CHILDREN'S ONCOLOGY GROUP

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.

TABLE OF CONTENTS

SECTION ..... PAGE
STUDY COMMITTEE ..... 4
ABSTRACT ..... 6
EXPERIMENTAL DESIGN SCHEMA ..... 7
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ..... 8
1.1 Primary Objective ..... 8
1.2 Secondary Objectives ..... 8
2.0 BACKGROUND ..... 8
2.1 Overview and Rationale for Study ..... 8
2.2 Selection of Study Medication ..... 9
2.3 Rationale for Platelia EIA Aspergillus GM and Serum Beta-D Glucan Assays ..... 12
3.0 STUDY ENROLLMENT AND PATIENT ELIGIBILITY ..... 13
3.1 Study Enrollment ..... 13
3.2 Patient Eligibility Criteria ..... 14
4.0 TREATMENT PLAN ..... 16
4.1 Overview of Treatment Plan ..... 16
4.2 Administration Schedule- FLUCONAZOLE ARM ..... 18
4.3 Administration Schedule- CASPOFUNGIN ARM ..... 20
5.0 DOSE MODIFICATIONS FOR TOXICITIES ..... 22
5.1 Impaired Renal Function ..... 22
5.2 Impaired Liver Function ..... 22
6.0 DRUG INFORMATION ..... 23
6.1 FLUCONAZOLE (Diflucan ) ..... 23
6.2 CASPOFUNGIN (caspofungin acetate, Cancidas ) (11/08/11) ..... 26
7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED ..... 29
7.1 Required and Optional Clinical, Laboratory and Disease Evaluations ..... 29
7.2 Optional Studies ..... 30
7.3 Follow-up ..... 30
8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA ..... 30
8.1 Criteria for Removal from Protocol Therapy ..... 30
8.2 Off Study Criteria ..... 30
8.3 Discontinuation from IFI Observation Criteria ..... 31
9.0 STATISTICAL CONSIDERATIONS ..... 31
9.1 Statistical Design ..... 31
9.2 Patient Accrual and Expected Duration of Trial ..... 31
9.3 Statistical Analysis Methods ..... 31
9.4 Gender and Minority Accrual Estimates ..... 35
10.0 EVALUATION CRITERIA ..... 36
10.1 Common Terminology Criteria for Adverse Events (CTCAE) ..... 36
10.2 IFI Checklist and Central Review ..... 36
11.0 ADVERSE EVENT REPORTING REQUIREMENTS ..... 36
11.1 Purpose ..... 36
11.2 Determination of Reporting Requirements ..... 37
11.4 Routine Adverse Event Reporting ..... 38
12.0 RECORDS AND REPORTING ..... 38
12.1 CDUS ..... 38
13.0 PROSPECTIVE EVALUATION OF GALACTOMANNAN AND ( ) BETA-D GLUCAN ASSAYS AS DIAGNOSTIC TOOLS FOR INVASIVE FUNGAL INFECTION IN CHILDREN WITH ACUTE MYELOID LEUKEMIA RECEIVING FUNGAL PROPHYLAXIS. ..... 39
13.1 Sample Collection and Testing Procedures (These studies are optional) ..... 39
13.2 Background ..... 42
13.3 Specific Aims ..... 45
13.4 Patient Accrual ..... 45
13.5 Gold Standards for IFI and IA Infections ..... 46
13.6 Methodology to Identify IFI and IA ..... 46
13.7 Factors resulting in False Positive Results ..... 47
13.8 Statistical Design ..... 47
13.9 Significance ..... 49
14.0 SPECIAL STUDIES SPECIMEN REQUIREMENTS ..... 50
14.1 Single Nucleotide Polymorphisms (This study is optional) ..... 50
15.0 BANKING SPECIMENS ..... 50
APPENDIX I: YOUTH INFORMATION SHEETS ..... 51
APPENDIX II: EORTC/MSG CRITERIA ..... 53
REFERENCES ..... 55
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM ..... 59

EXPERIMENTAL DESIGN SCHEMA

1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.1 Primary Objective

1.2 Secondary Objectives

Clinical

1.2.1

1.2.3

Biological

1.2.5

1.2.6

2.0 BACKGROUND

2.1 Overview and Rationale for Study

2.2 Selection of Study Medication

2.2.1 Choice of Fluconazole Prophylaxis as the Standard Arm

2.2.2 Choice of Caspofungin Prophylaxis as the Intervention Arm

2.2.2.1 Azole Antifungal Agents

2.2.2.2 Echinocandin Antifungal Agents

2.3 Rationale for Platelia EIA Aspergillus GM and Serum Beta-D Glucan Assays

2.4 Rationale for Single Nucleotide Polymorphism (SNP) Aim

3.0 STUDY ENROLLMENT AND PATIENT ELIGIBILITY

3.1 Study Enrollment

3.1.1 Patient Registration

3.1.2 IRB Approval

3.1.3 Study Enrollment

3.1.4 Timing

3.1.5 Bilingual Services

3.1.6 Randomization

3.2 Patient Eligibility Criteria

INCLUSION CRITERIA

3.2.1 Age

3.2.2 Diagnosis

• Newly diagnosed de novo AML
• First or subsequent relapse of AML
• Secondary AML
• Treatment with institutional standard AML therapy in those without AML (for example myelodysplastic syndrome, bone marrow blasts > 5% or biphenotypia).

3.2.3 Organ Function Requirements:

3.2.3.1 Adequate renal function defined as:

• Creatinine clearance or radioisotope GFR
• A serum creatinine based on age/gender as follows:

• Total bilirubin upper limit of normal (ULN) for age, and
• SGOT (AST) or SGPT (ALT) ULN for age.

EXCLUSION CRITERIA

• acute promyelocytic leukemia (APL)
• Down syndrome
• juvenile myelomonocytic leukemia (JMML)
  3.2.5 Patients with a documented history of IFI within the previous 30 days are not eligible.
  3.2.6 Patients with a history of echinocandin or fluconazole hypersensitivity are not eligible.
  3.2.7 Patients receiving treatment for an IFI are not eligible.
  3.2.8 Female patients of childbearing age must have a negative pregnancy test. Patients must agree to use an effective birth control method. Lactating patients must agree not to nurse a child while on this trial.

REGULATORY

4.0 TREATMENT PLAN

4.1 Overview of Treatment Plan

• If the patient has been randomized to fluconazole they can continue this therapy orally at home until the ANC is .
• If the patient is on caspofungin the parents and patient can decide to either remain in the hospital to continue caspofungin until the ANC is or be discharged home on daily IV caspofungin therapy until the ANC is . The latter may be associated with home healthcare costs that would not be funded by the study. It should be confirmed prior to discharge that the insurance company or other sources will cover such home healthcare costs.
• If the insurance company or other sources will not cover home healthcare costs not funded by the study, then the family can elect to pay for these services themselves or go home without continued caspofungin prophylaxis. In this circumstance, the treating physician should proceed with their standard clinical practices.

4.1.1. Randomization

4.1.2 Empirical Antifungal Therapy

4.1.3 Concomitant Therapy Restrictions

4.1.3.1 Fluconazole

4.1.3.2 Caspofungin

4.2 Administration Schedule- FLUCONAZOLE ARM

• following the nadir.

• The next chemotherapy course.

• Patient meets any of the off protocol therapy criteria (Section 8.1).

FLUCONAZOLE: by slow IV infusion over 1-2 hours* (or longer) OR by mouth.

SEE SECTION 5.0 FOR DOSE MODIFICATIONS FOR TOXICITIES. For COG Supportive Care Guidelines see https://members.childrensoncologygroup.org/prot/reference materials.asp

4.3 Administration Schedule- CASPOFUNGIN ARM

• following the nadir.

• The next chemotherapy course.

• Patient meets any of the off protocol therapy criteria (Section 8.1).

CASPOFUNGIN: by slow IV infusion over no less than hour.

SEE SECTION 5.0 FOR DOSE MODIFICATIONS AND TOXICITIES.

Enter Chemotherapy Course # Here

Date Due	Date Given	Day	CASPOFUNGIN Day 1: mg; Day 2 and Subsequently: mg	Studies	Comments (Include any held doses, or dose modifications)
			Enter calculated dose above and actual dose administered below
		1	LD:
		2	MD: mg
					□
			End Date:	b,
Continue prophylaxis until the criteria in Section 4.3 are met. Following completion of prophylaxis in each course of chemotherapy, prophylaxis will restart at the end of the subsequent chemotherapy course as outlined in Section 4.3.

5.0 DOSE MODIFICATIONS FOR TOXICITIES

5.1 Impaired Renal Function

Fluconazole:

Caspofungin:

5.2 Impaired Liver Function

Fluconazole:

Caspofungin:

6.0 DRUG INFORMATION

6.1 FLUCONAZOLE (Diflucan )

Source and Pharmacology:

Toxicity:

Formulation and Stability:

CANADIAN SITES:

Injection:

Source and Pharmacology:

Formulation and Stability:

Preparation instructions in this monograph apply only to the Merck USA product as supplied for this study.

7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED

• Submit relevant IFI checklist documents via the Document Imaging System: (626) 447-2204 at the end of each course of protocol therapy. See Section 10.2 for further details.
  % Obtain at end of Course 1, optimally when the patient has ANC and no circulating blasts.
  Collect specimens twice weekly during the period of neutropenia (until ANC ). See Section 13.1 for specimen collection details. It is suggested that specimens be obtained on Mondays and Thursdays but other days are acceptable if more convenient. A minimum of 2 days should separate each specimen collection. All specimens must be collected in the specimen vials provided by MiraVista Laboratories in the shipped lab collection kits. Alternative specimen vials should never be used as they may contribute to false results.

7.2 Optional Studies

7.2.1 Galactomannan and ( ) Beta-D Glucan Assays

7.2.2 SNP Analysis

7.3 Follow-up

8.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA

8.1 Criteria for Removal from Protocol Therapy

8.2 Off Study Criteria

8.3 Discontinuation from IFI Observation Criteria

9.0 STATISTICAL CONSIDERATIONS

9.1 Statistical Design

9.2 Patient Accrual and Expected Duration of Trial

9.3 Statistical Analysis Methods

9.3.1 Study Endpoints

Primary endpoint

Secondary Endpoints

9.3.2 Central Committee Review

9.3.3 Sample size with power justification

9.3.4 Analysis Plans

Descriptive Analyses

Analysis for Primary Objective and Secondary Clinical Objectives

Analysis of GM and beta-D Glucan Assays

9.3.5 Interim Monitoring

9.4 Gender and Minority Accrual Estimates

• These totals must agree.

10.0 EVALUATION CRITERIA

10.1 Common Terminology Criteria for Adverse Events (CTCAE)

10.2 IFI Checklist and Central Review

• Pathology reports (including autopsy reports),
• CT scan and MRI reports,
• Fungal Gram stain and microbiology culture results (including both positive and negative results),
• Non-culture mycology testing results (i.e. Histoplasma urine antigens, cryptococcal CSF and serum antigens),
• Ophthalmology exams (even if evidence of fungi not seen), and
• Bronchoscopy reports (even if evidence of fungi not seen).

11.0 ADVERSE EVENT REPORTING REQUIREMENTS

11.1 Purpose

11.2 Determination of Reporting Requirements

• 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

• Leukemia secondary to oncology chemotherapy
• Myelodysplastic syndrome
• Treatment related secondary malignancy

11.3 Reporting of Adverse Events for Commercial Agents - via CTEP-AERS

• 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.

Table B

CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy With a Commercial Agent or Within 30 Days

11.4 Routine Adverse Event Reporting

12.0 RECORDS AND REPORTING

12.1 CDUS

13.0 PROSPECTIVE EVALUATION OF GALACTOMANNAN AND BETA-D GLUCAN ASSAYS AS DIAGNOSTIC TOOLS FOR INVASIVE FUNGAL INFECTION IN CHILDREN WITH ACUTE MYELOID LEUKEMIA RECEIVING FUNGAL PROPHYLAXIS.

13.1 Sample Collection and Testing Procedures (These studies are optional)

13.1.1 Sample submission

13.1.2 Sample Collection

13.1.3 Specimen processing

1. Allow the blood to clot for minutes at room temperature.
2. Centrifuge the specimen for 15 minutes at .
3. Remove the serum from the clot and place it into the provided polypropylene storage tube and label the tube.
4. A total minimum volume of 2 mL of serum is required to run the Platelia Aspergillus EIA and Fungitell beta-D glucan assay.

13.1.4 Storing specimens

1. Specimens should be frozen at the day of collection after following the above processing steps.
2. Specimens can be stored at until shipment. Specimens stored at may be stored indefinitely.

13.1.5 Shipping of specimens:

1. Complete an ACCL0933 GM & BG Requisition Form for each specimen sent for testing. All areas of the requisition form must be completed.

1. Assure all specimen labels and packaging labels are correct and legible. Please use the labels provided in the kits as they are designed to withstand specimen freezing and thawing without disruption of the written patient identification information. A Sharpie marker is most effective for writing on these labels.
2. Place the labeled vials containing the patient serum into a biohazard plastic bag along with absorbent material such as gauze or paper towel and seal. Use the biohazard plastic bags provided in the kit.
3. Ship specimens in the boxes provided along with the cold pack that should be frozen.
4. Open the box and remove the Styrofoam liner lid and the sealing tape.
5. Place the frozen cold pack into the liner. The frozen cold pack will ensure specimen integrity during overnight shipment.
6. Place the biohazard plastic bag containing the requisition forms and specimens directly on top of the frozen cold pack.
7. Replace the Styrofoam liner lid.
8. Complete an ACCL0933 GM & BG Requisition Form for each specimen and place them on top of the liner before sealing the box.
9. Wet the sealing tape provided in the kit and seal the cardboard box.
10. If the specimen tube labels and requisition forms do not match when received at MiraVista Diagnostics, a call will be made to the study site on the day of receipt.

1. Ship packages to the following address:

MiraVista Diagnostics
4705 Decatur Blvd.
Indianapolis, IN 46241
317-856-2681

2. Use the FedEx website (www.fedex.com) to learn the current guidelines for the shipping of human body fluids and generating shipping labels.
3. Generate a label via the FedEx website and schedule a pick up (use the MiraVista FedEx account provided).
4. Affix the FedEx label to the top of the box.
5. Ship all packages Priority Overnight via FedEx to arrive at MiraVista Diagnostics by 10:30 AM the next morning.
6. Do not ship on a Friday, Saturday, or the day before a holiday. MiraVista is closed each weekend and on holidays.

13.1.6 Testing of specimens:

1. Testing of serum specimens for this study will be performed in batches.
   a. Negative results are final.
   b. Positive results are retested on the next work day for confirmation.
2. Testing will not occur under the following conditions:
   a. The specimen has been stored under unacceptable storage times and/or temperatures.
   b. The specimen has been shipped under unacceptable time and/or temperature conditions.
   c. The specimen volume is less than needed to complete the testing process.
   d. The specimen cannot be pipetted due to viscosity.
   e. The specimen is hemolyzed or icteric for Fungitell .
   f. The specimen is of a type other than serum separated off the clot.
3. Platelia Aspergillus EIA results are reported as a GM index.
4. Fungitell beta-D glucan assay results are reported as .

13.1.7 MiraVista Contact Information

13.1.8 Galactomannan and Beta-D glucan Assays

13.2 Background

13.2.1 Changing approach to antifungal therapy in pediatric AML patients

1. Prophylaxis: Initiation of antifungal therapy in asymptomatic patients without any evidence of IFI, during periods of high risk such as during prolonged neutropenia resulting from chemotherapy or bone marrow transplant.
2. Empirical antifungal therapy: Initiation or modification of antifungal therapy after persistence of fever in the setting of neutropenia and broad-spectrum antibiotics.
3. Preemptive therapy: Use of radiographic and/or specific biomarkers to identify and treat suspected IFI prior to overt clinical presentation.
4. Therapy for proven, probable or presumed IFI: Therapy initiated for the treatment of proven or probable IFI based on EORTC/MSG criteria or based on clinical presumption of IFI.

13.2.2 Traditional diagnostic studies to identify patients with suspected IFI

13.2.3 Galactomannan and Beta-D Glucan Assays

13.2.3.1 The Platelia Aspergillus EIA and Fungitell Assay in Adults

13.2.3.2 The Platelia Aspergillus EIA and Fungitell Assay in Children

13.2.4 Gaps in knowledge

13.2.5 Summary

13.3 Specific Aims

13.4 Patient Accrual

13.5 Gold Standards for IFI and IA Infections

13.6 Methodology to Identify IFI and IA

13.6.1 Justification of Methodologic Choices

13.6.1.1 Justification for Chosen Thresholds for Platelia Aspergillus EIA and Fungitell Assay

13.6.1.2 Justification for IFI Gold Standard

13.7 Factors resulting in False Positive Results

13.8 Statistical Design

13.8.1 Sample Size and Estimated Event Rates

13.8.2 Sensitivity, Specificity, PPV, and NPV

13.8.3 Receiver Operator Characteristics Curve

13.8.4 Sensitivity Analysis

13.9 Significance

14.0 SPECIAL STUDIES SPECIMEN REQUIREMENTS

14.1 Single Nucleotide Polymorphisms (This study is optional)

14.1.1 Sample Collection

All Other Patients:

14.1.2 Labeling:

14.1.3 Shipping:

15.0 BANKING SPECIMENS

APPENDIX I: YOUTH INFORMATION SHEETS

A Research Study Comparing 2 Drugs Used To Prevent Serious Fungal Infections In Children With Acute Myeloid Leukemia.

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

INFORMATION SHEET REGARDING RESEARCH STUDY ACCL0933 (for teens from 13 through 17 years of age)

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

APPENDIX II: EORTC/MSG CRITERIA

Criteria for proven invasive fungal disease except for endemic mycoses

Criteria for probable invasive fungal disease except for endemic mycoses

Host factors \({ }^{\text {a }}\)
    Recent history of neutropenia ( \(<0.5 \times 10^{9}\) neutrophils/ \(L \left[<500\right.\) neutrophils/ \(\left.mm ^{3}\right]\) 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- \(\alpha\) 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 criteria \({ }^{\text {b }}\)
    Lower respiratory tract fungal disease \({ }^{\text {c }}\)
        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 candidiasis \({ }^{ d }\)
    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) \({ }^{\text {e }}\)
        Aspergillosis
            Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF
        Invasive fungal disease other than cryptococcosis and zygomycoses
            \(\beta\)-D-glucan detected in serum

REFERENCES

1. Groll AH, Kurz M, Schneider W, et al: Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses 42:431-42, 1999
2. McNeil MM, Nash SL, Hajjeh RA, et al: Trends in mortality due to invasive mycotic diseases in the United States, 1980-1997. Clin Infect Dis 33:641-7, 2001
3. Edmond MB, Wallace SE, McClish DK, et al: Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis 29:239-44, 1999
4. Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546-54, 2003
5. Watson RS, Carcillo JA, Linde-Zwirble WT, et al: The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 167:695-701, 2003
6. Zaoutis TE, Argon J, Chu J, et al: The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 41:1232-9, 2005
7. Lin S-J, Schranz J, Teutsch. SM: Aspergillosis case-fatality rate: systemic review of the literature. Clinical Infectious Diseases 32:358-66, 2000
8. Walmsley S, Devi S, King S, et al: Invasive Aspergillus infections in a pediatric hospital: a tenyear review. Pediatr Infect Dis J 12:673-82, 1993
9. Abbasi S, Shenep JL, Hughes WT, et al: Aspergillosis in children with cancer: A 34-year experience. Clin Infect Dis 29:1210-9, 1999
10. 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
11. Burgos A, Zaoutis TE, Dvorak CC, et al: Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics 121:e1286-94, 2008
12. Sung L, Lange BJ, Gerbing RB, et al: Microbiologically documented infections and infectionrelated mortality in children with acute myeloid leukemia. Blood 110:3532-9, 2007
13. Robenshtok E, Gafter-Gvili A, Goldberg E, et al: Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 25(34):5471-5489, 2007
14. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. Cytotherapy 3(1):41-54, 2001
15. Maertens J: Evaluating prophylaxis of invasive fungal infections in patients with haematologic malignancies. Eur J Haematol 78(4):275-282, 2007
16. Goodman JL, Winston DJ, Greenfield RA, et al: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 326:845-51, 1992
17. Kanda Y, Yamamoto R, Chizuka A, et al: Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials. Cancer 89:1611-25, 2000
18. Wingard JR: Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation. Clin Infect Dis 39 Suppl 4:S176-180, 2004
19. 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
20. Wingard J: Results of a randomized, double-blind trial of fluconazole (FLU) vs. voriconazole (VORI) for the prevention of invasive fungal infections (IFI) in 600 allogeneic blood and marrow transplant (BMT) patients. Blood 110(Abstract 163):55a-56a, 2007
21. Mattiuzzi G: Intravenous voriconazole (IV-VORI) prevents invasive fungal infections (IF) in patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome. Paper presented at: 46th American Society of Hematology Annual Meeting; San Diego, CA., 2004
22. Walsh TJ, Pappas P, Winston DJ, et al: Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 346(4):225-234, 2002
23. Walsh TJ, Lutsar I, Driscoll T, et al: Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J 21:240-8, 2002
24. Johnson LB, Kauffman CA: Voriconazole: a new triazole antifungal agent. Clin Infect Dis 36:630-7, 2003
25. Cornely OA, Maertens J, Winston DJ, et al: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 356:348-59, 2007
26. van Burik JA, Ratanatharathorn V, Stepan DE, et al: Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 39:1407-16, 2004
27. Seibel NL, Schwartz C, Arrieta A, et al: Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother 49:3317-24, 2005
28. Denning DW, Marr KA, Lau WM, et al: Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 53:337-49, 2006
29. Stingl H, Chandramouli V, Schumann WC, et al: Changes in hepatic glycogen cycling during a glucose load in healthy humans. Diabetologia 49:360-8, 2006
30. Zaoutis TJH, Huang L, et al: Prospective Mulitcenter Study of Caspofungin for the treatment of documented fungal infections in pediatric patients. Infectious Diseases Society of America 45th Annual Meeting; San Diego, CA., 2008
31. Walsh TJ, Teppler H, Donowitz GR, et al: Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 351:1391-402, 2004
32. Zaoutis TLT, Groll A, et al e: Safety Experience with Caspofungin in Pediatric Patients. Pediatric Academic Societies Annual Meeting; Honolulu, HI. 2008
33. Assessment Report for Mycamine. European Medicines Agency EMEA/CHMP/121708/2008, 2008
34. Pfeiffer CD, Fine JP, Safdar N: Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 42:1417-27, 2006
35. Steinbach WJ, Addison RM, McLaughlin L, et al: Prospective Aspergillus galactomannan antigen testing in pediatric hematopoietic stem cell transplant recipients. Pediatr Infect Dis J 26:558-64, 2007
36. Ostrosky-Zeichner L, Alexander BD, Kett DH, 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
37. Rex JH: Galactomannan and the diagnosis of invasive aspergillosis. Clin Infect Dis 42:1428-30, 2006
38. Kwiatkowski D: Science, medicine, and the future: susceptibility to infection. BMJ 321:1061-5, 2000
39. Haralambous E, Weiss HA, Radalowicz A, et al: Sibling familial risk ratio of meningococcal disease in UK Caucasians. Epidemiol Infect 130:413-8, 2003
40. Sorensen TI, Nielsen GG, Andersen PK, et al: Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 318:727-32, 1988
41. Foster CB, Chanock SJ: Mining variations in genes of innate and phagocytic immunity: current status and future prospects. Curr Opin Hematol 7:9-15, 2000
42. Choi EH, Foster CB, Taylor JG, et al: Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes. J Infect Dis 187:1153-6, 2003
43. van der Poll T: Immunotherapy of sepsis. Lancet Infect Dis 1:165-74, 2001
44. Jurevic RJ, Bai M, Chadwick RB, et al: Single-nucleotide polymorphisms (SNPs) in human betadefensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls. J Clin Microbiol 41:90-6, 2003
45. Schwartz GJ, Gauthier B: A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr 106:522-6, 1985
46. Child CG, Turcotte JG: Surgery and portal hypertension. In: The liver and portal hypertension. Edited by CG Child. Philadelphia: Saunders:50-64, 1964
47. Pugh RN, Murray-Lyon IM, Dawson JL, et al: Transection of the oesophagus for bleeding oesophageal varices. The British journal of surgery 60 (8):646-9, 1973
48. 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 Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813-21, 2008
49. Schulgen G, Olschewski M, Krane V, et al: Sample sizes for clinical trials with time-to-event endpoints and competing risks. Contemp Clin Trials 26:386-96, 2005
50. Latouche A, Porcher R, Chevret S: Sample size formula for proportional hazards modelling of competing risks. Stat Med 23:3263-74, 2004
51. Gray RA: Class of K-sample tests for comparing the cumulative incidence of a competing risk. The annals of Stat 16:1141-54, 1988
52. Stephens M, Smith NJ, Donnelly P: A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978-89, 2001
53. Stephens M, Donnelly P: A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162-9, 2003
54. Benjamini Y, Drai D, Elmer G, et al: Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279-84, 2001
55. DeMets DL, Lan KK: Interim analysis: the alpha spending function approach. Stat Med 13:134152; discussion 1353-6, 1994
56. Segal BH, Almyroudis NG, Battiwalla M, et al: Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis 44:402-9, 2007
57. Kaya Z, Gursel T, Kocak U, et al: Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer 52:470-5, 2009
58. Kusuki S, Hashii Y, Yoshida H, et al: Antifungal prophylaxis with micafungin in patients treated for childhood cancer. Pediatr Blood Cancer 53:605-9, 2009
59. 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
60. 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
61. Maertens J, Verhaegen J, Lagrou K, et al: Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 97:1604-10, 2001
62. Leeflang MM, Debets-Ossenkopp YJ, Visser CE, et al: Galactomannan detection for invasive aspergillosis in immunocompromized patients. Cochrane Database Syst Rev:CD007394, 2008
63. 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 myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 39:199-205, 2004
64. Ellis M, Al-Ramadi B, Finkelman M, et al: Assessment of the clinical utility of serial beta-Dglucan concentrations in patients with persistent neutropenic fever. J Med Microbiol 57:287-95, 2008
65. Hovi L, Saxen H, Saarinen-Pihkala UM, et al: Prevention and monitoring of invasive fungal infections in pediatric patients with cancer and hematologic disorders. Pediatr Blood Cancer 48:28-34, 2007
66. Sulahian A, Boutboul F, Ribaud P, et al: Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of invasive aspergillosis in two adult and pediatric hematology units during a 4-year prospective study. Cancer 91:311-8, 2001
67. Rohrlich P, Sarfati J, Mariani P, et al: Prospective sandwich enzyme-linked immunosorbent assay for serum galactomannan: early predictive value and clinical use in invasive aspergillosis. Pediatr Infect Dis J 15:232-7, 1996
68. Smith PB, Benjamin DK, Jr., Alexander BD, et al: Quantification of 1,3-beta-D-glucan levels in children: preliminary data for diagnostic use of the beta-glucan assay in a pediatric setting. Clin Vaccine Immunol 14:924-5, 2007
69. Maertens J, Theunissen K, Verhoef G, et al: Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 41(9):1242-50, 2005
70. Herbrecht R, Letscher-Bru V, Oprea C, et al: Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 20:1898-906, 2002
71. Marty FM, Lowry CM, Lempitski SJ, et al: Reactivity of ( )-beta-d-glucan assay with commonly used intravenous antimicrobials. Antimicrob Agents Chemother 50:3450-3, 2006
72. Cook NR: Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin Chem 54:17-23, 2008

SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM

ACCL0933

Why am I being invited to take part in this study?

What is the current standard of treatment for this disease?

Why is this study being done?

• Compare the effects, good and/or bad, of 2 antifungal drugs: caspofungin and fluconazole on people getting treatment for AML, who are at risk of getting invasive fungal infections, to find out which is better. In this study, you will get either caspofungin or fluconazole. You will not get both.

What will happen on this study that is research?

• Fluconazole Arm - Current standard treatment; patients will get therapy with fluconazole.
• Caspofungin Arm - Experimental treatment; patients will get therapy with caspofungin.

Random Assignment

Diagram of Treatment

This chart shows the treatments on the study.

Treatment Plan Tables

• 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.

Research Study Procedures

Optional Research Study Tests

Platelia EIA Aspergillus Galactomannan (GM) Assay and Serum Beta-D-Glucan Testing Biomarker Studies

Single Nucleotide Polymorphisms (SNP) Analysis - Genetic Study

Future Studies:

What side effects or risks can I expect from being in the study?

Treatment Risks

Risks of Study

Are there benefits to taking part in the study?

What other options are there?

• Current standard therapy even if you do not take part in the study. Standard therapy is described on page 1. It is the Fluconazole Arm of this study.
• Receiving no prevention against fungal infections.
• Taking part in another study

How many people will take part in the study?

How long is the 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?

• The Children's Oncology Group
• The Representatives of the National Cancer Institute (NCI), Food and Drug Administration (FDA), and other U.S. and international governmental regulatory agencies involved in overseeing research
• The Institutional Review Board of this hospital
• The Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute
• The drug company that makes caspofungin or their designated reviewers.

What are the costs?