE: by slow IV infusion over 1-2 hours* (or longer) OR by mouth. 
 
Age ≥ 3 months to 17.99 years: Dose: 12 mg/kg/day once daily (maximum dose: 400 mg/day) 
Age ≥ 18 years to 20.99 years: Dose: 6 mg/kg/day once daily (maximum dose: 400 mg/day) 
 
*For IV: The rate of infusion should not exceed 200 mg/hour. 
 
Rounding:  
Tablets: Round the dose to the closest 50 mg. 
Suspension: Round the volume to the closest tenth of an 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.  
 
21 
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ACCL1131  
 
4.2.2 Fluconazole Treatment Arm. 
Patients randomized to fluconazole arm. 
      
_____________________________   ______________________ 
       Patient name or initials                                DOB 
 
Prophylaxis with fluconazole begins within 24 hours of transplant (Day 0). Extensive administration details are in Section 4.2.1. 
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 – 20.99 years: 
6 mg/kg/day 
(IV or enteral dose) 
Maximum dose: 
400 mg/day 
Once 
daily 
Start within 
24 hours of 
transplant (Day 0). 
 
*For IV: The 
infusion rate should 
not exceed 
200 mg/hour 
 
See Section 4.2.1 for 
oral drug 
administration. 
a. History, PE (ht, wt, BSA), 
albumin  
b. CBC, diff, plts, creatinine, 
AST, ALT, bilirubin 
c. GVHD Scoring 
d. IFI Checklist  
If patient consents: 
e. beta-D glucan testing (see 
Section 13) 
f. SNP (see Section 14) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
 
Enter Date of Transplant 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 
 
 
 
1 
[HCT Day 0 
or +1]^ 
____________mg 
 
a, b, e, f 
 
 
 
… 
 
 
 
 
4 
b 
 
 
 
… 
 
 
 
 
8 
a, b, e 
 
 
 
… 
 
 
 
 
11 
b 
 
 
 
… 
 
 
 
 
15 
a, b, c, e 
 
 
 
… 
 
 
 
 
18 
b 
 
 
 
… 
 
 
 
 
22 
a, b, c, e 
 
 
 
… 
 
 
 
 
25 
b 
 
 
 
… 
 
 
 
 
29 
a, b, c, e 
 
 
 
… 
 
 
 
 
32 
b 
 
 
 
… 
 
 
 
 
36 
a, b, c, e 
 
 
 
… 
 
 
 
 
39 
b 
 
 
 
… 
 
 
 
 
43*  
[HCT Day 
+42] 
Or End Date: ___________ 
a, b, c, d, e 
 
*Continue prophylaxis until criteria in Section 4.2.1 are met (may be less than 43 days). 
^Following completion of study prophylaxis, institutions may revert to local standard of care for post-engraftment antifungal prophylaxis.  
^Because study medication may be started within 24 hours of HCT, some patients may actually begin on HCT Day -1, such that they would potentially receive up to 
44 days of study medication. 
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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4.2.3 
VORICONAZOLE COMPARATOR 
 
Patients randomized to this regimen will start prophylaxis within 24 hours of transplant (Day 0). Continue 
prophylaxis until the occurrence of any of the following, whichever is sooner: 
 
• 
Day +42 
OR 
• 
Day of Hospital Discharge 
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 
voriconazole prophylaxis should be held and voriconazole should resume when other systemic antifungal 
therapy is discontinued if this occurs prior to Day +42, Day of Hospital Discharge, or patient off protocol.  
 
Following completion of study prophylaxis, institutions may revert to local standard of care for post-
engraftment anti-fungal prophylaxis. 
 
VORICONAZOLE: by slow IV infusion over 1-2 hours* (or longer) OR by mouth: 
 
Age 
Weight 
Loading dose* 
IV q12h x 2 doses 
Maintenance dose 
IV or PO q12h  
2 – 11.99 years 
all 
IV:  9 mg/kg 
IV: 8 mg/kg 
 
or 
 
PO: 9 mg/kg 
(max: 350 mg/dose) 
12 – 13.99 years 
< 50 kg 
IV:  9 mg/kg 
IV:  8 mg/kg 
 
or 
 
PO:  9 mg/kg  
(max: 350 mg/dose) 
12 – 13.99 years 
≥ 50 kg 
IV:  6 mg/kg 
IV:  4 mg/kg 
 
or 
 
PO:  200 mg 
≥ 14 years 
All 
IV:  6 mg/kg 
IV:  4 mg/kg 
 
or 
 
PO:  200 mg 
*All loading doses should be given IV q12h x 2 doses followed by either IV or PO maintenance 
dosing q12h. 
 
Centers that currently modify voriconazole prophylaxis dosing based on trough concentrations may continue 
this practice, and therefore may end up either exceeding the study recommended maximum dose listed above 
(if the trough is low) or be lower than the study recommended starting dose based on weight (if the trough is 
high). The actual dose administered and the reason for an adjustment to the study recommended dose will be 
recorded. 
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*For IV: The rate of infusion should not exceed 3 mg/kg/hour 
 
Oral voriconazole is available as 50 and 200 mg tablets and as an oral suspension at a concentration of 
40 mg/mL. 
 
Rounding:  
Tablets: Round the dose to the closest 50 mg. 
Suspension: Round the volume to the closest tenth of a mL. Round 0.05 mL up (e.g., round 3.15 mL to 
3.2 mL). 
 
Oral voriconazole is best taken 1 hour before or 1 hour after a meal. It should be administered at approximately 
the same times 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 voriconazole prophylaxis is on the next page.  
24 
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4.2.4 Voriconazole Treatment Arm. 
Patients randomized to voriconazole arm. 
 
_________________________    _______________________ 
       Patient name or initials                                    DOB 
Prophylaxis with voriconazole begins within 24 hours of transplant (Day 0). Extensive administration details are in Section 4.2.3. This TDM is on One (1) page. 
 
DRUG  
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES OBSERVATIONS 
VORICONAZOLE  
 
 
Slow IV infusion 
over 1-2 hours# 
(or longer) OR 
by mouth. 
 
 
2 - 11.99 years (all weights): 
LD IV:  9 mg/kg/dose 
MD IV: 8 mg/kg/dose or  
       PO: 9 mg/kg/dose 
(max: 350 mg/dose) 
 
12 – 13.99 years < 50 kg: 
LD IV:  9 mg/kg/dose 
MD IV: 8 mg/kg/dose or  
       PO: 9 mg/kg/dose  
(max: 350 mg/dose) 
 
12 – 13.99 years ≥ 50 kg: 
LD IV:   6 mg/kg/dose 
MD IV:  4 mg/kg/dose or  
       PO:  200 mg/dose 
 
≥ 14 years (all weights): 
LD IV:  6 mg/kg/dose 
MD IV: 4 mg/kg/dose or  
       PO: 200 mg/dose 
Twice daily 
Day 1 
Day 2 (and 
subsequently) 
 
 
Day 1 
Day 2 (and 
subsequently) 
 
 
Day 1 
Day 2 (and 
subsequently) 
 
 
Day 1 
Day 2 (and 
subsequently) 
Start within 
24 hours of 
transplant (Day 0). 
  
#For IV: The 
infusion rate should 
not exceed 
3 mg/kg/hour 
 
 
a. History, PE (ht, wt, 
BSA), albumin 
b. CBC, diff, plts, 
creatinine, AST, 
ALT, bilirubin 
c. GVHD Scoring 
d. IFI Checklist 
If patient consents: 
e. beta-D glucan 
testing (see Section 
13) 
f. SNP (see Section 14) 
 
 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Enter Date of Transplant Here___________ 
 
Ht_____cm 
    Wt____kg 
 
BSA____m2 
Date Due 
Date 
Given 
Day 
VORICONAZOLE 
Day 1:_________mg;  
Day 2 and Subsequently: ________mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
Enter calculated dose above & actual dose administered below 
 
 
 
1 [HCT Day 0 
or +1]^ 
LD:  _________mg     _________mg 
a, b, e, f 
 
 
 
2 
MD:  _________mg     _________mg 
 
 
 
 
 
… 
 
 
 
 
4 
b 
 
 
 
… 
 
 
 
 
8 
a, b, e 
 
 
 
… 
 
 
 
 
11 
b 
 
 
 
… 
 
 
 
 
15 
a, b, c, e 
 
 
 
… 
 
 
 
 
18 
b 
 
 
 
… 
 
 
 
 
22 
a, b, c, e 
 
 
 
… 
 
 
 
 
25 
b 
 
 
 
… 
 
 
 
 
29 
a, b, c, e 
 
 
 
… 
 
 
 
 
32 
b 
 
 
 
… 
 
 
 
 
36 
a, b, c, e 
 
 
 
… 
 
 
 
 
39 
b 
 
 
 
… 
 
 
 
 
43*[HCT Day +42] 
Or End Date: _____________ 
a, b, c, d, e 
 
*Continue prophylaxis until criteria in Section 4.2.1 are met (may be less than 43 days). 
^ Following completion of study prophylaxis, institutions may revert to local standard of care for post-engraftment antifungal prophylaxis. ^Because study medication may be 
started within 24 hours of HCT, some patients may actually begin on HCT Day -1, such that they would potentially receive up to 44 days of study medication.  
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 hours of transplant (Day 0). Continue 
prophylaxis until the occurrence of any of the following, whichever is sooner: 
 
• 
Day +42 
OR 
• 
Day of Hospital Discharge 
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 Day +42, Day of Hospital Discharge, or patient off protocol.  
 
Following completion of study prophylaxis, institutions may revert to local standard of care for post-
engraftment anti-fungal prophylaxis. 
 
CASPOFUNGIN: by slow IV infusion over no less than 1 hour. 
 
Loading dose (LD): 70 mg/m2/day*(Maximum dose: 70 mg/day) First day of therapy. 
Maintenance dose (MD): 50 mg/m2/day*(Maximum dose: 50 mg/day) – Subsequent days  
 
*Use the Mosteller Formula for BSA calculation. 
 
SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES.  
 
The therapy delivery map (TDM) for caspofungin prophylaxis is on the next page.  
 
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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 hours of transplant (Day 0). 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 hours of 
transplant (Day 0). 
 
LD: Maximum dose: 
70 mg/day 
 
MD: Maximum dose: 
50 mg/day 
a. History, PE (ht, wt, BSA), 
albumin 
b. CBC, diff, plts, creatinine, 
AST, ALT, bilirubin 
c. GVHD Scoring 
d. IFI Checklist (see Section 10.2) 
 
If patient consents:: 
e. beta-D glucan testing (see 
Section 13) 
f. SNP (see Section 14) 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
 
Enter Date of Transplant 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 
[HCT Day 0 
or +1]^ 
LD:  __________mg 
a, b, e,f 
 
 
 
2 
MD: __________mg 
 
 
 
 
… 
 
 
 
 
4 
b 
 
 
 
… 
 
 
 
 
8 
a, b, e 
 
 
 
… 
 
 
 
 
11 
b 
 
 
 
… 
 
 
 
 
15 
a, b, c, e 
 
 
 
… 
 
 
 
 
18 
b 
 
 
 
… 
 
 
 
 
22 
a, b, c, e 
 
 
 
… 
 
 
 
 
25 
b 
 
 
 
… 
 
 
 
 
29 
a, b, c, e 
 
 
 
… 
 
 
 
 
32 
b 
 
 
 
… 
 
 
 
 
36 
a, b, c, e 
 
 
 
… 
 
 
 
 
39 
b 
 
 
 
… 
 
 
 
 
43* [HCT Day +42] 
Or End Date: ______________ 
a, b, c, d, e 
 
*Continue prophylaxis until criteria in Section 4.2.1 are met (may be less than 43 days).^ Following completion of study prophylaxis, institutions may revert to local 
standard of care for post-engraftment antifungal prophylaxis. 
^Because study medication may be started within 24 hours of HCT, some patients may actually begin on HCT Day -1, such that they would potentially receive up to 
44 days of study medication. 
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 20.99 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) 
 
Voriconazole: 
Creatinine clearance 
(mL/min/1.73m2) 
Percent of dose 
Dose in mg/kg (max dose) 
> 50 
PO & IV: 100% 
Per Section 4.2.3 
< 50 (no dialysis) 
PO: 100%  
IV: Switch patient to oral 
voriconazole*  
Per Section 4.2.3 
Hemodialysis 
PO: 100% after each dialysis 
Avoid IV dosage form* 
Per Section 4.2.3 
*Parenteral formulation of voriconazole contains the excipient sulfobutyl ether beta-cyclodextrin sodium 
which accumulates in patients with renal impairment, and can worsen renal impairment. If a patient with 
renal failure cannot take the oral formulation of voriconazole, then voriconazole should be held until either 
the renal failure or inability to tolerate oral medications improves, at which point it may be restarted. 
 
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 total bilirubin 
> 2 x ULN. Once the ALT and AST are < 2.5 x ULN for age and the serum total bilirubin is < 1.5 x ULN 
for age, the fluconazole can be re-started at the calculated dose (no dose adjustment). More frequent 
monitoring (2-3 times per week) of ALT, AST, and total bilirubin should be considered upon resumption 
of fluconazole. If the ALT, AST, or total bilirubin again become elevated past these criteria (ALT or AST 
> 5 x ULN or serum total bilirubin > 2 x ULN), then fluconazole should be discontinued (the patient will 
be removed from protocol therapy).  
 
Voriconazole: 
Voriconazole 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 total bilirubin 
> 2 x ULN. Once the ALT and AST are < 2.5 x ULN for age and the serum total bilirubin is < 1.5 x ULN 
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for age, the voriconazole can be re-started at the calculated dose (no dose adjustment). More frequent 
monitoring (2-3 times per week) of ALT, AST, and total bilirubin should be considered upon resumption 
of voriconazole. If the ALT, AST, or total bilirubin again become elevated past these criteria (ALT or AST 
> 5 x ULN or serum total bilirubin > 2 x ULN), then voriconazole should be discontinued (the patient will 
be removed from protocol therapy).  
 
 
Caspofungin: 
 
For all patients: 
Child – Pugh score52 Percent of dose 
Dose in mg/m2 (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. 
 
5.3 
Other Toxicities 
Fluconazole, voriconazole, and caspofungin can be held (for up to a seven day window) in patients who 
develop any toxicity that the local investigator believes may be related to the drug. If the protocol agent is 
ultimately deemed to not be responsible for the toxicity, the agent can be re-started at the calculated dose. 
If the toxicity returns, then the agent should be discontinued (the patient will be removed from protocol 
therapy). Other systemic antifungal prophylactic agents should not be utilized during this potential toxicity 
window. 
 
 
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6.0 
DRUG INFORMATION 
 
Please see Appendix IV for drug interactions associated with the drugs used in this study. 
See the consent document for toxicities. All other information is available on the COG website in 
the commercial agent monographs manual titled “Drug Information for Commercial Agents used 
by the Children’s Oncology Group.” This manual is provided under Standard Sections for Protocols 
at: https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
6.1 
CASPOFUNGIN (caspofungin acetate, Cancidas)  
 
(01/25/13) 
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, co-administration 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 co-administration 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). Only the 50 mg vials will be provided for use in this study. Each vials contains 
an intentional overfill. The 50 mg vials contain 54.6 mg. The 50 mg vials also contain 39 mg of sucrose 
and 26 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 
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: 
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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  
*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. Commercial supplies of caspofungin may be utilized in place of the study-
supplied drug. 
 
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6.2 
FLUCONAZOLE (Diflucan) 
 
 
 
 
(08/12/11) 
 
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 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. 
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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). Co-administration 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 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. 
 
 
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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 and 100 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. To prepare the infusion, the calculated dose volume in NS or D5W 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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6.3 
VORICONIZOLE (Vfend)  
 
 
 
 
 
(06/24/11) 
 
Source and Pharmacology:  
Voriconazole is a triazole antifungal derived from fluconazole with the aim of enhanced potency and 
spectrum of activity. Voriconazole has been studied in a variety of fungal infections and has demonstrated 
efficacy in those caused by Aspergillus sp, Candida sp, Cryptococcus neoformans, and Fusarium sp.; 
conversely, voriconazole has demonstrated poor in vitro activity against Zygomycetes and Sporothrix 
schenckii. Voriconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a 
cytochrome P450 enzyme necessary for the conversion of lanosterol to ergosterol. Inhibition of ergosterol 
synthesis results in increased cellular permeability and subsequent leakage of intracellular contents. Several 
other antifungal mechanisms have been proposed in certain yeast and filamentous fungi. 
 
The oral bioavailability of voriconazole is around 96%; peak plasma levels occur 1 to 2 hours after an oral 
dose. Steady-state concentrations are achieved within 24 hours after an oral loading dose; in the absence of 
a loading dose, 6 days of accumulation are required to reach steady state. The absorption of voriconazole 
is not affected by increases in gastric pH, however, the mean Cmax and AUC are reduced by 34% and 24%, 
respectively, following a high fat meal. Voriconazole is widely distributed, with a volume of distribution 
of 4.6 L/kg. Approximately 58% of a dose of voriconazole is bound to plasma proteins. Voriconazole 
concentrations in human CSF are between 40% and 70% of the concentrations in the plasma.  
 
Voriconazole displays nonlinear pharmacokinetics due to saturation of its metabolism in adult patients. It 
is metabolized by and is an inhibitor of cytochrome P450 enzymes 2C19, 2C9 and 3A4. Significant 
interpatient variability exists as a result of polymorphisms in the CYP2C19 isoenzyme, resulting in varying 
rates of metabolism. Genetic polymorphisms in CYP2C19 may result in approximately 4-fold higher 
voriconazole exposure in poor metabolizers vs. extensive metabolizers. Approximately 85% of a single 
dose appears in the urine with < 2% as unchanged drug. The elimination half-life has been reported as 6 
hours; in patients receiving prolonged therapy it may take up to 6 days to recover 90% of the drug in the 
urine and feces. 
 
Children < 12 years of age have a larger volume of distribution and a faster clearance of voriconazole than 
adolescents and adults. A pharmacokinetic analysis in 35 children age 2 to 12 years revealed that a 
maintenance dose of 4 mg/kg every 12 hours resulted in a similar steady state concentration compared to 
adults receiving 3 mg/kg every 12 hours. Unlike adult patients, voriconazole elimination was found to 
follow a linear model throughout the dosage range studied. The median (5th and 95th percentiles) terminal 
half-life was 7.5 (3.5 and 21.4) hours. Population pharmacokinetic modeling was performed in a 
retrospective evaluation of 108 voriconazole serum concentrations from 40 hospitalized pediatric patients. 
The mean oral bioavailability in the study was 75% in children < 12 years and 81% in patients ≥ 12 years. 
Simulations of fixed oral doses (200 mg twice daily) demonstrated a consistent increase in concentration 
by 520 ng/mL for a 1 mg/kg increase in dose; this is consistent with Michaelis-Menten kinetics. The authors 
concluded that 7 mg/kg IV every 12 hours is likely to achieve an appropriate voriconazole trough 
concentration in the majority of pediatric patients up to 12 years of age. 
 
 
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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 
Visual changes (e.g., 
photophobia, color 
changes, increased or 
decreased visual acuity, 
or blurred vision) 
Auditory or visual 
hallucinations, fever, 
nausea, rash 
 
Anaphylactoid reactions, flushing, 
sweating, tachycardia, chest tightness, 
dyspnea, faintness, pruritis, chills, 
headache, hypokalemia, vomiting, QT 
interval prolongation, ventricular 
arrhythmias, torsade de pointes, cardiac 
arrest, sudden death 
Prompt: 
Within 2-3 
weeks, prior to 
next course 
 
 
Increased serum creatinine, acute kidney 
failure, increased AST, increased ALT, 
increased alkaline phosphatase, cholestatic 
jaundice, clinical hepatitis, cholestasis, 
fulminant hepatic failure (including death), 
optic neuritis, papilledema, pancreatitis, 
Stevens-Johnson syndrome, toxic 
epidermal necrolysis, erythema multiforme, 
photosensitivity  
 
Other less common adverse events have 
been reported; refer to the package insert 
for additional details. 
Unknown 
Frequency 
and Timing: 
U.S. Food and Drug Administration's Pregnancy Category: Category D. 
Voriconazole can cause fetal harm when administered to a pregnant woman. Voriconazole was 
teratogenic in rats at doses 0.3 times the adult recommended dose and embryotoxic in rabbits at 
6 times the recommended adult dose. Reduced fetal weight, skeletal abnormalities, and 
embryomortality were also reported in animal models. Additionally, plasma estradiol levels were 
reduced in pregnant rats at all dose levels of voriconazole. 
 
Formulation and Stability: 
Injection 
Voriconazole for injection is available in a single use vial as a sterile lyophilized powder without 
preservatives equivalent to 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium 
(SBECD). The powder for injection should be stored at 15°C to 30°C (59°F to 86°F). Reconstituted 
solutions are stable for up to 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F). 
 
Tablets 
Voriconazole 50 mg tablets are white, film-coated, and round; voriconazole 200 mg tablets are white, film-
coated, and capsule shaped. Both tablet types are debossed with “Pfizer” on one side and either “VOR50” 
or “VOR200” on the reverse, for the 50 mg and 200 mg tablets, respectively. Tablets should be stored at 
15°C to 30°C (59°F to 86°F). 
 
Powder for Oral Suspension 
Voriconazole for Oral Suspension is supplied in 100 mL high density polyethylene (HDPE) bottles with an 
accompanying 5 mL oral dispenser and press-in bottle adaptor. Each bottle contains 45 g of powder for oral 
suspension. Following reconstitution, the bottle contains 40 mg voriconazole per mL in a usable volume of 
70 mL and approximately 5 mL of overfill. The powder for oral suspension should be stored at 2°C to 8°C 
(36°F to 46°F). Once reconstituted, the oral suspension should be stored at 15°C to 30°C (59°F to 86°F). 
 
 
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Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
Powder for injection 
Aseptically reconstitute one 200 mg vial with 19 mL of sterile water for injection; the use of an automated 
syringe is not recommended. The resulting product is a clear, particle-free solution in a concentration of 
10 mg/mL (20 mL total volume). This product should be further diluted with NS, LR, D5WLR, D5W1/2NS, 
D5W, D5W with KCl 20 mEq, 1/2NS, or D5WNS to a final concentration of 0.5 to 5 mg/mL prior to 
administration. Do not dilute with 4.2% sodium bicarbonate infusion; slight degradation of voriconazole 
can occur.  
 
Voriconazole powder for injection does not contain preservatives. The manufacturer recommends using the 
reconstituted solution immediately. Chemical and physical in-use stability has been demonstrated for 
24 hours at 2°C to 8°C (36°F to 46°F). Any unused solution should be discarded. The final voriconazole 
solution should be infused over 1 to 2 hours at a rate not to exceed 3 mg/kg/hr. 
 
Powder for oral suspension 
A 40 mg/mL suspension is made by adding 46 mL of water to the powder in bottle. Shake well for 
approximately 60 seconds. Place the push-in bottle adaptor in place prior to dispensing to the patient. Prior 
to each dose, the bottle containing suspension should be shaken well for at least 10 seconds. Each dose 
should be withdrawn from the vial using the provided oral dose dispenser. Do not refrigerate or freeze. 
Discard any unused suspension 14 days after reconstitution. 
 
Supplier: Commercially available product. 
 
 
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7.0 
REQUIRED OBSERVATIONS/MATERIAL AND DATA TO BE ACCESSIONED  
 
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). 
 
7.1 
Required and Optional Clinical, Laboratory and Disease Evaluations 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated below. 
These studies should be obtained even if the patient has been removed from protocol therapy, unless they 
are off study (see Section 8.0).  
 
 
STUDIES TO BE OBTAINED 
Baseline 
Day 0 to Day 42  
(or Discharge)  
Day 100^ 
End of ACCL1131 
Monitoring 
REQUIRED 
CBC, differential, platelets 
X 
Twice Weekly 
X 
Performance Status 
X 
 
X 
Creatinine, AST, ALT, bilirubin 
X 
Twice Weekly 
X 
Albumin 
X 
Weekly 
X 
IFI checklist 
 
X* 
 X* 
GVHD Scoring 
 
Weekly(after Day 14) 
X 
OPTIONAL (IF PATIENT CONSENTS) 
Beta-D Glucan Assays 
 
Weekly@ 
 
Sample for SNP Genotyping 
X# 
 
 X# 
^Day 100-114  
*Submit relevant IFI checklist documents via the Document Imaging System: (626) 447-2204 as of Day 42 
and Day 100. See Section 10.2 for further details. 
@ See Section 13 for details. It is suggested that specimens be obtained on Thursdays but other days are 
acceptable if more convenient. During the prophylaxis period, documentation of exposure or lack of 
exposure to each of the following will be performed: amoxicillin-clavulanate and intravenous 
immunoglobulin.  
# See Section 14 for details. End of study sample may be collected on Day +100 +/-7 days. 
 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain other 
studies as indicated for good clinical care. 
 
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7.1.1 
History, Demographic and Clinical Information 
Demographic and clinical information collected at baseline will include age, sex, performance status, Down 
syndrome, ethnicity, height, weight, and episodes of fully-treated proven/probable yeast infection in the 
3 months prior and receipt of systemic antifungal therapy within 7 days prior to enrollment. Other 
information collected will include type of malignancy or underlying diagnosis, relapse status, donor type, 
degree of donor match, stem cell source, conditioning regimen and graft-versus-host disease (GVHD) 
prophylaxis. 
 
 
7.2 
Optional Studies  
 
7.2.1 
 (1→3) Beta-D Glucan Assays 
If patient consent is obtained, Fungitell beta-D-glucan Assay will be performed during the period of 
neutropenia in order to identify IFI. 5 mL of whole blood will be collected in a gold top serum-separator 
tube once weekly. See Section 13 for sample collection, processing and shipping details.  
 
7.2.2 
SNP Analysis 
If patient consent is obtained, specimens will be collected and banked for genotyping. SNP analysis will be 
conducted in order to determine genes mediating immune function. Peripheral blood (5 mL) will be collected 
in a purple top tube at study entry and at end of study (Day +100 +/-7 days), optimally when the patient has an 
ANC > 1000/µL. Patients with weights less than 20 kg may have only 3 mL collected. 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 the institutional diagnosis. 
b) Refusal of further protocol therapy by patient/parent/guardian. 
c) Completion of planned therapy (Day 42 or Day of Discharge).  
d) Physician determines it is in patient’s best interest. 
e) Repeat eligibility studies are outside the parameters required for eligibility (if applicable, see 
Section 3.2 – only for patients that have not yet started protocol therapy). 
f) Intolerable toxicities as outlined in Section 5.2 and Section 5.3. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below). 
Follow-up data (including IFI checklist) will be required unless consent was withdrawn.  
 
8.2 
Off Study Criteria 
 
a) Death. 
b) Lost to follow-up. 
c) Withdrawal of consent for any further data submission. 
d) Completion of Day 100 evaluation. 
 
 
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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Statistical Design 
This is a randomized open-label trial of anti-fungal prophylaxis for patients at high risk for IFI following 
allogeneic hematopoietic cell transplantation. Eligible patients are those undergoing an allogeneic HCT 
from an unrelated donor or mismatched family donor. Patients will be randomized at the time of enrollment 
to receive caspofungin or an azole comparator (fluconazole or voriconazole). Each participating institution 
will choose the comparator based upon institution standard of care and the choice of comparator should 
remain constant for the duration of the study. Randomization will be stratified by: 1) the comparator of 
choice: fluconazole or voriconazole; 2) Age: ≥12 years vs. < 12 years; 3) Type of transplant: Umbilical 
cord blood (UCB) donor vs. Non-UCB donor with ex vivo T-cell-depletion vs. Non-UCB donor with 
standard pharmacologic GVHD prophylaxis. Protocol-specified anti-fungal prophylaxis will start with 24 
hours of Day 0 and continue until Day +42, day of discharge, or withdrawal from study for any reason. The 
primary aim of the study is to evaluate whether the caspofungin arm has a lower incidence of 
proven/probable IFI than the azole arm during the first 42 days following allogeneic HCT. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
In North America, from 2006-2008, an average of 688 patients per year were transplanted at COG centers 
that fit the eligibility criteria for this trial (CIBMTR, personal communication). Presuming constant 
numbers and a 20% participation rate, this trial would accrue about 138 patients per year and require 4.5-5 
years (including an estimated 6 months delay for IRB approvals) to complete the accrual of 560 eligible 
patients, with a maximum enrollment of 590 patients to account for up to 5% ineligible enrollments. 
Because we will allow institutions to choose the comparator (fluconazole or voriconazole), we anticipate a 
high acceptance of this trial by local physicians, and indeed, our survey of the COG Transplant Centers 
indicated that 89% of the centers who responded would enroll patients on this trial, with a survey response 
rate of 80%.  
 
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).31 These definitions have been used in major 
trials of antifungal drug efficacy, in strategy trials, for formulating clinical practice guidelines, for validating 
diagnostic tests, as well as for undertaking epidemiologic studies. A Data Review Committee, blinded to 
study drug assignment, will review all clinical documentation used to determine the presence of an IFI and 
classify it based on the EORTC criteria. The period at risk for primary IFI endpoint will begin at Day 0 and 
extend until 42 days following stem cell infusion. Some patients at high-risk for IFI may have prolonged 
inpatient stays, but in order to obtain a relatively homogenous duration of study drug administration, Day +42 
was chosen as the maximal period of administration, as was done in the micafungin trial. Based on intent-to-
treat principle, the at-risk period will be the same for patients who terminated protocol prophylaxis prior to 
Day +42 (due to withdrawal or discharge) as long as data regarding IFI are available. For the primary 
endpoint, deaths that occur in the absence of proven/probable IFI will be counted as censoring events; as a 
comparison, for the exploratory endpoint of fungal-free-survival (see below), deaths without 
proven/probable IFI will be counted as events. 
 
 
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The rationale for the duration of therapy and the measurement of the primary endpoint was based upon 
three issues. First, the major time period that patients are at risk for invasive candidiasis is during the period 
of combined neutropenia, monocytopenia, and lymphopenia.53 The second reason is that this time frame 
was the same as was used in the NIAID-supported micafungin trial by Van Burik et al., and thus, allows us 
to compare our results to what was seen in that lower-risk, primarily-adult population.14 The final issue was 
one of feasibility. The goal was to design a trial that would not mandate a practice that is not standard to 
local institutions, namely continuing an intravenous medication past the time of hospital discharge, when 
an acceptable oral medication exists. It was felt that this burden would potentially represent a serious 
obstacle to widespread acceptance and participation in the trial. This pragmatic trial is designed to 
determine whether the intervention works under the usual circumstances in which it is used. Once the period 
of neutropenia and monocytopenia has resolved many patients will be clinically ready for discharge from 
the hospital. Since caspofungin is only available in an intravenous formulation, continuing the treatment 
past the time of discharge represents a significant burden of effort and cost, which the data currently do not 
support undertaking.  
  
 
Exploratory Endpoints 
Endpoints for the exploratory objectives include: development of proven or probable IFI during the first 
100 days following allogeneic HCT, fungal-free-survival which is defined as time to death or 
proven/probable IFI during the first 42 and 100 days following allogeneic HCT, and onset and severity of 
acute GVHD, and results from beta-D glucan assay for the diagnosis of IFI. 
 
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 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 exploratory endpoints. 
 
9.3.3 
Sample size with power justification 
 
IFI incidence 
There has never been a randomized prospective trial of anti-fungal prophylaxis in this population of 
patients. Consequently, it is difficult to measure the expected rate of IFI in the control arm. Pediatric patients 
have represented less than 10% of the subject population in all but one prospective trial to date.3,14,19,20,29,54 
And every prospective trial to date has had > 50% of their patients undergoing lower-risk forms of 
transplantation, including matched sibling donor HCTs, and even autologous HCTs in some cases. Given 
these limitations, the incidence of IFI on these trials has ranged dramatically, from as low as 2.4% at 70 
days,14 to as high as 25% at 180 days post HCT.20 A simple calculation achieved by combining the results 
of the 3 trials with 180 day endpoints demonstrates that, in patients receiving fluconazole prophylaxis, there 
is an approximately 14.5% incidence of IFI at 180 days, while in those receiving mold-active prophylaxis 
(itraconazole or voriconazole) there was an approximately 9.1% incidence of IFI at 180 days.3,19,20 If there 
was an even split between the number of patients receiving fluconazole vs. a mold-active azole, then a very 
rough estimate of the IFI incidence at 180 days would be 10.9%. Since the distribution of IFIs post-
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transplant is bimodal, with one main peak being during the neutropenic period immediately post-HCT,25,30,53 
we would expect roughly half of this, or ~6% to occur during the first 42 days.  
 
Other reports support the hypothesis that roughly half of the “early” (< 180 days post-HCT) IFIs occur 
within the first 6 weeks. Figure 1A from Wingard et al. demonstrates a cumulative incidence curve of IFI; 
while only the number at 180 days is reported, it is clear that there is a sharp rise between Days 0 and 42, 
followed by a slower rise from Day 42 to Day 180, so that roughly half of the IFIs have occurred by Day 42.3 
Three retrospective reports show similar conclusions. Hovi et al. reported that 5 of 11 (45%) IFI that were 
found in pediatric allogeneic HCT recipients during the first year post-HCT occurred during the first 6 
weeks post-HCT.27 Dvorak et al. reported that 10 of 12 (84%) cases of IFI occurred in the first month after 
pediatric allogeneic HCT.26 Benjamin et al. reported that, in pediatric patients undergoing unrelated or 
haploidentical HCT (the population in question in this trial), the number of patients with Aspergillosis or 
Candidiasis (the 2 most common IFIs) was 22 from Days 0 to 30 post-HCT, 25 from Days 31-100, and only 
5 from Days 101-365.55 Thus, in Benjamin et al. 22 of 52 (42%) total IFIs occurring within the first year 
post-HCT happened within the first 30 days. Combining the small numbers from each of these retrospective 
studies would suggest that 39 of 77 (51%) of IFIs during the first year post-HCT actually occur within the 
first 4-6 weeks. Furthermore, a query of the International Pediatric Fungal Network database demonstrates 
that from July 2008 to December 2010, there were 14 pediatric patients who developed an IFI within 180 
days from HCT. Eight of these (57%) occurred by Day 42, 2 between Days 43 and 100, and 4 from Days 
101 to 180 (William Steinbach, personal communication). This data provides justification of the use of one-
half of the reported Day 180 incidences from the published prospective trial of Wingard et al. 
 
However, it should be strongly stressed that these numbers were generated from trials involving a lower-
risk patient population in which < 50% of the patients underwent alternative donor HCT, which is the study 
population proposed for this trial. None of the prospective trials report whether alternative donors 
demonstrated a higher incidence of IFI than matched-siblings, but based on the largest available series of 
retrospective data the risk of IFI at 1 year in alternate donors is ~2% higher than seen in matched-siblings.56 
Benjamin et al. report a greater difference between matched sibling donor recipients and alternative donor 
recipients of 16% vs. 22% (at 100 days),55 but we will use the more conservative 2% estimate. Once again, 
based on a bimodal distribution, we would expect approximately half of that increased IFI incidence to 
occur early post-transplant, thus increasing our overall estimate to ~7%. 
 
Another source of data to inform this estimate is the various retrospective studies that have been performed, 
although these have inherent biases. There have been three pediatric-specific studies, which unfortunately 
have used different end-point times and methods.26,27,55 One study demonstrated an 8.7% incidence of IFI 
at 30 days in a mixed-risk patient population utilizing fluconazole prophylaxis.26 Another demonstrated a 
10.9% incidence of IFI at 30 days in our exact population of high-risk patients, but utilizing low-dose 
amphotericin B as prophylaxis.55 Another informative study involved a very high number (> 2500) of 
primarily adult patients undergoing transplant from alternative donors and demonstrated an approximately 
8% risk of IFI at 365 days post-HCT.56 However, this population included ~30% non-myeloablative HCTs, 
which have a very different pattern of IFI than those undergoing myeloablative transplant57 (the study 
population for this trial), making it difficult to fully utilize this data. Another group of patients who appear 
to be at high-risk for the development of IFI post-HCT are those undergoing HCT utilizing an umbilical 
cord blood (UCB), likely due to the extended period of neutropenia commonly seen in these patients. A 
report by Sadfar et al. demonstrated that 12.4% of their UCB HCT patients had developed an IFI by Day 
30, and 22.6% by Day 100.58 The prospective trials to date have included very few UCB recipients, 
including only 2 of 600 in the trial by Wingard et al.3 Finally, a report analyzed the infectious complications 
of high-risk (unrelated donor) HCTs done on the NHLBI-funded trial of ex vivo T-cell depletion vs. standard 
cyclosporine and methotrexate for GVHD prophylaxis.30 The methodology of this study did not report an 
IFI incidence at 180 days, but at the time of data censoring, 31% of patients had ultimately gone on to 
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develop an IFI. This highlights the elevated risk of IFI in this population of patients, and underscores the 
danger of utilizing data generated from a lower-risk population to inform an IFI estimate for this trial. 
 
We determined the magnitude of absolute IFI risk reduction by starting with the rate of 4% seen in the trial 
by Wingard et al.3 On that trial, in the early post-HCT period only 2 infections were due to organisms other 
than Candida and Aspergillus, (which would thus also not be covered by caspofungin). There are several 
theories why patients receiving a mold-active agent developed breakthrough Aspergillus or Candida. One 
possible reason is the inherent variability in voriconazole pharmacokinetics (as noted above), which may 
have led to inadequate serum levels in a significant number of patients.5,49 We would not expect a similar 
problem utilizing caspofungin, which has very predictable pharmacokinetics,59 even in the setting of renal 
or hepatic insufficiency. Another possible reason is that 36% of the IFIs occurred after premature 
withdrawal of voriconazole.3 Since echinocandins are generally exceptionally well-tolerated, we expect a 
lower rate of premature stoppage of caspofungin when compared to the azole group, a finding also 
demonstrated in the trial by Van Burik et al.14 Given these inherent benefits of the echinocandin class, we 
therefore expect that caspofungin’s magnitude of benefit will be slightly higher than seen in trials of other 
mold-active agents. 
 
Therefore, we assume that the incidence of IFI during the period at risk for the primary objective (Day 0 to 
Day 42) is 7% in the control patients (with fluconazole or voriconazole) and that the incidence of IFI is 2% 
with caspofungin prophylaxis, which is a clinically important decrease in the risk of IFI. 
 
Sample Size and Estimated Power 
Assuming the incidence of IFI during the period at risk for the primary objective (Day 0 to Day 42) is 7% 
in the control patients (with fluconazole or voriconazole) and that the incidence of IFI is 2% with 
caspofungin prophylaxis, we will require 560 randomized patients (approximately 280 per arm) to achieve 
80% power at 2-sided alpha level of 0.05. The power consideration is based on a 2-sample log rank test 
comparing the time to (first occurrence of proven/probable) IFI. Time to IFI is assumed to follow an 
exponential distribution. The observation period for the primary endpoint is from Day 0 till Day +42 
following high-risk allogeneic HCT. Under an exponential time-to-IFI model with these parameters, the 
incidence of IFI is distributed almost evenly during the at-risk period; for each one-third of at-risk period 
(~14 days), the incidence of IFI is 2.3%-2.4% for patients on the azole arm and is 0.66%-0.67% for patients 
on the caspofungin arm. A 5% exponential loss-to-follow-up during the at-risk period is also included in 
the power consideration. Considering up to 5% of the enrolled patients might be deemed ineligible, the 
maximum enrollment number is adjusted to 590. The expected number of IFI among 280 eligible azole arm 
patients is 19.6. 
 
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  
For the primary endpoint, the at-risk period for IFI is from Day 0 until Day +42. Events that will shorten 
the at-risk IFI observation period (including death, withdrawal consent for data submission, or patient loss 
to follow-up) prior to Day +42 are expected to be rare. Since death (a true competing risk event) prior to 
Day +42 is expected to be rare, in the primary analysis all these events will be treated as censoring events 
and standard survival data methods will be performed. 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 
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compliance with the assigned treatment). All eligible and randomized patients with available IFI data will 
be included in this analysis. A modified intention to treat analysis which only includes patients who 
complied with the randomized treatment will also be performed as an exploratory analysis to evaluate 
whether its result differs from that of the intention to treat analysis. Kaplan-Meier curves will be used to 
estimate the time to onset of proven/probable IFI for patients randomized to the 2 arms. Log rank test will 
be used to compare the incidence of IFI between the 2 randomized arms during the at-risk period up to Day 
+42. The primary analyses will be performed at overall 2-sided alpha level of 0.05, with two planned interim 
efficacy analyses (see Section 9.3.5). Cox proportional hazards models will also be used to explore the 
treatment difference between the 2 arms on time to IFI with adjustment for covariates such as stratification 
factors or other potential risk factors. 
 
Exploratory Analyses on Clinical Endpoints 
For exploratory objective 1, to examine the longer term treatment effect, a similar log rank test will be 
performed comparing the incidence of proven/probable IFI between the 2 randomization arms by extending 
the observation period up to Day +100. For exploratory objective 2 & 3, log rank test will be used to 
compare the incidence of proven/probable IFI of patients randomized to caspofungin within the particular 
randomization stratum defined by the comparator (fluconazole or voriconazole) to that of patients 
randomized to the comparator within the same stratum. For exploratory objective 4 on fungal-free-survival, 
failures for this endpoint will include death or proven/probable invasive fungal infection. Log rank test will 
be used to explore any treatment differences between the 2 arms on fungal-free-survival. For exploratory 
objectives 1-4, Cox proportional hazards models will also be used to examine the treatment difference 
between the 2 arms on time to IFI or fungal-free-survival with adjustment for other risk factors. For 
exploratory objective 5, the binary incidence of acute GVHD and the percentage distribution of acute 
GVHD by stage and by overall clinical grade will be estimated for each arm and compared between the 2 
arms by Chi-square test. Logistic regression models (for the binary GVHD incidence data) or proportional 
odds models (for the ordinal GVHD data by stage or overall clinical grade) will also be used to explore the 
treatment difference between the 2 arms with adjustment for other risk factors such as donor HLA match 
score. 
 
Based on the survey we performed, we expect about half of the enrolled patients will use fluconazole as the 
comparator and the other half will use voriconazole as the comparator. For the exploratory objective on 
comparing the incidence of IFI during the first 42 days between caspofungin and fluconazole or between 
caspofungin and voriconazole, with 140 patients per arm, the power to detect a difference in IFI incidence 
of 7% (comparator) vs. 2% (caspofungin) will be only about 51%. The power for a difference in IFI 
incidence of 7% (comparator) vs. 1% (caspofungin), 8% (comparator) vs. 2% (caspofungin), and 9% 
(comparator) vs. 2% (caspofungin) are 71%, 62%, and 71% respectively. These power considerations 
follow the same assumptions as those for the primary objective. For the exploratory objective on comparing 
the incidence of IFI during the first 100 days following high risk allogeneic HCT using the entire study 
population, assuming IFI incidence of 12% (with fluconazole or voriconazole) vs. 5% (caspofungin), the 
power to detect the difference is 81%. The incidence of IFI during this longer at-risk-period might be 
bimodal with the main peak during neutropenic period immediately after HCT; however due to lack of good 
estimate for such bimodal distribution, this power consideration is still based on exponential models and 
the incidence is distributed roughly evenly under these incidence assumptions. The power consideration for 
IFI up to Day 100 also includes a 15% exponential loss-to-follow-up. When only comparing patients 
randomized between caspofungin and one comparator (fluconazole or voriconazole), again with about half 
of the sample size (about 140 per arm), the power to detect IFI incidence during the first 100 days of 12% 
(comparator) vs. 5% (caspofungin) is only 52%. The power will be about 78% if the IFI incidence during 
the first 100 days is 14% (comparator) vs. 3% (caspofungin).  
 
 
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Analysis of beta-D Glucan Assay 
Sensitivity, specificity, positive predictive value, and negative predictive value of the beta-D glucan assay 
will be determined using standard formulas and EORTC/MSG criteria as the gold standard. Please see 
Section 13.9 for additional statistical considerations for this aim. 
 
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. Two formal interim efficacy analyses on the 
primary endpoint will be performed, after approximately one third and two thirds of the patients have 
completed study treatment and IFI observation. Monitoring boundary for the primary endpoint on IFI will 
be based on Lan-Demet’s method with spending function αt2.  
 
At the time of primary efficacy monitoring, the observed incidence of IFI during the first 42 days following 
HCT in patients randomized to the comparator arm will be monitored. If the 95% 1-sided confidence 
interval does not contain the assumed rate of 7%, the study will be referred to DSMC for consideration of 
study closure. Roughly speaking, if ≤ 2 IFI out of 93 patients, or ≤ 7 out of 187 patients, the rule will be 
met. However, the exact rule at the time of monitoring will depend on the exact N at the time of the interim 
analysis and whether there is censoring and how much. If no censoring and exactly at the numbers listed 
above, the rule will be those above. 
 
Informal safety analyses will also be performed on the observed adverse events at each DSMC review. This 
analysis will include all patients who receive at least one dose of study medication. The proportion of 
patients experiencing any reportable grade 4 or higher adverse event will be compared between the 2 arms 
using chi-square tests. For such informal safety analyses, each test will be at two-sided level of 0.05 without 
adjustment for multiple testing. If a significant difference between the 2 arms is found (P < .05), the study 
committee will perform a review of the adverse event profiles and report the finding to DSMC for their 
evaluation, with a recommendation about action with respect to the study. 
 
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 
66 
96 
162 
Not Hispanic or Latino 
179 
249 
428 
Ethnic Category: Total of all subjects 
245 
345 
590 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
5 
9 
14 
Black or African American 
24 
29 
53 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
216 
307 
523 
Racial Category: Total of all subjects 
245 
345 
590 
 
 
 
 
This distribution was derived from ASCT0431. 
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10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). Additionally, toxicities are 
to be reported on the appropriate data collection forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE v4.0 as 
referenced on the CTEP website (i.e. v4.02 and all subsequent iterations prior to version 5.0). 
 
10.2 
IFI Checklist: Submission & Central Review 
Institutions will be provided with CRA worksheets (IFI Checklist) to complete which will help to identify 
whether patients had an IFI. 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 criteria.60 The committee will then submit a Central Review CRF 
via eRDES. 
 
The following IFI checklist materials will be submitted (via the Document Imaging System:  
(626) 447-2204) as of Day 42 and as of Day 100, 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, 
• 
Non-culture mycology testing results (i.e. Histoplasma urine antigens, cryptococcal CSF and serum 
antigens),  
• 
Ophthalmology exams, and 
• 
Bronchoscopy reports. 
 
In addition, dosing and duration of steroid exposure will be collected and entered via eRDES. All reviewers 
will be blinded to the patient’s antifungal exposures in order to limit any bias in determining the primary 
and secondary endpoints.  
 
10.3 
Acute GVHD 
The staging of acute GVHD will follow National Marrow Donor Program (NMDP) guidelines 
(Appendix III).  
 
 
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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.  
 
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. 
 
 
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CTCAE term (AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 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. 
 
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 S 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 (1→3) BETA-D GLUCAN ASSAY AS A 
DIAGNOSTIC TOOL FOR INVASIVE FUNGAL INFECTION IN CHILDREN UNDERGOING 
ALLOGENEIC HCT RECEIVING FUNGAL PROPHYLAXIS. (FOR PATIENTS THAT 
CONSENT ONLY) 
 
13.1 
Background 
The crippling mortality associated with IFI in HCT recipients is in part related to the difficulty in diagnosing 
them in a reasonable time frame. In fact, IFI are frequently only diagnosed on autopsy.61 As noted above, 
almost all major pediatric HCT centers prescribe some form of antifungal prophylaxis during periods of 
immune suppression. Fluconazole is frequently used but it does not have activity against mold organisms 
such as Aspergillus. This fact has led many to theorize that using an antifungal agent with anti-Aspergillus 
activity would provide additional benefits. However, the studies comparing fluconazole to a mold active 
agent have been conflicting.3,19,42 In an effort to standardize antifungal prophylaxis, the parent randomized 
clinical trial described above will compare the efficacy of an azole agent (voriconazole or fluconazole) to 
that of caspofungin. This study will potentially define the appropriate antifungal prophylactic agent.  
 
Regardless of the antifungal agent ultimately chosen, prophylaxis will not prevent all IFI. In those patients 
with a breakthrough IFI, a modification to the antifungal regimen will be necessary. The challenge is to 
identify those patients sustaining breakthrough IFI at the earliest possible point. The recent Infectious 
Disease Society of America (IDSA) guidelines for fever and neutropenia suggests a pre-emptive therapeutic 
approach.62 This approach requires the use of adjunctive diagnostic biomarker assays such as the Fungitell 
Assay, to help inform the decision to modify antifungal therapy. The utility of this assay has been well 
defined in adult immunocompromised patients but to date there are limited data on the operating 
characteristics of this assay in pediatric patients undergoing HCT and receiving antifungal prophylaxis. In 
order to endorse this as a useful adjunctive study, the operating characteristics must be defined in a high-
risk pediatric population. We propose to prospectively study this biomarker in the parent COG trial. This 
parent study cohort provides a one-time opportunity to rigorously evaluate the ability of this fungal 
biomarker to identify IFI in a homogeneous cohort of pediatric HCT patients receiving antifungal 
prophylaxis. Knowledge of the operating characteristics of the Fungitell Assay under these study conditions 
is necessary to inform its potential future utility.  
 
13.1.2 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. 
 
13.1.3 Beta-D Glucan (Fungitell) Assay 
The testing approach of this ancillary study involves the serial evaluation of a patient’s serum for the 
presence of BG. The Fungitell Assay is a commercially available kit from the Associates of Cape Cod, Inc. 
for the identification of BG, present in a vast majority of pathogenic fungi, in the serum of patients with 
IFI. This assay received FDA approval for use in adults in May of 2004 to assist in the diagnosis of most 
IFI (including IA). The operating characteristics of the assay have been elucidated in two separate adult 
cohorts and are reassuring.63,64 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.64 The 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 
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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%. 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.63 More recently, a meta-analysis 
including 16 prospective and retrospective studies evaluating BG levels reported a combined sensitivity of 
77% and specificity of 85%.65 
 
One pediatric study evaluated BG levels in children using the Fungitell Assay. This study was limited to 
healthy children and revealed elevated baseline levels of BG in a subset of the patients.66 To date, the 
Fungitell Assay testing has never been performed prospectively in immunocompromised pediatric patients 
and never in a population of only HCT recipients. Even if one tried to extrapolate the previously described 
adult data for BG testing, the results are conflicting with some studies revealing a reassuringly high 
sensitivity and others with a poor sensitivity. This variation likely stems from the variation across each 
study for testing frequency, timing of testing, and variation in the type of immunosuppressed patients. 
Furthermore, the elevated baseline BG levels in the one study of healthy children suggest that a higher 
threshold for a positive test would be necessary in a pediatric patient population. 
 
13.1.5 Gaps in knowledge 
The Fungitell Assay has shown reassuring operating characteristics in adults. Because of the proven utility 
of this test in adults, guidelines from the Infectious Disease Society of America have endorsed it as 
adjunctive diagnostic tool to guide the clinical choice for pre-emptive antifungal therapy in neutropenic 
adult patients at high risk for IFI despite receiving antifungal prophylaxis. A similar approach is certainly 
attractive to those clinicians caring for children undergoing HCT. However, there is a paucity of data 
regarding the operating characteristics of the Fungitell Assay in large homogeneous cohorts of children 
undergoing an HCT and receiving antifungal prophylaxis. It is not reasonable or appropriate to extrapolate 
results from adult studies and employ a similar pre-emptive approach in children. Prospective study in 
children is absolutely necessary to allow clinicians to transition from the traditional empiric antifungal 
approach to a pre-emptive strategy. The planned COG multicenter randomized controlled trial comparing 
the efficacy of an azole agent to caspofungin for prophylaxis against IFI in children undergoing an HCT 
offers a unique and likely one-time-only opportunity to establish the utility of the Fungitell Assay in a large 
cohort of pediatric HCT recipients. 
 
13.2 
Specific Aims and Hypotheses 
 
Specific Aim: To define the test characteristics of weekly Fungitell beta-D-glucan Assay testing for 
identifying IFI in pediatric HSCT recipients receiving antifungal prophylaxis during the post-transplant 
neutropenic period. 
 
Hypothesis: The Fungitell beta-D-glucan Assay will have a sensitivity that is > 90% for identifying IFI in 
this population of pediatric HSCT recipients. Alternatively stated, more than 90% of patients that ultimately 
are diagnosed with an IFI will have at least one positive Fungitell beta-D-glucan Assay prior to the actual 
IFI diagnosis. 
 
13.3 
Study Design 
This ancillary study is a prospective observational cohort study for defining the operating characteristics 
of the Fungitell Assay in children enrolled on ACCL1131.  
 
 
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13.4 
Patient Accrual  
All patients to be enrolled on ACCL1131 will be offered the chance to participate in this ancillary fungal 
infection screening study. Those who consent will undergo weekly Fungitell Assay testing from the time 
of the HCT until Day +42 or until withdrawal from the study for any reason. It is suggested that specimens 
be obtained on Thursdays but other days are acceptable if more convenient. For those patients discharged 
prior to Day +42 weekly outpatient testing will be performed when possible. Each patient will have the 
potential for 7 separate testing points (once a week for 7 weeks). The proposed ancillary study will 
concurrently enroll patients from the parent trial with a goal of enrolling 400 patients.  
 
13.5  
Sample Collection and Testing Procedures (For Consenting Patients Only) 
 
13.5.1  Sample:  
In order to perform the Fungitell® beta-D-glucan Assay 5 mL of whole blood will be collected in a gold top 
serum-separator tube and labeled 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 on a HCT recipient during the period of 1 week, it may result in an 
important increase in certain patients (e.g., 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. 
 
13.5.2  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 1.8 mL of serum is required to run the Fungitell® beta-D-glucan Assay.  
 
13.5.3  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. 
 
13.5.4  Shipping of specimens: 
Each center will be provided with specimen collection kits that will be shipped to the center after patient 
enrollment. These kits will contain specimen collection tubes, Styrofoam lined boxes, sealing tape, labels, 
the ACCL1131 Fungitell® beta-D-glucan Assay Requisition form and a gel pack. The boxes can hold 
multiple frozen serum specimens. In order to optimize efficiency, specimens should not be sent until 10 
specimens have been collected or every 6 months whichever comes first. As soon as a patient is enrolled, 
please email Sarah Klieger, at the Children’s Hospital of Philadelphia (Klieger@email.chop.edu) to order 
a specimen collection kit. The shipping kit will be shipped by two-day courier. Kit requests placed on the 
weekend will be shipped the following Monday. 
 
 
Requisitions: 
 
 Complete an ACCL1131 Fungitell® beta-D-glucan Assay Requisition Form for each specimen sent 
for testing. All areas of the requisition form must be completed to assure accurate result reporting. 
 
 
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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 and should be used to avoid smudging of 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 frozen gel pack that should be frozen. 
4. Open the box and remove the Styrofoam liner lid. 
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. Add the completed ACCL1131 Fungitell® beta-D-glucan Assay Requisition Form for each 
specimen and place on top of the Styrofoam liner before sealing the box. 
9. Wet the sealing tape provided in the kit and seal the cardboard box. 
10. Affix the UN3373 “Biological Substance Category B” label to a vertical side of the box. 
11. If the specimen tube labels and requisition forms do not match when received at the testing 
site the specimens will not be considered valid and testing will not be performed. 
 
Shipping Instructions: 
The courier account information can be found on the ACCL1131 Fungitell® beta-D-glucan 
Assay Requisition Form provided with the shipping kit.  
 
1. Refer to UPS website 
http://www.ups.com/content/us/en/resources/ship/hazardous/biological_substances.html 
to learn the current guidelines, in accordance with IATA (International Air Transport 
Association) for the shipping and Packaging Requirements of human body fluids.  
2. Affix the UPS label to the top of the box. (The UPS label will be included in the shipping 
kit.) Take care not to cover any of the UN markings. 
3. If your institution has a mailroom that uses UPS, take the package to the pickup area. 
4. Ship packages to the following address: 
 
UT Health Science Center at Houston 
Attention: Jose Rodriguez 
6431 Fannin R219 MSE 
Houston TX, 77030 
(713)-500-6755 
5. Do not ship on a Friday, Saturday, or the day before a holiday.  
 
13.5.5  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. If original   
 
 
 
test is performed on Friday, repeat testing of positive specimens will be performed the  
 
 
 
following Monday.  
 
2. Testing will not occur under the following conditions: 
a. The specimen stored under unacceptable storage times and/or temperatures. 
b. The specimen has been shipped under unacceptable time and/or temperature conditions  
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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 
f. 
The specimen is of a type other than serum separated off the clot. 
 
3. If a specimen is received and falls under one of the five criteria listed above, a call will be 
made to the study site to inform them that testing on the specimen could not be performed. 
 
4. Fungitell® beta-D glucan Assay results are reported as pg/mL. 
 
13.5.7 Laboratory of Mycology Research key personnel:  
 
Technical Assistance: 
 
Jose Rodriguez 
 
713-500-6755 
 
jose.rodriguez@uth.tmc.edu 
 
Director: Luis Ostrosky-Zeichner, MD, 713-500-6733 
 
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. Regardless of the number of institutions offering such BG testing, we anticipate 
that such testing will be ordered by a subset of treating physicians. The local BG results will not be included 
in our final analysis of the biomarker assay’s 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 Fungitell beta-D-glucan Assay’s operating characteristics. For each patient 
we will identify whether local BG 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 13.9.4 below. 
 
The Fungitell beta-D-glucan Assay is reported in pg/ 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. 
 
 
13.6  
Gold Standards for IFI Infections  
The criteria established by the EORTC/MSG for proven or probable IFI IA will be used as the gold standard. 
These definitions have been used as the primary endpoints for prior studies validating the Fungitell beta-
D-glucan Assay. 
 
13.6.1 Methodology to Identify IFI:  
The EORTC/MSG guidelines incorporate clinical, microbiologic, histopathologic, and radiographic data 
for classification of proven or probable IFI. Therefore, in order to establish these diagnoses, the following 
data will be obtained on 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 as 
proven, probable, or possible, according to the consensus criteria of the EORTC/MSG. 
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13.7  Justification of Methodologic Choices 
 
13.7.1  Justification for Chosen Threshold for the Fungitell beta-D-glucan Assay: 
IFI outcomes are often devastating; thus it is desirable to optimize sensitivity at the potential expense of 
specificity. Furthermore, a highly sensitive test will likely result in few false negatives. 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 value was chosen to conclude negative and positive 
results. 
 
The Fungitell beta-D-glucan 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 is 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.66 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. 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 (please 
see statistical analysis below). 
 
13.7.2  Justification for IFI Gold Standard: 
We have chosen to use EORTC/MSG defined proven or probable IFI as the gold standard. The ideal gold 
standard to compare the 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 based on just 
the isolation of the fungal organism itself. Certain molds such as Aspergillus 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 2008.31,67 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 our resultant data to prior and future 
studies. 
 
13.8  
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 testing.68-70 Table 2 lists the potential causes of false positive results reported 
in the literature. It is anticipated that recipients of a HCT 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 13.9.4 below) will be performed to investigate the impact of these false positive 
inducing factors on the operating characteristics of the 2 biomarkers.  The starred factors are likely to be 
the most clinically relevant and thus they will be focused on. 
 
 
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Table 2. Potential factors resulting in false positive testing for (1→3) beta-D glucan  
Medications 
*Amoxicillin-clavulanate 
 
Infusions 
 
*Intravenous immune globulin 
Cellulose filters for IV infusion 
Albumin 
Medical interventions 
Hemodialysis with cellulose 
  filter 
Gauze packing on serosal 
  Surfaces 
Other infections 
*Pneumocystis jiroveci 
 
 
13.9  
Statistical Design 
 
13.9.1 Sample Size and Estimated Event Rates:  
The parent trial comparing prophylaxis with an azole (fluconazole or voriconazole) to caspofungin in newly 
diagnosed AML patients anticipates enrollment of at least 280 patients for each arm with a total cohort of 
approximately 560 patients. As noted above we anticipate enrollment of approximately 400 patients. This 
will result in 200 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. 
 
The estimated number of probable or proven IFI events for final analyses will vary by study arm. The 
Fungitell beta-D-glucan Assay has the potential to identify most pathogenic fungi (with the exception of 
Mucorales species and Cryptococci) and thus a majority of the probable or proven IFIs will be considered 
as true events.  
 
It is challenging to establish an estimate of the event rate for IFI in this patient population as a prospective 
trial of anti-fungal prophylaxis in pediatric HCT recipients has never been performed. There have been 
three retrospective pediatric-specific studies that have attempted to define these event rates.26,27,55 The 
cumulative incidence of IFI in these three studies ranged from 8- 13%. It should be noted that these studies 
varied in follow-up time, in the types of transplants included, in the antifungal prophylaxis utilized and in 
the definition for IFI used to define the outcome. More recently an adult randomized and double blind 
controlled trial compared the efficacy of fluconazole prophylaxis to that of voriconazole in HCT recipients.3 
Within 180 days from transplantation, 8.1% of patients on fluconazole and 4.6% of patients on voriconazole 
developed a breakthrough IFI. This patient population had almost no unrelated umbilical cord blood 
transplant patients making it a much lower risk group for IFI than our proposed patient population. 
 
In the proposed parent trial included patients will be the recipients of allogeneic stem cells (bone marrow, 
peripheral blood stem cells, or umbilical cord blood). These HCT patients are those at high-risk for an IFI 
and thus the anticipated incidence rate of IFI may be higher than that reported in the above referenced adult 
trial. Alternatively, the proposed trial will only follow patients for 100 days from transplantation and thus 
later onset IFI will not be identifiable. Considering the data presented above and the proposed study 
parameters, the COG parent trial has conservatively estimated that the IFI incidence rate will be 7% (20 
events) in the azole treatment arm and 2% (6 events) in the caspofungin study arm. Because this ancillary 
study plans to enroll 70% (400 patients) of the parent trial patients over a three-year period the estimated 
event rates for the azole and caspofungin arms are 14 and 4 respectively (table 3).  
 
 
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13.9.2  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. Each component of the operating characteristics will be calculated based first on the entire 
cohort. As indicated in the estimates above, the incidence of is expected to 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 the Fungitellbeta-D-glucan Assay will be computed as follows: 
• Outcome of all IFI defined as a single positive test for the Fungitell beta-D-glucan 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 12.0 (College Station, TX). As noted above, these parameters 
will first be calculated for the entire cohort and then for each study arm separately. A patient with multiple 
episodes of IFI will only be included in the analyses as a single IFI. As would be expected in the setting of 
low incidence, we anticipate that the results will show a low PPV and high NPV. This will not be an 
indication that the assay is not useful. The intended goal of the assay is to identify all patients with IFI at 
the earliest time point. In order to identify all such patients there will need to be a tolerance for a certain 
number of false positive results. Thus in this clinical setting the sensitivity of these assays is the most 
relevant parameter assuming the number of false positive results is not excessive. 
 
13.9.3  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- 
characteristics (ROC) curve will be generated with a series of sensitivities and specificities derived from 
various cutoff values. For the Fungitell Assay cutoffs of ≥ 60, ≥ 80, ≥ 100, and ≥ 120 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.71 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 the 
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 ” and “not likely to 
have IFI ”. Once these 2 sub-groups are defined we will calculate the incidence rates of IFI for each sub-
group and compare them. Because the anticipated incidence for IFI may be variable between the two study 
Table 3.  Estimated IFI and IA event rates  
 
Total 
Azole Arm 
Caspofungin Arm 
Number 
400 
200 
200 
IFI Rate 
4.6% 
7.0% 
2.0% 
IFI Events 
18 
14 
4 
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arms (those receiving an azole 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 Fungitell beta-D-glucan 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. 
 
13.9.4  Sensitivity Analysis:  
Sensitivity analyses will be explored for the reasons expressed in Section 13.7.1 and 13.8. The first 
sensitivity analysis will attempt to identify the direction and magnitude of the bias resulting from the 
availability of clinical BG testing performed 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 (e.g. 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, 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 13.8 that may contribute to a positive result for the 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 2 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 the assay’s 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 starred 
factors listed in Table 2. 
 
13.10 Significance 
Fungal infections continue to be major contributors to morbidity and mortality in children undergoing HCT. 
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 Fungitell beta-D-glucan Assay is a potential diagnostic tool that could 
improve the time to diagnosis of IFI. More definitive data regarding the operating characteristics of these 2 
biomarkers interpreted separately and simultaneously in the setting of a large pediatric cohort receiving 
anti-fungal prophylaxis are necessary. Evaluating the biomarker first as an integrated test will provide 
valuable information regarding the utility of each test for future pediatric patients being treated under 
similar circumstances. It is important to realize that the results of this study (either to support or not support 
the routine clinical use of the biomarker) will have an important impact on the provision of future clinical 
care. If the results support the biomarker as an adjunctive diagnostic tool for identifying IFI, then clinicians 
will be better informed on the clinical application of the assay results. However, if the assay does not 
perform well in identifying IFI, then clinicians will know that this assay is not useful in this clinical scenario 
and thus will not order the test. This would result in the conservation of finite resources and redirect the 
focus of researchers to other modalities for diagnosing fungal infections.  
 
 
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14.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS FOR PATIENTS THAT CONSENT 
ONLY 
 
14.1 
Single Nucleotide Polymorphisms  
 
Genotypes of interest in genes mediating immune function will be determined by review of the literature. 
Analysis will be performed on the Taqman Open Array Platform according to the manufacturer’s 
instructions.  
 
14.1.1 Sample Collection 
Collect 5 mL of peripheral blood in a purple top (EDTA) tube at study entry and at end of study (Day +100 
+/- 7 days), optimally when the patient has an ANC >1000/µL. Patients with weights less than 20 kg may have 
only 3 mL collected. Specimens may be shipped fresh to the BPC, where the plasma and buffy coat will be 
stored at -20°C. 
 
14.1.2 Labeling:  
Label the tubes with the patient’s BPC #, specimen type, and date of collection.  
 
14.1.3 Shipping:  
Ship sample at room temperature by FedEx priority overnight delivery. Shipping labels can be obtained via 
the Biopathology Center’s Kit Management application. Blood may be shipped Monday through Friday for 
receipt on Tuesday through Saturday. Include a COG Specimen Transmittal Form with each shipment. 
 
 
 
The SNP sample should be shipped to:  
 
COG Biopathology Center – ACCL1131  
Nationwide Children’s Hospital  
700 Children’s Drive, WA1340*  
Columbus, OH 43205  
Phone: 614-722-2865  
Fax: 614-722-2897  
 
*Be sure to include the room number. Packages received without the room number may be returned to the 
sender. 
 
 
15.0 
BANKING SPECIMENS 
If the patient consents, leftover blood samples (from the studies described in Section 14) will be returned 
to the BPC and banked for future research studies. 
 
 
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APPENDIX I:  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ACCL1131 
(for children from 7 through 12 years of age) 
 
A Research Study Comparing Drugs Used To Prevent Serious Fungal Infections In Children Receiving a 
Stem Cell Transplant 
 
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) and radiation used in stem cell transplants reduce your immunity and 
make you more 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 receiving a stem cell transplant. 
 
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 drugs called fluconazole or voriconazole. 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 stem cell transplant, 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 stem cell transplant. 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 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 
collect extra blood samples to see if doctors can detect fungal infections as early as possible, 
and better than the usual tests used. We also want extra blood samples to look at your genes 
for any changes that may make a person 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 ACCL1131 
(for teens from 13 through 17 years of age) 
 
A Research Study Comparing Drugs Used To Prevent Serious Fungal Infections In Children and 
Adolescents Receiving a Stem Cell Transplant 
 
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) and radiation used in stem cell transplants reduce your immunity and make you 
more 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 receiving a stem cell transplant. 
 
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 one of the usual antifungal drugs, 
called fluconazole or voriconazole. 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 stem cell transplant, 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 stem 
cell transplant. 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 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 
a new blood tests can help doctors detect fungal infections as early as possible, and better than the 
usual tests used. This new test is called beta-D glucan. We also want extra blood samples to look 
at your genes for any changes that may make an individual more likely to get invasive fungal 
infections. This is called single nucleotide polymorphism (SNP) analysis. Blood 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 mycoses31 
 
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 mycoses 
 
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-α 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  
β-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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APPENDIX III: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR 
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS 
HOST DISEASE (GVHD)  
 
Reporting Requirements for Acute GVHD in COG Studies 
In an attempt to standardize reporting of acute GVHD, the COG Stem Cell Transplantation Committee has 
adopted a modification of guidelines that were originally developed at the University of Michigan.  
 
Table 1 outlines standard criteria for GVHD organ staging. However, confounding clinical syndromes (such 
as non-GVHD causes of hyperbilirubinemia) may make staging GVHD in a given organ difficult. In 
addition, timing of organ specific symptoms affects whether that symptom is more or less likely to be true 
GVHD. Please refer to Tables 2 and 3 to assist you in deciding whether to attribute these clinical findings 
to GVHD, especially in situations where a biopsy is not possible. For additional help, please see the text 
which follows the tables.  
 
Table 4 reviews the approach to assessing GVHD as acute, chronic, or the overlap between the two. 
 
Finally, engraftment syndrome will be reported separately from the GVHD scoring presented below. 
 
Engraftment Syndrome 
A clinical syndrome of fever, rash, respiratory distress, and diarrhea has been described just prior to 
engraftment in patients undergoing unrelated cord blood and mismatched transplantation. If in the judgment 
of the local investigator a patient experiences this syndrome, details of the event should be reported when 
requested in the study CRFs. 
 
Modified Glucksberg Staging Criteria for Acute Graft versus Host Disease 
 
Table 1. Organ Staging (See tables and text below for details) 
Stage  
Skin  
Liver (bilirubin)  
Gut (stool output/day)  
0  
No GVHD rash  
< 2 mg/dL  
Adult: < 500 mL/day  
Child: < 10 mL/kg/day  
1  
Maculopapular rash  
< 25% BSA  
2-3 mg/dL 
Adult: 500-999 mL/day  
Child: 10-19.9 mL/kg/day 
Or persistent nausea, 
vomiting, or anorexia, with 
a positive upper GI biopsy.  
2  
Maculopapular rash  
25% – 50% BSA  
3.1-6 mg/dL  
Adult: 1000-1500 mL/day 
Child: 20-30 mL/kg/day  
3  
Maculopapular rash 
> 50% BSA  
6.1-15 mg/dL  
Adult: >1500 mL/day  
Child: > 30 mL/kg/day  
4  
Generalized 
erythroderma plus 
bullous formation and 
desquamation > 5% BSA  
>15 mg/dL  
Severe abdominal pain with 
or without ileus, or grossly 
bloody stool (regardless of 
stool volume).  
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For GI staging: The “adult” stool output values should be used for patients > 50 kg in weight. Use 
3 day averages for GI staging based on stool output. If stool and urine are mixed, stool output is 
presumed to be 50% of total stool/urine mix. 
 
For Stage 4 GI: the term “severe abdominal pain” will be defined as: 
(a) Pain control requiring institution of opioid use, or an increase in on-going opioid use, PLUS 
(b) Pain that significantly impacts performance status, as determined by the treating MD.  
 
If colon or rectal biopsy is +, but stool output is < 500 mL/day (< 10 mL/kg/day), then consider as 
GI Stage 0.  
 
There is no modification of liver staging for other causes of hyperbilirubinemia 
 
Overall Clinical Grade (based on the highest stage obtained):    
Grade 0: No Stage 1-4 of any organ  
Grade I: Stage 1-2 skin and no liver or gut involvement  
Grade II: Stage 3 skin, or Stage 1 liver involvement, or Stage 1 GI 
Grade III: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI  
Grade IV: Stage 4 skin, liver or GI involvement  
 
Table 2. Evaluating Liver GVHD in the Absence of Biopsy Confirmation 
 
Establishing liver GVHD with no skin or GI GVHD 
No Skin/GI GVHD 
Day 0-35 
Assume no liver GVHD unless proven by biopsy  
No Skin/GI GVHD  
Day 36-100 
If NO other etiology identified, NO 
improvement with stopping 
hepatotoxic medications/TPN: 
Stage as liver GVHD  
If other etiology identified or 
improves with stopping hepatotoxic 
drugs/TPN: 
 
Do not stage as liver GVHD  
Establishing liver GVHD with skin or GI GVHD and other cause of hyperbilirubinemia 
Skin and/or GI GVHD 
present  
Worsening bilirubin level (includes 
worsening just prior to onset of skin 
or GI tract GVHD) OR stable 
elevated bilirubin despite resolution 
of non-GVHD cause of increased 
bilirubin:  
Stage as liver GVHD  
Stable or improving bilirubin after 
diagnosis of skin or GI GVHD, 
irrespective of treatment:  
 
 
Do not stage as liver GVHD 
  
Changing liver GVHD stage with other cause of hyperbilirubinemia 
Skin and GI GVHD 
stable, improving, or 
absent  
Liver GVHD staging is carried forward without increase in stage until other 
disease process resolves (e.g., if TTP is diagnosed in the presence of Stage 2 
liver GVHD, the liver GVHD Stage 2 is carried forward despite rising 
bilirubin level until TTP is resolved. If there is no liver GVHD – Stage 0 – 
and new onset TTP, the Stage 0 is carried forward until TTP is resolved).  
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Skin and/or GI GVHD 
worsening  
Liver GVHD is staged according to the Glucksberg criteria. The 
elevated bili is attributed to GVHD alone. 
 
Thus, when skin or GI GVHD is worsening, there is no downgrading of 
liver GVHD staging for other causes of hyperbilirubinemia. (e.g., if TTP is 
diagnosed in the presence of Stage 2 liver GVHD and worsening skin or GI 
GVHD, the liver is staged according to the actual bilirubin level even if 
some of the rise in bilirubin is attributed to TTP). 
 
Similarly, even if there is no liver GVHD at onset of a new process, (such 
as TPN cholestasis), but skin or GI GVHD worsen during that process, then 
liver GVHD is diagnosed and staged according to the height of the 
bilirubin. 
 
There is one exception to this: the diagnosis of TTP, with high LDH and 
unconjugated bilirubin precludes the diagnosis and staging of new liver 
GVHD in the absence of a confirmatory liver biopsy. 
 
 
Table 3. Evaluating GI GVHD in the Absence of Biopsy Confirmation  
 
Establishing GI GVHD with new onset diarrhea and no skin or liver GVHD 
No Skin/liver GVHD  
Day 0 through 
engraftment 
Assume no GI GVHD unless proven by biopsy  
 
No Skin/liver GVHD 
Engraftment through 
Day 100  
NO other etiology of diarrhea 
identified: 
Stage as GI GVHD  
Any other etiology of diarrhea 
identified: 
Do not stage as GI GVHD  
Establishing GI GVHD with pre-existing diarrhea and skin or liver GVHD 
Skin and/or liver GVHD 
present  
Worsening diarrhea (includes 
worsening just prior to onset of skin 
or liver GVHD) OR persistent 
diarrhea despite resolution of non-
GVHD cause: 
Stage as GI GVHD  
Improving diarrhea after the 
diagnosis of skin or liver GVHD 
(irrespective of treatment) OR 
persistent diarrhea without resolution 
of underlying non-GVHD cause: 
Do not stage as GI GVHD  
 
Differentiating Acute GVHD, Chronic GVHD, and Overlap Syndrome  
There is often confusion differentiating acute from chronic GVHD, especially in the setting of reduced 
intensity transplants, DLI and new prophylactic treatments. The NIH Working Group recently published 
new classifications for GVHD:  
 
 
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Table 4. Acute GVHD, Chronic GVHD, and Overlap Syndrome 
Category  
Time of Symptoms 
after HCT or DLI  
Presence of Acute 
GVHD features  
Presence of Chronic 
GVHD features  
Acute GVHD  
 
 
 
Classic acute GVHD  
≤100 d  
Yes  
No  
Persistent, recurrent, or 
late-onset acute GVHD  
>100 d  
Yes  
No  
Chronic GVHD  
 
 
 
Classic chronic GVHD  
No time limit  
No  
Yes  
Overlap syndrome  
No time limit  
Yes  
Yes  
 
• 
Scoring of acute GVHD may need to occur past Day 100. In particular, patients should continue to 
be scored for acute GVHD when classic acute GVHD symptoms (maculopapular rash, nausea, 
vomiting, anorexia, profuse diarrhea - particularly if bloody and ileus) persist past Day 100 or if 
identical symptoms previously scored as acute GVHD resolve and then recur within 30 days during 
immunosuppression taper but past Day 100. 
• 
Those patients being scored as having acute GVHD should NOT have diagnostic or distinctive 
signs of chronic GVHD. 
• 
Patients with both acute and chronic symptoms should be diagnosed as having Overlap Syndrome 
and scored according to their chronic GVHD score.  
Further Explanation of Criteria presented in Tables 2 and 3 
Assessment of Skin GVHD  
Presence or Absence of Skin GVHD: Skin GVHD will be considered present if a rash characteristic of 
acute GVHD develops after allogeneic marrow transplantation involving more than 25% of the body 
surface not clearly attributable to causes such as drug administration or infection. The extent of the body 
surface area involved can be estimated by the “Rule of Nines”. In estimating the extent of skin GVHD, the 
area involved is calculated for individual anatomic areas, such as the arm or leg, and then the total is 
derived from a simple summation. Areas that are non-blanching should not be considered involved 
regardless of the overlying color of the rash (red, brown, etc.). Limited distribution erythema (with the 
exception of palms and soles) in the absence of associated rash elsewhere on the body will not be 
considered GVHD.  
 
Assessment of Liver GVHD  
Assessing for the Presence or Absence of Liver GVHD  
A. Hyperbilirubinemia (total bilirubin ≥ 2.0 mg/dL) in the absence of other signs of acute GVHD in 
the skin or GI tract:  
i) Day 0-35: If hyperbilirubinemia alone is present with no other signs of acute GVHD in other 
organ systems, acute GVHD will not be diagnosed based solely on laboratory abnormalities. 
Acute GVHD will be diagnosed if findings on histopathology studies of liver from a biopsy or 
autopsy are confirmatory.  
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ii) Day 35-100: If hyperbilirubinemia (must be conjugated bilirubin) is not improving or is 
exacerbated (especially if serum alkaline phosphatase is increased), in the absence of acute 
GVHD in other organ systems, no other etiologies are identified, and does not improve with 
discontinuation of hepatotoxic drugs, acute GVHD will be diagnosed. However, it is 
distinctly unusual to develop ascites or a coagulopathy in the early stages of acute GVHD of 
the liver alone. In the absence of histopathology studies of liver from a biopsy or autopsy 
specimen, ascites or a coagulopathy secondary to liver dysfunction will be considered to 
indicate the presence of another disease process (e.g., veno-occlusive disease). 
Recommended non-invasive studies to define an etiology for hyperbilirubinemia are:  
a. Imaging of liver (CT or ultrasound)  
b. Hepatitis screen (only if ALT is elevated)  
c. PT  
d. Blood cultures  
e. Review of medication list for potentially hepatotoxic drugs  
f. 
Review of risk factors for viral liver infection (HSV, CMV, VZV, adenovirus, EBV, HBV, 
HCV)  
g. Hemolysis screen  
 
B. Pre-existing hyperbilirubinemia clearly attributed to an etiology other than acute GVHD in the 
presence of signs of acute GVHD in other organ systems.  
i) If pre-existing non-GVHD liver disease (documented clinically, by lab assessment, or by 
imaging studies) is stable or improving at the onset of signs of acute GVHD in other organs, 
then acute GVHD of the liver will not be considered to be present unless proven by liver 
biopsy or autopsy.  
ii) If hyperbilirubinemia worsens several days before or at the time of onset of signs of acute GVHD 
in other organ systems, GVHD will be considered to be present unless histopathology studies 
of liver are available and negative on a biopsy during that time interval or autopsy results 
exclude GVHD.  
iii) If hyperbilirubinemia persists and is not improving after resolution of a pre-existing non-GVHD 
liver disease process (e.g. localized infection of liver, systemic sepsis, biliary tract obstruction) 
when signs of acute GVHD are present in other organ systems or no other intervening cause 
has been diagnosed, then acute GVHD will be considered to be present in the absence of a new, 
clearly identifiable cause of non-GVHD liver disease or unless a liver biopsy or autopsy 
specimen is negative.  
 
C. Prior acute GVHD in liver with new onset of a disease process that exacerbates pre-existing or 
recently resolved hyperbilirubinemia:  
i) If an etiology other than acute GVHD is clearly identified as causing or exacerbating 
hyperbilirubinemia and acute liver GVHD has been diagnosed and has been stable, improving, or 
resolved, then the liver will not be restaged for acute GVHD until the resolution or stabilizing of 
the concurrent disease process (i.e., the liver stage prior to the onset of the new disease process will 
be carried forward until the new disease process resolves). Example: Acute GVHD of the liver and 
gut is diagnosed on Day 20. Treatment of acute GVHD results in falling bilirubin levels to liver 
Stage 1. Sepsis or TTP develops with transient worsening of the hyperbilirubinemia. The liver stage 
is not increased, despite a higher bilirubin level, because the cause of worsening hyperbilirubinemia 
is attributed to sepsis or TTP. 
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ii) If an etiology other than acute GVHD is clearly identified as causing or exacerbating 
hyperbilirubinemia in the presence of already worsening acute liver GVHD or GVHD of the skin 
or GI tract is simultaneously worsening, then the liver GVHD will be staged according to the actual 
bilirubin level, even though another cause of hyperbilirubinemia is present.  
 
Assessment of GVHD of the Gastrointestinal Tract  
Assessing for the Presence or Absence of GVHD of the Gastrointestinal Tract  
A. Diarrhea (≥ 500 mL/day in adults or > 10 mL/kg in pediatric patients) in the absence of other signs 
of acute GVHD in other organ systems  
i) Day 0-engraftment: If diarrhea alone is present without other signs of acute GVHD in other 
organ systems, acute GVHD will not be considered present. Diarrhea will be attributed to acute 
GVHD if histopathology studies of gastrointestinal tract from a biopsy or autopsy are 
diagnostic.  
 
ii) Engraftment-Day 100: If diarrhea persists and is not improving, is exacerbated, or develops de 
novo in the absence of acute GVHD in other organ systems, histopathology studies of gut 
biopsies or from autopsy specimens are not available, and no other etiologies are clearly 
identified, acute GVHD will be considered to be the cause. A stool specimen should be 
examined to rule out infectious causes (e.g., rotavirus, adenovirus, and C. difficile toxin). It is 
recommended, if at all possible, that biopsies be obtained for diagnostic purposes.  
B. Pre-existing diarrhea clearly attributed to an etiology other than acute GVHD in the presence of 
signs of acute GVHD in other organ systems:  
i) If pre-existing diarrhea caused by a process other than GVHD has been documented clinically 
or by lab assessment and is stable or improving at the onset of signs of acute GVHD in the skin 
or liver, then acute GVHD of the intestine will not be considered to be present in the absence 
of biopsy confirmation or autopsy report.  
ii)  If diarrhea or gastrointestinal symptoms are already present, but worsen significantly at the 
time of onset of signs of acute GVHD in the skin or liver, GVHD will be considered present, 
unless biopsy or autopsy are negative.  
iii) If diarrhea persists after resolution of a pre-existing disease process with signs of acute GVHD 
present in other organ systems, GVHD will be considered present, unless biopsy or autopsy are 
negative.  
C. Prior or present acute GVHD in other organ systems with new onset of diarrhea:  
If diarrhea is clearly attributable to an etiology other than acute GVHD (e.g., infection) and a 
history of acute GVHD exists or acute GVHD is present in other organ systems and is stable, then 
the gastrointestinal tract will not be evaluable for acute GVHD until the resolution or stabilizing of 
the other disease process (e.g., infection) in the absence of biopsy or autopsy confirmation.  
D. Persistent anorexia, nausea or vomiting in the absence of signs of acute GVHD in other organ 
systems:  
Persistent anorexia, nausea or vomiting in the absence of other known causes of these symptoms 
will be considered Stage 1 acute GVHD if confirmed by endoscopic biopsy.  
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If a biopsy is not possible (e.g., secondary to thrombocytopenia) but the clinical findings are 
compatible with acute GVHD, then the patient will be treated and recorded as having acute 
GVHD.  
Staging of the Gastrointestinal Tract for the Severity of Acute GVHD  
The severity of gastrointestinal tract GVHD will be staged according to modified Glucksberg criteria. 
To minimize errors caused by large day-to-day variation, diarrhea volume is measured as an average 
over 3 days and reported as the volume in ml per day. When urinary mixing is noted the stool volume 
will be considered half of the total volume unless nursing staff is able to give a better estimate from 
direct observation. Abdominal cramps are considered significant for staging if the severity results in a 
clinical intervention (e.g., analgesia, fasting, etc.). Blood in the stools is considered significant if the 
blood is visible or hematochezia/melena is present and not clearly attributed to a cause other than 
GVHD (e.g. epistaxis/hemorrhoids).  
 
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APPENDIX IV: POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study patients and/or 
their parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in the diet. 
 
Caspofungin 
Drugs that may interact with caspofungin 
• 
Anti-rejection medications 
o Cyclosporine, tacrolimus 
• 
Anti-seizure medications  
o Carbamazepine, phenytoin 
• 
Other medications such as dexamethasone, efavirenz, nevirapine, and rifampin 
 
Food and supplements that may interact with caspofungin* 
• Florastor 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or 
dried herbs. All forms should be avoided.  
 
Fluconazole 
Drugs that may interact with fluconazole 
• 
Antibiotics, antifungals, and other drugs for infections 
o Artemether/lumefantrine, ciprofloxacin, clarithromycin, erythromycin, levofloxacin, 
moxifloxacin, pentamidine, rifabutin, rifampin 
• 
Antidepressants and antipsychotics  
o Buspirone, citalopram, clozapine, escitalopram, fluoxetine, lurasidone, nefazodone, olanzapine, 
paliperidone, quetiapine, sertraline, thioridazine, trazodone 
• 
Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delavirdine, didanosine, efavirenz, etravirine, 
fosamprenavir, maraviroc, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, telaprevir, 
zidovudine 
• 
Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• 
Cholesterol, heart and blood pressure medications  
o Amiodarone, atorvastatin, carvedilol, clopidogrel, dofetilide, eplerenone, gemfibrozil, 
lovastatin, nicardipine, nisoldipine, procainamide, simvastatin, sotalol, verapamil 
• 
Diabetes medications 
o Glipizide, glyburide, repaglinide, saxagliptin 
• 
Nausea medications 
o Aprepitant, dolasetron, droperidol, haloperidol 
• 
Oral contraceptives (“birth control”), including emergency oral contraceptives 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Stomach and reflux medications 
o Cimetidine, esomeprazole, lansoprazole, omeprazole 
• 
Many other drugs, including the following: 
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o Apixaban, bosentan, budesonide, diazepam, dihydroergotamine, eletriptan, ergotamine, 
eszopiclone, guanfacine, ivacaftor, lomitapide, methadone, methylprednisolone, mifepristone, 
oxycodone, pimozide, salmeterol, sitaxentan, sildenafil, tofacitinib, warfarin, zolpidem 
 
Food and supplements that may interact with fluconazole* 
• Florastor 
• Milk thistle 
• Red rice yeast 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
Voriconazole 
Drugs that may interact with voriconazole 
• 
Antibiotics, antifungals, and other drugs for infections 
o Artemether/lumefantrine, ciprofloxacin, clarithromycin, erythromycin, isoniazid, 
levofloxacin, moxifloxacin, pentamidine, rifabutin, rifampin 
• 
Antidepressants and antipsychotics  
o Buspirone, citalopram, clozapine, escitalopram, fluoxetine, fluvoxamine, lurasidone, 
nefazodone, olanzapine, paliperidone, quetiapine, sertraline, thioridazine, trazodone 
• 
Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• 
Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delavirdine, didanosine, efavirenz, etravirine, 
fosamprenavir, lopinavir, maraviroc, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, 
Stribild, telaprevir 
• 
Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• 
Cholesterol, heart and blood pressure medications  
o Amiodarone, atorvastatin, carvedilol, clopidogrel, dofetilide, eplerenone, gemfibrozil, 
lovastatin, nicardipine, nisoldipine, procainamide, simvastatin, sotalol, verapamil 
• 
Diabetes medications 
o Glipizide, glyburide, repaglinide, saxagliptin 
• 
Nausea medications 
o Aprepitant, dolasetron, droperidol, haloperidol 
• 
Oral contraceptives (“birth control”), including emergency oral contraceptives 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Stomach and reflux medications 
o Cimetidine, esomeprazole, lansoprazole, omeprazole 
• 
Many other drugs, including the following: 
o Apixaban, bosentan, budesonide, dihydroergotamine, eletriptan, ergotamine, eszopiclone, 
guanfacine, ivacaftor, lomitapide, methadone, methylprednisolone, mifepristone, oxycodone, 
pimozide, salmeterol, sitaxentan, sildenafil, tofacitinib, warfarin, zolpidem 
 
 
Food and supplements that may interact with voriconazole* 
• Florastor 
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• Milk thistle 
• Red rice yeast 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
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REFERENCES 
 
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Wingard JR, Carter SL, Walsh TJ, et al: Randomized double-blind trial of fluconazole 
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Smith J, Safdar N, Knasinski V, et al: Voriconazole therapeutic drug monitoring. 
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Trifilio S, Scheetz M, Pi J, et al: Tacrolimus use in adult allogeneic stem cell transplant 
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Shima H, Miharu M, Osumi T, et al: Differences in voriconazole trough plasma 
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Neely M, Rushing T, Kovacs A, et al: Voriconazole pharmacokinetics and 
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12. 
Marty F, Lowry C, Cutler C, et al: Voriconazole and sirolimus coadministration after 
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13. 
Pfaller M, Boyken L, Hollis R, et al: In vitro susceptibility of invasive isolates of Candida 
spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin 
Microbiol. 46:150-6, 2008 
14. 
van Burik J, Ratanatharathorn V, Stepan D, et al: Micafungin versus fluconazole for 
prophylaxis against invasive fungal infections during neutropenia in patients undergoing 
hematopoietic stem cell transplantation. Clin Infect Dis 39:1407-1416, 2004 
15. 
Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious complications 
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Zwarenstein M, Treweek S, Gagnier J, et al: Improving the reporting of pragmatic trials: 
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Winston D, Maziarz R, Chandrasekar P, et al: Intravenous and oral itraconazole versus 
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Herbrecht R, Denning D, Patterson T, et al: Voriconazole versus amphotericin B for 
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Cornely OA, Maertens J, Winston DJ, et al: Posaconazole vs. Fluconazole or Itraconazole 
Prophylaxis in Patients with Neutropenia. N Engl J Med 356:348-359, 2007 
23. 
Walsh T, Pappas P, Winston D, et al: Voriconazole compared with liposomal amphotericin 
B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl 
J Med 346:225-34, 2002 
24. 
Hol JA, Wolfs TF, Bierings MB, et al: Predictors of invasive fungal infection in pediatric 
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25. 
van Burik J, Weisdorf D: Infections in recipients of blood and marrow transplantation. 
Hematol Oncol Clin North Am 13:1065-89, 1999 
26. 
Dvorak C, Steinbach W, Brown J, et al: Risks and outcomes of invasive fungal infections 
in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone 
Marrow Transplant 36:621-629, 2005 
27. 
Hovi L, Saarinen-Pihkala UM, Vettenranta K, et al: Invasive fungal infections in pediatric 
bone marrow transplant recipients: single center experience of 10 years. Bone Marrow 
Transplant 26:999-1004, 2000 
28. 
Mikulska M, Raiola A, Bruno B, et al: Risk factors for invasive aspergillosis and related 
mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 
patients. Bone Marrow Transplant 44:361-70, 2009 
29. 
Marr KA, Seidel K, Slavin MA, et al: Prolonged fluconazole prophylaxis is associated with 
persistent protection against candidiasis-related death in allogeneic marrow transplant 
recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 96:2055-
2061, 2000 
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van Burik J, Carter S, Freifeld A, et al: Higher risk of cytomegalovirus and aspergillus 
infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious 
complications in patients treated with T cell depletion versus immunosuppressive therapy 
to prevent graft-versus-host disease. Biol Blood Marrow Transplant 13:1487-98, 2007 
31. 
De Pauw B, Walsh T, Donnelly J, et al: Revised definitions of invasive fungal disease from 
the European Organization for Research and Treatment of Cancer/Invasive Fungal 
Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases 
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Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813-21, 
2008 
32. 
Ostrosky-Zeichner L, Alexander B, Kett D, et al: Multicenter clinical evaluation of the (1-
->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. . Clin Infect 
Dis. 41:654-9, 2005 
33. 
Bochud P-Y, Chien JW, Marr KA, et al: Toll-like Receptor 4 Polymorphisms and 
Aspergillosis in Stem-Cell Transplantation. N Engl J Med 359:1766-1777, 2008 
34. 
Mezger M, Steffens M, Beyer M, et al: Polymorphisms in the chemokine (C-X-C motif) 
ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell 
transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. 
Blood 111:534-6, 2008 
35. 
Cunha C, Di Ianni M, Bozza S, et al: Dectin-1 Y238X polymorphism associates with 
susceptibility to invasive aspergillosis in hematopoietic transplantation through 
impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. 
Blood 116:5394-402, 2010 
36. 
Zaas A, Liao G, Chien J, et al: Plasminogen alleles influence susceptibility to invasive 
aspergillosis. PLoS Genet 4:e1000101, 2008 
37. 
Brammer KW, Coates PE: Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin 
Microbiol Infect Dis 13:325-9, 1994 
38. 
Lee JW, Seibel NL, Amantea M, et al: Safety and pharmacokinetics of fluconazole in 
children with neoplastic diseases. Journal of Pediatrics 120:987-93, 1992 
39. 
Novelli V, Holzel H: Safety and tolerability of fluconazole in children. Antimicrob Agents 
Chemother 43:1955-60, 1999 
40. 
Seay RE, Larson TA, Toscano JP, et al: Pharmacokinetics of fluconazole in immune-
compromised children with leukemia or other hematologic diseases. Pharmacotherapy 
15:52-8, 1995 
41. 
Steinbach WJ: Antifungal agents in children. Pediatr Clin North Am 52:895-915, viii, 2005 
42. 
Wolff S, Fay J, Stevens D, et al: Fluconazole vs low-dose amphotericin B for the prevention 
of fungal infections in patients undergoing bone marrow transplantation: a study of the 
North American Marrow Transplant Group. Bone Marrow Transplant 25:853-9, 2000 
43. 
Lignell A, Löwdin E, Cars O, et al: Characterization of the inhibitory effect of voriconazole 
on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic 
model. J Antimicrob Chemother 62:142-8, 2008 
44. 
Friberg L, Ravva P, Karlsson M, et al: Integrated population pharmacokinetics of 
voriconazole in children, adolescents and adults. American College of Pharmacometrics 
Abstract, 2011 
45. 
Reboli A, Rotstein C, Pappas P, et al: Anidulafungin versus fluconazole for invasive 
candidiasis. N Engl J Med 356:2472-82, 2007 
46. 
Mora-Duarte J, Betts R, Rotstein C, et al: Comparison of caspofungin and amphotericin B 
for invasive candidiasis. N Engl J Med 347:2020-9, 2002 
47. 
Chou L, Lewis R, Ippoliti C, et al: Caspofungin as primary antifungal prophylaxis in stem 
cell transplant recipients. Pharmacotherapy 27:1644-50, 2007 
48. 
Lehrnbecher T, Ethier M, Zaoutis T, et al: International variations in infection supportive 
care practices for paediatric patients with acute myeloid leukaemia. Br J Haematol 
147:125-8, 2009 
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Trifilio S, Singhal S, Williams S, et al: Breakthrough fungal infections after allogeneic 
hematopoietic stem cell transplantation in patients on prophylactic voriconazole. Bone 
Marrow Transplant 40:451-6, 2007 
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J Pediatr 106:522-6, 1985 
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Hughes W, Armstrong D, Bodey G, et al: 1997 guidelines for the use of antimicrobial 
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Pugh RN, Murray-Lyon IM, Dawson JL, et al: Transection of the oesophagus for bleeding 
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Marr K: Fungal infections in hematopoietic stem cell transplant recipients. Med Mycol 
46:293-302, 2008 
54. 
MacMillan M, Goodman J, DeFor T, et al: Fluconazole to prevent yeast infections in bone 
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determination of the value of maintenance therapy. Am J Med 112:369-79, 2002 
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Benjamin DJ, Miller W, Bayliff S, et al: Infections diagnosed in the first year after pediatric 
stem cell transplantation. Pediatr Infect Dis J 21:227-34, 2002 
56. 
Kontoyiannis D, Marr K, Park B, et al: Prospective surveillance for invasive fungal 
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Infect Dis 50:1091-100, 2010 
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Fukuda T, Boeckh M, Carter RA, et al: Risks and outcomes of invasive fungal infections 
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conditioning. Blood 102:827-833, 2003 
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Safdar A, Rodriguez G, De Lima M, et al: Infections in 100 cord blood transplantations: 
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Walsh T, Adamson P, Seibel N, et al: Pharmacokinetics, safety, and tolerability of 
caspofungin in children and adolescents. Antimicrob Agents Chemother 49:4536-45, 2005 
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De Pauw B, Walsh TJ, Donnelly JP, et al: Revised definitions of invasive fungal disease 
from the European Organization for Research and Treatment of Cancer/Invasive Fungal 
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Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813-21, 
2008 
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Lehrnbecher T, Ethier MC, Zaoutis T, et al: International variations in infection supportive 
care practices for paediatric patients with acute myeloid leukaemia. Br J Haematol 
147:125-8, 2009 
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63. 
Ellis M, Al-Ramadi B, Finkelman M, et al: Assessment of the clinical utility of serial beta-
D-glucan concentrations in patients with persistent neutropenic fever. J Med Microbiol 
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Odabasi Z, Mattiuzzi G, Estey E, et al: Beta-D-glucan as a diagnostic adjunct for invasive 
fungal infections: validation, cutoff development, and performance in patients with acute 
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diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 52:750-70 
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levels in children: preliminary data for diagnostic use of the beta-glucan assay in a pediatric 
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67. 
Ascioglu S, Rex J, de Pauw B, et al: Defining opportunistic invasive fungal infections in 
immunocompromised patients with cancer and hematopoietic stem cell transplants: an 
international consensus. Clin Infect Dis 34:7-14, 2002 
68. 
Marty FM, Koo S: Role of (1-->3)-beta-D-glucan in the diagnosis of invasive aspergillosis. 
Med Mycol 47 Suppl 1:S233-40, 2009 
69. 
Marty FM, Lowry CM, Lempitski SJ, et al: Reactivity of (1-->3)-beta-d-glucan assay with 
commonly used intravenous antimicrobials. Antimicrob Agents Chemother 50:3450-3, 
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Wheat LJ, Walsh TJ: Diagnosis of invasive aspergillosis by galactomannan antigenemia 
detection using an enzyme immunoassay. Eur J Clin Microbiol Infect Dis 27:245-51, 2008 
71. 
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curve. Clin Chem 54:17-23, 2008 
 
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SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM –FOR 
INSTITUTIONS WITH STANDARD USE OF FLUCONAZOLE 
ACCL1131 
 
A Phase III Open-Label Trial of Caspofungin vs. Azole Prophylaxis for Patients at High-
Risk for Invasive Fungal Infections (IFI) Following Allogeneic Hematopoietic Cell 
Transplantation (HCT)  
 
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 about to undergo a stem 
cell transplant (SCT). More information about SCT can be found in the COG Family Handbook 
for Children with Cancer. Patients undergoing SCT are 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. Treatment with high doses of chemotherapy 
and radiation, which are used as part of SCT, severely reduces the body’s natural infection fighting 
ability. In patients who died from infections while receiving SCT, an invasive fungal infection was 
the cause in more than half of the cases. Preventing invasive fungal infections is therefore very 
important for the treatment success of people receiving SCT.  
 
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 SCT is the use of fungi fighting drugs (called antifungal therapy). The current standard 
antifungal drugs are called fluconazole and voriconazole. Fluconazole and voriconazole are part 
of a group of agents called azoles. The azole utilized by your center is fluconazole.  
 
Why is this study being done? 
 
Current standard antifungal therapy agents (fluconazole and voriconazole) have been shown to 
be equally effective in preventing invasive fungal infections in people receiving a SCT; especially 
those caused by the fungi Candida. However, previous studies have shown that they do 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 will 
be better than the current standard antifungal drugs at preventing invasive fungal infections when 
given to people receiving SCT.  
 
The drug caspofungin was chosen because a drug very similar to caspofungin has been shown 
to be effective in the prevention of various fungal infections, including Candida and Aspergillus in 
a study for adult patients. 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 caspofungin vs azole antifungals on 
people receiving SCT, who are at risk of getting invasive fungal infections, to find 
out which is better. In this study, you will get either caspofungin or an azole 
antifungal (fluconazole or voriconazole). 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 the SCT conditioning regimen (high doses of 
chemotherapy or radiation). 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: 
 
• 
Azole Antifungal Arm – Current standard treatment; patients will get therapy with 
fluconazole. The azole utilized by your center was determined to be fluconazole.  
 
• 
Caspofungin Arm – Experimental treatment; patients will get therapy with caspofungin. 
 
 
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ACCL1131 
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 azole (fluconazole) arm. The randomization process is described in the 
COG Family Handbook for Children with Cancer. 
 
Subjects (people who agree to be part of this study) will receive their planned SCT conditioning 
regimen. Before the SCT conditioning regimen is completed, some subjects will be randomized 
to receive fluconazole while others will get caspofungin. On the day of the SCT (called Day 0) you 
will begin receiving the assigned antifungal treatment 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. 
 
 
Subjects randomized 
Azole (Fluconazole) arm 
Caspofungin starting on 
SCT Day 0 until Day 42 or 
discharge from hospital  
Fluconazole starting on 
SCT Day 0 until Day 42 or 
discharge from hospital 
Caspofungin arm 
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ACCL1131 
Treatment for participants who are on the Azole (Fluconazole) Arm- Standard Treatment 
Drug 
How the drug will be given  
Days 
Fluconazole 
IV Infusion over 1-2 hours (or 
longer) or PO 
 
Start on SCT Day 0 & continue until 
Day +42 or discharge from hospital. 
 
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) 
This medication is not available 
PO 
Start on SCT Day 0 & continue until 
Day +42 or discharge from hospital. 
 
 
Research Study Procedures 
If you have a fungal infection while you are on this study, copies of some of the scans or 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.  
 
Serum Beta–D Glucan Testing - Biomarker Study 
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 biomarker that will be measured in your blood is called beta-D glucan. Findings from this 
research will help researchers know more about fungal infections, as well how to diagnose and 
treat them better in future patients. 
 
If you agree, about a teaspoon of blood will be taken from you once a week while you are receiving 
antifungal treatment. This will be drawn from your central line when other routine blood tests are 
being performed. 
 
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. 
 
If you agree, about a teaspoon of blood will be collected at 2 time points for SNP analysis. The 
samples will be collected prior to transplant and about 100 days after transplant when other 
routine blood tests are performed.  
 
 
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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 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 
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. 
 
 
 
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Risks and side effects reported or expected with caspofungin include: 
 
 COMMON, SOME MAY BE SERIOUS 
In 100 people receiving caspofungin, more than 20 may have: 
• Reaction during or following infusion of the drug which may cause fever, chills, rash, 
low blood pressure 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving caspofungin, from 4 to 20 may have: 
• Low blood pressure which may cause feeling faint 
• High blood pressure which may cause dizziness, blurred vision 
• Swelling of the body 
• Blood clot 
• Abnormal heartbeat  
• Rash, itching  
• Pain in the belly 
• Diarrhea, nausea, vomiting  
• Anemia which may require blood transfusion 
• Damage to the liver which may cause belly pain, bleeding 
• Severe blood infection  
• Headache  
• Kidney damage which may require dialysis  
• Cough 
• Damage to or fluid around the lungs which may cause shortness of breath 
• Low levels of certain salts in the body which may require you to take another medicine 
to correct the salt level 
 
RARE, AND SERIOUS 
In 100 people receiving caspofungin, 3 or fewer may have: 
• Severe skin rash with blisters and peeling which can involve mouth and other parts of 
the body  
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 
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 there is no proof of this 
yet. 
 
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. 
 
 
 
 
 
 
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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 with a SCT. 
 
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 Azole (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 590. 
 
How long is the study? 
 
Subjects in this clinical trial are expected to receive treatment on this study for up to 45 days. After 
treatment, you will have follow-up examinations and medical tests. 
 
We would like to continue to find out about your health for 100 days after your SCT.  
 
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 
 
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. 
 
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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. 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 the drug 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. Please direct any questions related the cost of getting caspofungin ready and giving it to you 
to _________________ [please insert contact information for the appropriate institutional 
representative]. 
 
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 azole antifungal 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.  
 
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.  
 
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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, you may ask to be given a summary of the study results, which will 
only be available after the study is fully completed. A summary of the study results will also be 
posted on the Children’s Oncology Group website (http://www.childrensoncologygroup.org/). To 
receive the results, you may either (1) go to the COG website to check if results are available or 
(2) register your information with the COG on its web site and have an email sent to you when 
the results are available. Your pediatric oncology team from your hospital can give you 
additional instructions on how to do this. Please note, that the summary of results may not be 
available until several years after treatment for all children on the study is completed, and not 
only when your child completes 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. 
 
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).  
 
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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 anytime. 
 
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. 
 
There are few risks to you from the genetic research studies, either from the SNP studies 
described above or other potential genomic studies performed if you consent to bank your 
samples for future research. The greatest risk is the release of information from your health 
records, but the tissue bank will protect your records so that your name, date of birth, and other 
identifiable information will be kept private. The chance of these personal facts being given to 
someone else is very small. Special precautions will be taken with studies that involve genetic 
information about the normal cells in your body. Studies of this type will only be performed on 
samples that have a second de-identified number (instead of your name or the COG patient 
number).  
 
Researchers will only be allowed to have access to your genetic information if they sign a special 
agreement and certify that they will keep all records confidential. Those researchers will not 
receive any personal information about you such as your name, date of birth, address, or phone 
number. This type of genetic research is also protected by a recent federal law in the United 
States called the Genetic Information Nondiscrimination Act (GINA), which generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on genetic information. 
 
Some of your genetic and health information may be placed in a central database along with 
information from many other people. This database will be available only to those with authorized 
access. There is a risk that someone could trace the information in the controlled-access 
database back to you. Even without your name or other identifiers, your genetic information is 
unique to you. In spite of all of the safety measures that we will use, we cannot guarantee that 
your identity will never become known. Although your genetic information is unique to you, you 
do share some genetic information with your children, parents, brothers, sisters, and other blood 
relatives. Consequently, it may be possible that genetic information from them could be used to 
help identify you. Similarly, it may be possible that genetic information from you could be used to 
help identify them.  
 
The researchers believe the chance that someone will identify you is very small, but the risk may 
change in the future as people come up with new ways of tracing information. 
 
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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 leftover 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 called biomarkers in 
the blood to study fungal infections. 
 
 
Yes_____ 
No_____ 
 
________ / _______ 
 
 
 
 
 
 
   Initials         Date 
 
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 leftover after the SNP 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 leftover after the SNP 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 
 
 
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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 (ACCL1131) 
 
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 the Azole Arm: Fluconazole Treatment Plan (Standard Treatment 
Arm) 
The purpose of fluconazole therapy is to prevent the development of invasive fungal infections 
following SCT. 
 
Drug 
How the drug will be given  
Days 
Fluconazole 
IV infusion over 1-2 hours (or longer) 
or PO once a day 
Start on SCT Day 0 & 
continue until Day +42 or 
discharge from hospital. 
 
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 
 
Possible Side Effects of fluconazole 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving fluconazole, more than 20 may have: 
• None known 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving fluconazole, from 4 to 20 may have: 
• Nausea, vomiting, diarrhea 
• Pain in the belly 
• Headache 
• Rash, itching  
• Increased blood level of liver tests which may mean there has been damage to the 
liver 
 
RARE, AND SERIOUS 
In 100 people receiving fluconazole, 3 or fewer may have: 
• Abnormal heartbeat which may cause fainting 
• Severe skin rash with blisters and peeling which can involve mouth and other 
parts of the body  
• Infection, especially when white blood cell count is low  
• Bruising, bleeding 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
• Seizure  
 
 
 
 
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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. 
 
 
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SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM –FOR 
INSTITUTIONS WITH STANDARD USE OF VORICONAZOLE 
ACCL1131 
A Phase III Open-Label Trial of Caspofungin vs. Azole Prophylaxis for Patients at High-
Risk for Invasive Fungal Infections (IFI) Following Allogeneic Hematopoietic Cell 
Transplantation (HCT)  
 
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 about to undergo a stem 
cell transplant (SCT). More information about SCT can be found in the COG Family Handbook 
for Children with Cancer. Patients undergoing SCT are 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. Treatment with high doses of chemotherapy 
and radiation, which are used as part of SCT, severely reduces the body’s natural infection fighting 
ability. In patients who died from infections while receiving SCT, an invasive fungal infection was 
the cause in more than half of the cases. Preventing invasive fungal infections is therefore very 
important for the treatment success of people receiving SCT.  
 
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 SCT is the use of fungi fighting drugs (called antifungal therapy). The current standard 
antifungal drugs are called fluconazole and voriconazole. Fluconazole and voriconazole are part 
of a group of agents called azoles. The azole utilized by your center is voriconazole.  
 
Why is this study being done? 
Current standard antifungal therapy agents (fluconazole and voriconazole) have been shown to 
be equally effective in preventing invasive fungal infections in people receiving a SCT; especially 
those caused by the fungi Candida. However, previous studies have shown that they do 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 will 
be better than the current standard antifungal drugs at preventing invasive fungal infections when 
given to people receiving SCT.  
 
The drug caspofungin was chosen because a drug very similar to caspofungin has been shown 
to be effective in the prevention of various fungal infections, including Candida and Aspergillus in 
a study for adult patients. 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 caspofungin vs azole antifungals on 
people receiving SCT, who are at risk of getting invasive fungal infections, to find 
out which is better. In this study, you will get either caspofungin or an azole 
antifungal (fluconazole or voriconazole). 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 the SCT conditioning regimen (high doses of 
chemotherapy or radiation). 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: 
 
• 
Azole Antifungal Arm – Current standard treatment; patients will get therapy with 
voriconazole. The azole utilized by your center was determined to be voriconazole.  
 
• 
Caspofungin Arm – Experimental treatment; patients will get therapy with caspofungin. 
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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 azole (voriconazole) arm. The randomization process is described in the 
COG Family Handbook for Children with Cancer. 
 
Subjects (people who agree to be part of this study) will receive their planned SCT conditioning 
regimen. Before the SCT conditioning regimen is completed, some subjects will be randomized 
to receive voriconazole while others will get caspofungin. On the day of the SCT (called Day 0) 
you will begin receiving the assigned antifungal treatment 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. 
 
 
Subjects randomized 
Azole (Voriconazole) arm 
Caspofungin starting on 
SCT Day 0 until Day 42 or 
discharge from hospital  
Voriconazole starting on 
SCT Day 0 until Day 42 or 
discharge from hospital 
Caspofungin arm 
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Treatment for participants who are on the Azole (voriconazole) Arm- Standard Treatment 
Drug 
How the drug will be given  
Days 
Voriconazole 
IV Infusion over 1-2 hours (or longer) or 
PO twice a day 
(Dose on first day is different from dose 
given in the days that follow) 
Start on SCT Day 0 & continue until 
Day +42 or discharge from hospital.  
 
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) 
This medication is not available PO 
Start on SCT Day 0 & continue until 
Day +42 or discharge from hospital. 
 
Research Study Procedures 
If you have a fungal infection while you are on this study, copies of some of the scans or 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.  
 
Serum Beta–D Glucan Testing - Biomarker Study 
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 biomarker that will be measured in your blood is called beta-D glucan. Findings from this 
research will help researchers know more about fungal infections, as well how to diagnose and 
treat them better in future patients. 
 
If you agree, about a teaspoon of blood will be taken from you once a week while you are receiving 
antifungal treatment. This will be drawn from your central line when other routine blood tests are 
being performed. 
 
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. 
 
If you agree, about a teaspoon of blood will be collected at 2 time points for SNP analysis. The 
samples will be collected prior to transplant and about 100 days after transplant when other 
routine blood tests are performed.  
 
 
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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 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 
The use of caspofungin may cause more complications than the use of voriconazole.  
 
The caspofungin treatment that is being studied could be less effective than the current 
standard treatment with voriconazole. 
 
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. 
 
 
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Possible Side Effects of Caspofungin  
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving caspofungin, more than 20 may have: 
• Reaction during or following infusion of the drug which may cause fever, chills, 
rash, low blood pressure 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving caspofungin, from 4 to 20 may have: 
• Low blood pressure which may cause feeling faint 
• High blood pressure which may cause dizziness, blurred vision 
• Swelling of the body 
• Blood clot 
• Abnormal heartbeat  
• Rash, itching  
• Pain in the belly 
• Diarrhea, nausea, vomiting  
• Anemia which may require blood transfusion 
• Damage to the liver which may cause belly pain, bleeding 
• Severe blood infection  
• Headache  
• Kidney damage which may require dialysis  
• Cough 
• Damage to or fluid around the lungs which may cause shortness of breath 
• Low levels of certain salts in the body which may require you to take another 
medicine to correct the salt level 
 
RARE, AND SERIOUS 
In 100 people receiving caspofungin, 3 or fewer may have: 
• Severe skin rash with blisters and peeling which can involve mouth and other 
parts of the body  
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
 
Although caspofungin has the potential risks noted above, it may be better at preventing invasive 
fungal infections caused by Aspergillus as compared to voriconazole, but there is no proof of this 
yet. 
 
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 with a SCT. 
We expect that the information learned from this study will benefit other patients in the future. 
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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 Azole (voriconazole) 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 590. 
 
How long is the study? 
Subjects in this clinical trial are expected to receive treatment on this study for up to 45 days. After 
treatment, you will have follow-up examinations and medical tests. 
 
We would like to continue to find out about your health for 100 days after your SCT.  
 
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 
 
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 
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• 
The drug company that makes the drug 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. Please direct any questions related the cost of getting caspofungin ready and giving it to you 
to _________________ [please insert contact information for the appropriate institutional 
representative]. 
 
Voriconazole 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 azole antifungal arm, you or your 
insurance company will be charged for the voriconazole. 
 
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.  
 
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.  
 
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.  
 
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During your follow-up visits, you may ask to be given a summary of the study results, which will 
only be available after the study is fully completed. A summary of the study results will also be 
posted on the Children’s Oncology Group website (http://www.childrensoncologygroup.org/). To 
receive the results, you may either (1) go to the COG website to check if results are available or 
(2) register your information with the COG on its web site and have an email sent to you when 
the results are available. Your pediatric oncology team from your hospital can give you additional 
instructions on how to do this. Please note, that the summary of results may not be available until 
several years after treatment for all children on the study is completed, and not only when your 
child completes 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. 
 
 
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 anytime. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
 
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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. 
 
There are few risks to you from the genetic research studies, either from the SNP studies 
described above or other potential genomic studies performed if you consent to bank your 
samples for future research. The greatest risk is the release of information from your health 
records, but the tissue bank will protect your records so that your name, date of birth, and other 
identifiable information will be kept private. The chance of these personal facts being given to 
someone else is very small. Special precautions will be taken with studies that involve genetic 
information about the normal cells in your body. Studies of this type will only be performed on 
samples that have a second de-identified number (instead of your name or the COG patient 
number).  
 
Researchers will only be allowed to have access to your genetic information if they sign a special 
agreement and certify that they will keep all records confidential. Those researchers will not 
receive any personal information about you such as your name, date of birth, address, or phone 
number. This type of genetic research is also protected by a recent federal law in the United 
States called the Genetic Information Nondiscrimination Act (GINA), which generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on genetic information. 
 
Some of your genetic and health information may be placed in a central database along with 
information from many other people. This database will be available only to those with authorized 
access. There is a risk that someone could trace the information in the controlled-access 
database back to you. Even without your name or other identifiers, your genetic information is 
unique to you. In spite of all of the safety measures that we will use, we cannot guarantee that 
your identity will never become known. Although your genetic information is unique to you, you 
do share some genetic information with your children, parents, brothers, sisters, and other blood 
relatives. Consequently, it may be possible that genetic information from them could be used to 
help identify you. Similarly, it may be possible that genetic information from you could be used to 
help identify them.  
 
The researchers believe the chance that someone will identify you is very small, but the risk may 
change in the future as people come up with new ways of tracing information. 
 
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 
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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 called biomarkers in 
the blood to study fungal infections. 
 
 
Yes_____ 
No_____ 
 
________ / _______ 
 
 
 
 
 
 
   Initials         Date 
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 SNP 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 SNP 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 (ACCL1131) 
 
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 the Azole Arm: Voriconazole Treatment Plan (Standard Treatment 
Arm) 
The purpose of voriconazole therapy is to prevent the development of invasive fungal infections 
following SCT. 
 
Drug 
How the drug will be given  
Days 
Voriconazole  
IV infusion over 1-2 hours (or longer) 
or PO twice a day. 
 (Dose on first day is different from 
dose given in the days that follow) 
Start on SCT Day 0 & 
continue until Day +42 or 
discharge from hospital. 
 
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 
 
Possible Side Effects of Voriconazole  
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving voriconazole, more than 20 may have: 
• Blurred vision, vision changes, discomfort from light 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving voriconazole, from 4 to 20 may have: 
• Rash 
• Fever  
• Nausea, vomiting 
• Damage to the liver which may cause belly pain, bleeding 
• Hepatitis which may cause yellow eyes and skin, tiredness 
• Muscle weakness 
• Numbness and tingling of the arms and legs 
• Confusion, sensing things that are not there 
 
RARE, AND SERIOUS 
In 100 people receiving voriconazole, 3 or fewer may have: 
• Low blood pressure which may cause you to feel faint 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Swelling of the body 
• 
Pain in the belly  
• 
Abnormal heartbeat which may cause fainting 
• 
Increased risk of sunburn  
• 
Severe skin rash with blisters and peeling which can involve mouth and other parts 
of the body  
• 
A new cancer of the skin 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat  
• 
Blurred vision with a chance of blindness 
• 
Kidney damage which may require dialysis 
 
 
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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. 
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