Clinical trial NCT02349178
Conditions: Leukemia, Acute Lymphoblastic Acute Myeloid Leukemia
Sponsor: Medical College of Wisconsin
Start date: 2014-12-08; Completion date: 2017-03-16
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2 study designed for the purpose of estimating various parameters surrounding the efficacy of Clofarabine, Cyclophosphamide and Etoposide in eliminating minimal residual disease (MRD) in acute leukemia patients otherwise in remission and without causing significant delay of HCT due to treatment related toxicity.

A single course of "bridge" chemotherapy is given prior to the transplant procedure as an approach to improved disease-free survival in a patient group who historically has had inferior outcomes.

Detailed description:
Study entry is open to patients regardless of gender or ethnic background.

The intent of this study design is for all patients to receive and complete one course of therapy. Patients who exhibit signs of disease progression or experience an unacceptable toxicity will be discontinued from treatment.

There will be no dose delays or dose reductions of study drugs for hematologic toxicity during Consolidation "Bridging" therapy (Day 1 through Day 30); however, prolonged hematopoietic recovery or bone marrow aplasia during the first 42 days may meet a study stopping rule.

Arms: arm 1: Days 1-5 Receive 20 mg/m2 IV Clofarabine (CLOLAR) over 2 hours followed by 100 mg/m2 IV Etoposide (VP-16, Etopophos) over 2 hours followed by 300 mg/m2 IV Cyclophosphamide (Cytoxan, CTX) as a 30-60 minute infusion
Interventions: intervention 1: Clofarabine intervention 2: Cyclophosphamide intervention 3: Etoposide
Intervention descriptions: intervention 1: Days 1-5 receive Clofarabine 20 mg/m2 IV over 2 hours intervention 2: Days 1-5 receive Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion intervention 3: Days 1-5 receive Etoposide 100 mg/m2 IV over 2 hours

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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Bridging Study 
Version No. 5.0 
 
 
 
 
 
 
Version Date:  02/08/2016  
 
Bridging Study 
 
 
A Phase 2 Study Investigating Clofarabine, Cyclophosphamide and Etoposide for 
Children, Adolescents, and Young Adults (AYA) with Acute Leukemia and Minimal 
Residual Disease  
 
 
Study Chair: 
 
Michael J. Burke, MD  
 
 
Medical College of Wisconsin  
 
 
Department of Pediatrics 
 
 
Division of Hematology/Oncology/BMT 
 
Study Vice Chairs: 
Julie-An M. Talano, MD 
 
Medical College of Wisconsin 
 
Department of Pediatrics 
 
Division of Hematology/Oncology/BMT 
 
 
Ehab L. Atallah, MD 
 
Medical College of Wisconsin 
 
Department of Medicine 
 
Division of Hematology/Oncology/BMT 
 
Study Committee: 
Karen Sue Carlson, MD, PhD 
 
Timothy Fenske, MD 
 
Mehdi Hamadani, MD 
 
Laura Michaelis, MD 
 
Hari Parameswaran, MD 
 
Marcelo Pasquini, MD 
 
 
  
Gabriella Gheorghe, MD 
 
Paul Harker-Murray, MD, PhD  
 
Michael Kelly, MD, PhD 
 
Dave Margolis, MD  
 
Monica Thakar, MD 
 
Richard Tower, MD 
 
Statistician: 
Raymond Hoffmann, PhD  
 
Additional Performance Sites: 
Children’s Hospital of Wisconsin  
University of Wisconsin Hospital and Clinics  
Nationwide Children’s Hospital 
 
 
 
 
 
 
 


 
 
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Bridging Study 
TABLE OF CONTENTS 
 
Section 
 
 
 
 
 
 
 
 
 
Page 
Study Committee 
 
 
 
 
 
 
 
 
  4 
List of Abbreviations 
 
 
 
 
 
 
 
  6 
Synopsis 
 
 
 
 
 
 
 
 
 
  8 
Protocol Revision History  
 
 
 
 
 
 
11 
1. 
Background  
 
 
 
 
 
 
 
13 
 
1.1 
High Risk ALL and AML in Children and Adults 
 
   
13 
1.2 
Overview of Cyclophosphamide and Etoposide 
 
 
14 
1.3 
Overview of Clofarabine 
 
 
 
 
 
14 
2. 
Study Design  
 
 
 
 
 
 
 
19 
3. 
Selection of Patients  
 
 
 
 
 
 
19 
 
3.1 
Inclusion Criteria 
 
 
 
 
 
 
19 
 
3.2 
Exclusion Criteria 
 
 
 
 
 
 
21 
4. 
Registration Procedures 
 
 
 
 
 
 
22 
 
4.1 
Registration 
 
 
 
 
 
 
 
22 
4.2 
Patients Who Do Not Begin Study Treatment 
 
 
22 
5. 
Treatment Plan 
 
 
 
 
 
 
 
22 
5.1 
Treatment Plan Regardless of Diagnosis 
 
 
 
22 
5.2 
Supportive Care Guidelines  
 
 
 
 
23 
5.3 
Duration of Therapy  
 
 
 
 
 
23 
5.4 
Follow-Up 
 
 
 
 
 
 
 
23 
6.  
Dose Modification 
 
 
 
 
 
 
 
24 
6.1 
Clofarabine   
 
 
 
 
 
 
24 
6.2 
Cyclophosphamide   
 
 
 
 
 
25 
6.3 
Etoposide (VP-16)  
 
 
 
 
 
 
25 
7.  
Study Calendar 
 
 
 
 
 
 
 
26 
7.1 
Standard of Care 
 
 
 
 
 
 
26 
8. 
Drug Formulation and Procurement 
 
 
 
 
27 
8.1 
Clofarabine 
 
 
 
 
 
 
 
27 
8.2 
Cyclophosphamide 
 
 
 
 
 
 
29 
8.3 
Etoposide 
 
 
 
 
 
 
 
30 
9. 
Adverse Event Monitoring, Documentation, and Reporting 
 
31 
 
9.1 
Definitions 
 
 
 
 
 
 
 
31 
9.2 
Adverse Event Documentation 
 
 
 
 
31 
9.3 
Adverse Event Reporting Requirements 
 
 
 
33 
9.4 
Event Notification, Deviations, and Patient Complaints 
 
34 
10. 
Study Data Collection and Monitoring 
 
 
 
 
34 
10.1 
Data Management 
 
 
 
 
 
 
34 
10.2 
Case Report Forms 
 
 
 
 
 
 
35 
10.3 
Data and Safety Monitoring Plan (DSMP) 
 
 
 
35 
10.4     Monitoring 
36 
 
10.5 
Record Retention 
 
 
 
 
 
 
36 
11. 
Statistical Considerations 
 
 
 
 
 
 
37 
11.1  Statistic Endpoints 
 
 
 
 
 
 
37 
11.2    Statistical Analysis 
 
 
 
 
 
 
37 
11.3 
Sample Size Justification 
 
 
 
 
 
37 
11.4 
Early Stopping Rule for Excessive Toxicity (pre-HCT) and   
38 


 
 
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Bridging Study 
 
TRM (post-HCT) 
Section 
 
 
 
 
 
 
 
 
 
Page 
12.  
Conduct of Study 
 
 
 
 
 
 
 
39 
12.1 
Good Clinical Practice 
 
 
 
 
 
39 
12.2 
Ethical Considerations 
 
 
 
 
 
39 
12.3 
Informed Consent 
 
 
 
 
 
 
39 
 
12.4 
Clinical Trial Registration 
 
 
 
 
 
39 
References 
 
 
 
 
 
 
 
 
 
40 
Appendix 1 – Eligibility Checklist  
 
 
 
 
 
45 
Appendix 2 – Performance Status Criteria 
 
 
 
 
47 
Appendix 3 – Response Criteria 
 
 
 
 
 
 
48 
Appendix 4 – Known and Expected Toxicities of Study Treatment 
 
49 
Appendix 5 – Bridging Therapy Roadmap                                                            52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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STUDY COMMITTEE MEMBERS 
 
Study Chairs 
CHAIR 
Michael J. Burke, MD 
Associate Professor of Pediatrics 
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: 414-955-4198 
Fax:  414-955-6543 
Email:  mmburke@mcw.edu 
Emergency Contact 
Children’s Hospital Switchboard:   
414-266-2000 ask for Pediatric Oncologist On-Call 
VICE CHAIR 
Julie-An M. Talano, MD 
Associate Professor of Pediatrics 
Pediatric Hematology/Oncology/BMT 
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: 414-955-4185 
Email:  jtalano@mcw.edu 
VICE CHAIR 
Ehab L. Atallah, MD 
Assistant Professor of Medicine 
Division of Hematology and Oncology 
Medical College of Wisconsin 
Froedtert Memorial Lutheran Hospital 
Clinical Cancer Center 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: 414-805-4600 
Email:  eatallah@mcw.edu  
 
Study Committee Members 
Karen Sue Carlson, MD, PhD 
Department of Medicine – Oncology/Hematology 
Medical College of Wisconsin 
Blood Research Institute 
Phone: 414-805-4600 
Email:  kabarker@mcw.edu 
Timothy Fenske, MD 
Department of Medicine – 
Oncology/Hematology/BMT 
Medical College of Wisconsin 
Froedtert East Clinic 
Phone: 414-805-4633 
Email:  tfenske@mcw.edu 
Gabriella Gheorghe, MD 
Pediatric Medicine – Pathology 
Medical College of Wisconsin 
Phone: 414-266-2530 
Email:  ggheorghe@mcw.edu 
Mehdi Hamadani, MD 
Department of Medicine – 
Oncology/Hematology/BMT 
Medical College of Wisconsin 
Clinical Cancer Center 
Phone: 414-805-4600 
Email:  mhamadani@mcw.edu 
Parameswaran Hari, MD 
Department of Medicine – Oncology/Hematology 
Medical College of Wisconsin 
Clinical Cancer Center 
Phone: 414-805-4602 
Email:  phari@mcw.edu 
Paul Harker-Murray, MD, PhD  
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4170 
Email:  pharker@mcw.edu 


 
 
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Study Committee Members 
Michael Kelly, MD, PhD 
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4170 
Email:  mekelly@mcw.edu 
David Margolis, MD  
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4170 
Email:  dmargolis@mcw.edu 
Laura Michaelis, MD 
Department of Medicine – 
Oncology/Hematology/BMT 
Medical College of Wisconsin 
Phone: 414-805-4600 
Email:  lmichaelis@mcw.edu 
Marcelo Pasquini, MD 
Department of Medicine – 
Oncology/Hematology/BMT 
Medical College of Wisconsin 
CIBMTR 
Phone: 414-805-0700 
Email:  mpasquini@mcw.edu 
Monica Thakar, MD  
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4170 
Email:  mthakar@mcw.edu 
Richard Tower, MD 
Pediatric Hematology/Oncology/BMT  
Medical College of Wisconsin 
Children’s Hospital of Wisconsin 
Phone: 414-955-4170 
Email:  rtower@mcw.edu 
 
Performance Site – Sub-Investigators 
Neha J. Patel, MD 
Department of Pediatrics 
University of Wisconsin Madison 
1111 Highland Ave. 
WIMR 4th floor North, Office # 4133 
Madison, WI 53705 
Phone: 608-263-8554 
Fax: 608-265-9721 
Email:  npatel@pediatrics.wisc.edu 
Ryan Mattison, MD 
University of Wisconsin Madison 
1111 Highland Ave. 
4039 Wisconsin Institute for Medical Research 
Madison, WI 53705 
Phone: 608-262-5697 
Fax: 608-262-4598 
Email:  rjmattison@medicine.wisc.edu 
Susan Vear, MD 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, OH 43205 
Phone: 614-722-3583 
Fax: 614-722-3369 
Email:  Susan.Vear@nationwidechildrens.org 
 
 
Midwest Area Research Consortium for Health (MARCH) Central Administration 
Debra Kruser 
MARCH Director 
2112d Health Sciences Learning Center 
750 Highland Ave. 
Madison, WI 53705 
Phone:  608-262-7217 or 608-260-7633 
Email: djkruser@wisc.edu  
MJ Washburn 
Regional Research Networks Coordinator 
2112 HSLC 
750 Highland Ave. 
Madison, WI 53705 
Phone:  608-262-7365 or 608-333-1962 
Email:  mwashburn@wisc.edu  
 


 
 
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Bridging Study 
LIST OF ABBREVIATIONS 
 
AE 
 
 
adverse event 
ALL 
 
 
acute lymphoblastic leukemia 
ALT 
 
 
Alanine Aminotransferase 
AML  
 
acute myeloid leukemia 
ANC  
 
absolute neutrophil count 
APL 
 
 
acute promyelocytic leukemia 
AST 
 
 
aspartate aminotransferase 
AUC  
 
area under the concentration time curve 
 
 
BMT  
 
bone marrow transplant 
BP 
 
 
blood pressure 
BUN  
 
blood urea nitrogen 
CART Therapy 
chimeric antigen receptor T-cell therapy 
CHW  
 
Children’s Hospital of Wisconsin 
CI 
 
 
confidence interval 
CLL 
 
 
chronic lymphocytic leukemia 
CNS  
 
central nervous system 
 
CR 
 
 
complete remission 
CrCl 
 
 
creatinine clearance  
CRF 
 
 
case report forms 
CRp 
 
 
complete remission without platelet recovery 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program 
CTMS  
 
Clinical Trials Management System  
CTO  
 
Clinical Trials Office 
DEHP  
 
Bis(2-ethylhexyl) phthalate 
DFS 
 
 
disease free survival 
DLT 
 
 
dose limiting toxicity 
DSMC  
 
data safety monitoring committee 
DSMP  
 
data safety monitoring plan 
ECHO  
 
echocardiogram 
EFS 
 
 
event free survival 
EP 
 
 
European Pharmacopeia 
 
FISH  
 
fluorescence in situ hybridisation 
GFR  
 
glomerular filtration rate 
GVHD  
 
graft versus host disease 
GVL  
 
graft versus leukemia 
HCT  
 
hematopoietic cell transplantation 
HgB 
 
 
hemoglobin 
HPLC  
 
high performance liquid chromatography 
HSCT  
 
hematopoietic stem cell transplantation 
HSV  
 
herpes simplex virus 
IRB 
 
 
Institutional Review Board 
LDH  
 
lactate dehydrogenase 
MACC Fund Center Midwest Athletes Against Childhood Cancer Fund Center 
MCW  
 
Medical College of Wisconsin 
MFC  
 
multiparameter flow cytometry 
MRD  
 
minimal residual disease 


 
 
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Bridging Study 
LIST OF ABBREVIATIONS (CONTINUED) 
 
MTD  
 
maximum tolerated dose 
MUGA 
 
multi gated acquisition scan 
NOS  
 
not otherwise specified 
NRM  
 
non relapse mortality 
NS 
 
 
normal saline 
ORR  
 
overall response rate  
OS 
 
 
overall survival 
PCP 
 
 
pneumocystis carinii pneumonia 
PCR 
 
 
polymerase chain reaction 
PI 
 
 
principal investigator 
PR 
 
 
partial responsego 
PVC  
 
polyvinyl chloride 
RFS 
 
 
relapse free survival 
RIC 
reduced intensity conditioning 
SAE 
 
 
serious adverse event 
SIRS  
 
systemic inflammatory response 
SRC 
 
 
Scientific Review Committee 
UCBT  
 
umbilical cord blood transplantation 
ULN  
 
upper limit of normal 
UPIRSO 
 
unanticipated problems involving risks to subjects or others 
USP 
 
 
United States Pharmacopeia 
WBC  
 
white blood count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Bridging Study 
SYNOPSIS 
 
Study Title: A Phase 2 Study Investigating Clofarabine, Cyclophosphamide and Etoposide for 
Children, Adolescents and Young Adults (AYA) with Acute Leukemia and Minimal Residual 
Disease 
 
Phase 2 
 
Number of Patients: 50 evaluable [25 adult (19 to 39 years) and 25 pediatric (0-18 years)] 
 
Study Objectives 
 
 Primary Objectives 
o The effect of Clofarabine, Cyclophosphamide, and Etoposide in eliminating the 
presence of persistent disease without causing a significant delay of HCT due to 
treatment related toxicity, defined as greater than 56 days from completion of 
bridging therapy to start of HCT. 
o The proportion of any toxicities associated with Clofarabine, Cyclophosphamide, 
and Etoposide 
 
 Secondary Objectives 
o The proportion of pre-transplant chemotherapy-induced aplasia (defined as 
greater than 42 days after infusion of chemotherapy) 
o The proportion of infectious complications following bridging therapy and before 
HCT 
o Treatment related mortality at Day 100 after HCT 
o One year disease-free survival after HCT 
o The proportion of relapse within one year of HCT 
 
Treatment Plan: Only 1 treatment course will be permitted 
 
Day 
Agent/Procedure 
Baseline 
Peripheral blood draw and bone marrow aspirate (within 14 days of enrollment) 
Day 1 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 2 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 3 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 4 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 5 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 


 
 
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Bridging Study 
Day 
Agent/Procedure 
Day 30* 
Perform bone marrow biopsy/aspirate (*Or upon adequate blood count recover 
(ANC > 0.5 AND plt > 50,000) whichever comes first 
Between Day 28 & 42 
Proceed to HCT independent of this study 
 
Study Population: 
 Diagnosis of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) 
with  < 5% blasts in the bone marrow (M1) by morphology and that meets one of the 
following criteria: 
 
o Flow cytometric evidence of MRD (≥ 0.01% leukemic blasts for ALL or ≥ 0.5% 
leukemic blasts for AML detected in the bone marrow) 
OR 
o Molecular/cytogenetic evidence of disease (FISH or PCR methodology) 
performed within 14 days And with the intent of going on to an allogeneic 
hematopoietic cell transplantation (HCT) independent of this study 
 Patients must have an available donor and have intention of proceeding directly to ALL-
HCT after completion of 1 cycle of Bridging therapy. 
 Age 0 to 39 years 
 Karnofsky Performance Status ≥ 50% for patients 16 years and older and Lansky Play 
Score ≥ 50 for patients under 16 years of age (see Appendix 2) 
 Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling 
investigator 
 Have acceptable organ function as defined within 7 days of study registration 
o Renal:  creatinine  clearance  ≥ 60 mL/min/1.73 m2 or 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 year to < 2 years 
0.6 
0.6 
2 years to < 6 years 
0.8 
0.8 
6 years to < 10 years 
1.0 
1.0 
10 years to < 13 years 
1.2 
1.2 
13 years to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
o Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x upper 
limit of normal (ULN) for age 
o Cardiac:  left ventricular ejection fraction ≥ 40% by ECHO/MUGA 
 Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, 
immunotherapy, or radiotherapy prior to entering this study. At least 7 days must have 
elapsed from prior chemotherapy. 
 Hematopoietic Growth Factors: At least 7 days since the completion of therapy with 
a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration. 


 
 
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Bridging Study 
 Sexually active females of child bearing potential must agree to use adequate 
contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], 
surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of 
treatment and for 2 months after the last dose of chemotherapy.  Sexually active men 
must agree to use barrier contraceptive for the duration of treatment and for 2 months 
after the last dose of chemotherapy. 
 Voluntary written consent before performance of any study-related procedure not part of 
normal medical care, with the understanding that consent may be withdrawn by the 
subject at any time without prejudice to future medical care. 
 
Exclusion Criteria: 
 Acute Promyelocytic Leukemia (APL) 
 Active extramedullary disease (CNS ≥ CNS2 and/or testicular leukemia) or presence of 
chloromatous disease 
 Receiving concomitant chemotherapy, radiation therapy; immunotherapy or other anti-
cancer therapy other than is specified in the protocol 
 Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting 
ongoing signs/symptoms related to the infection and without improvement, despite 
appropriate antibiotics or other treatment) 
 Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus 
and there is no information on the excretion of agents into breast milk. All females of 
childbearing potential must have a blood test or urine study within 2 weeks prior to 
registration to rule out pregnancy. 
 Known allergy to any of the agents or their ingredients used in this study 
 Participating in a concomitant Phase 1 or 2 study 
 
Duration of Study: 2 years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Bridging Study 
PROTOCOL REVISION HISTORY 
 
Version 
No. 
Revision 
Date 
Summary of Changes 
Consent Revised 
Yes/No 
2.0 
02/20/15 
Added Section 12.4 NCI trial designation number Yes – Trial number 
has been added to the 
Consent as well 
3.0 
03/20/2015 Added Consents for Nationwide Children’s and 
UW Madison following official deferral to MCW 
IRB 
 
 
 
Synopsis Primary Objectives updated to provide 
clarification on what constitutes a delay of HCT 
by adding :”defined as greater than 56 days from 
completion of bridging therapy to start of HCT.” 
 
 
Section 2 Primary Objectives updated to provide 
clarification on what constitutes a delay of HCT 
by adding :”defined as greater than 56 days from 
completion of bridging therapy to start of HCT.” 
 
Section 3.1.1 updated to clarify and correct an 
inconsistency regarding inclusion criteria: flow 
evidence of MRD or Molecular/cytogenetic FISH 
or PCR evidence of disease to be performed 
within 14 days of enrollment 
 
 
Section 11.1 Statistical Endpoints updated to add 
the definition of delay in HCT: “defined as 
greater than 56 days from completion of bridging 
therapy to start of HCT” 
 
Section 11.2 Statistical Analysis correction made 
to SAS 9.3 changing this to SAS 9.4 
 
Section 11.3 Sample Size Justification was 
revised. Previous paragraph replaced with new 
one to strengthen the justification.  
 
Section 11.4 Early Stopping Rule for Excessive 
Toxicity section – previous paragraph replaced 
with new paragraph to clarify and strengthen 
rationale.  
Yes 
– 
Added 
consents specific to 
Nationwide 
Children’s and UW 
Madison 
 
No 
 
 
 
 
 
No 
 
 
 
 
No 
 
 
 
 
 
 
No 
 
 
 
 
No 
 
 
No 
 
 
 
No 
4.0 
09/04/2015 Page 9 Synopsis and Page 19 Section 3.1.1-
Eligibility Criteria changed bone marrow to be 
No 
 


 
 
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Bridging Study 
performed 
within 
14 
days 
of 
enrollment 
(increased from within 7 days). This change did 
not appear in the protocol after the previous 
amendment and is being corrected with this 
amendment. This change now makes these 2 
sections consistent with the table on page 26.  
 
Added Appendix 5 – Bridging therapy roadmap 
 
Protocol Version number and date changed in the 
headers and footers to reflect the current version.  
 
 
 
Table of contents updated.  
 
 
 
 
 
 
 
No 
 
Yes 
– 
updated 
footers and version 
number – no content 
changes 
 
No 
5.0 
02/08/2016 Headers and Footers updated with new version 
number and date 
 
Page 5 Performance Site Sub Investigators: 
Replaced Robyn Dennis, MD with Susan Vear, 
MD at Nationwide Children’s Hospital 
Yes- updated footers 
with new protocol 
version number and 
date.  
All Assents section 
E2 replaced Robyn 
Dennis, 
MD 
with 
Susan Vear, MD as 
contact 
for 
Nationwide 
Children’s Hospital 
All Consents Section 
D5 replaced Robyn 
Dennis, 
MD 
with 
Susan Vear, MD as 
contact 
for 
Nationwide 
Children’s Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Bridging Study 
 
 
 
1. 
BACKGROUND 
 
1.1 
High Risk ALL and AML in Children and Adults 
 
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) remain two of 
the most common forms of leukemia diagnosed in both children and adults, as well as 
two of the most common hematological diseases for which allogeneic hematopoietic cell 
transplantation (HCT) is currently used.12 There is mounting evidence to support that 
for patients in hematological remission, the presence of minute amounts of leukemia 
(known as minimal residual disease (MRD)), identified immediately prior to HCT is 
associated with higher rates of ALL and AML relapse following HCT.1-11 Therefore we 
hypothesize that transplant outcomes can be improved by reducing pre-HCT disease 
burden by attaining a pre-HCT MRD negative state. We designed this protocol to test the 
combination of clofarabine, cyclophosphamide and etoposide, which are known active 
agents in the treatment of lymphoid and myeloid hematologic malignancies, in their 
ability to both lower MRD and improve post-HCT outcomes for patients with 
ALL/AML who are in morphological remission but have evidence of MRD pre-HCT. 
 
 
Impact of MRD Positive Disease Prior to HCT: Patients with acute leukemia and sub-
morphologic disease at the time of conditioning are at high risk of relapse following 
HCT. Recent studies have demonstrated that even low levels of MRD (> 0.01% 
abnormal blasts by multi-parameter flow cytometry, MFC) after aggressive re-induction 
therapy portends  a  relatively  poor  outcome  in  relapsed  ALL  patients,  including  
those  who proceed to HCT.7 Foster et al. recently reported 116 pediatric patients who 
were in morphologic remission and underwent MRD evaluation with multi-parameter 
flow cytometry (MFC) prior to ablative transplant for ALL. For the group as a whole, 
the EFS for MRD positive and negative patients was 11% and 58% respectively, (p 
< 0.001).3 
 
Likewise, the BFM Study Group has also evaluated the impact of MRD prior to HCT for 
relapsed ALL using a PCR-based assay. Their multivariate Cox regression analysis 
revealed MRD as the only independent parameter predictive for EFS (p < 0.006).7 
 
MRD identified prior to HCT for AML portends a poor prognosis in both pediatric and 
adult patients.13-16 In a report by Walter et al. 99 pediatric and adult patients with AML 
receiving a HCT in CR1 were evaluated for pre-HCT MRD using MFC with any 
detectable MRD defined as MRD-positive.13 The 2-year EFS for MRD-positive patients 
was 9% with a relapse rate of 64.9% compared to 74.8% and 17.6% in MRD-negative 
patients respectively. The multivariate analysis identified pre-HCT MRD as a significant 
risk factor for both overall mortality (HR 4.05 95% CI 1.90-8.62, p < 0.001) and relapse 
(HR 8.49 95% CI 3.67-19.65, p < 0.001). In another analysis reporting a larger group of 
pediatric and adult patients with AML (n=253) receiving HCT in CR1 or CR2, OS 
(HR 2.61, 95% CI 1.62-4.20, p < 0.001), DFS (HR 3.74, 95% CI 2.38-5.87, p < 0.001), 
and relapse (HR 4.90, 95% CI 2.87-8.37, p < 0.001) were all significantly worse for 
patients identified as MRD-positive MFC (≥ 0.1% blasts), compared to MRD-negative 
patients in multivariate cox regression model.14 


 
 
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Bridging Study 
 
Numerous monitoring techniques such as MFC, monitoring of known cytogenetic 
abnormalities, and molecular abnormalities such as NPM-1 and WT-1 have identified 
MRD in this patient population.14,17,18 One of the larger recent studies investigating the 
impact of MRD on post-transplant outcomes for AML patients evaluated 88 patients 
with morphologic CR, 24 of which had MRD by MFC, who went on to receive a 
myeloablative transplant. Survival and relapse were strongly associated with absence or 
presence of MRD. Specifically, two year overall survival was 30.2% (range 13-49%) for 
the MRD-positive patients compared with 76.6% (64.4-85.1%) for those who were 
MRD-negative. Two year estimates of relapse also correlated with MRD status with 
rates of  65%  in  those  who  were  MRD-positive  compared  with  17.6%  in  those  
MRD-negative.13 These data highlight the significance of MRD on post-transplant 
relapse and the need for improved therapy. 
 
Investigators at the University of Minnesota analyzed 97 adult AML patients; 14 had 
detectable MRD prior to allogeneic donor HCT.  Overall  survival  and  disease  free 
survival were markedly worse in MRD-positive patients receiving RIC compared to 
MRD-negative cohort.19 This research also investigated impact of pre-transplant MRD 
(assessed by MFC) in adults and children with ALL prior to umbilical cord blood 
transplantation.  Patients with MRD-positive prior to UCBT had a greater incidence of 
relapse at 2-years (30% (95% CI: 4-56%) and lower 3-year disease-free survival (DFS) 
(30%; 95% CI 7-58%) compared to MRD-patients (relapse 16% (95% CI: 8-25%: 
p=0.05 and DFS 55%; 95% CI: 43-66%; p=0.02).20 These data suggest that in the 
majority of patients with residual leukemia at the time of HCT, neither the preparative 
regimen,  nor  the  GVL  effect  of  the  allograft  is  sufficient  to  prevent  relapse.  
Thus, methods to eliminate persistent leukemia that have low toxicity profiles and can 
serve as a “bridge” to transplant are needed. 
 
1.2 
Overview of Cyclophosphamide and Etoposide 
 
 
The combination of the alkylating agent cyclophosphamide with the topoisomerase II 
inhibitor etoposide has been a common re-induction therapy for relapse/refractory acute 
leukemia. These two agents have been used in combination in a number of recent studies 
through the Children’s Oncology Group (COG) in both AALL01P2 for relapse B-
Precursor ALL as well as the Infant ALL study CCG 1953 with limited toxicities.21,22 In 
addition the combination has been evaluated in adult patients with relapsed/refractory 
AML. Of the 34 patients enrolled, 27 received etoposide 3 gm/m2 by continuous 
infusion over 48-72 hours, immediately followed by cyclophosphamide 50 mg/kg iv 
over 3 hours daily for 3 or 4 days (150-200 mg/kg total dose). The other seven patients 
received a lower etoposide dose, 1.8–2.4 gm/m2 over 48-72 hours followed by 
cyclophosphamide 50 mg/kg IV over 3 hours for 3 or 4 days. The complete remission 
rate and treatment related mortality was 32% and 18% respectively.  These results 
compare favorably to other salvage regimens used in the treatment of patients with 
relapsed refractory AML.23 Recently they have been shown to be synergistic with the 
relatively new purine nucleoside analogue clofarabine. 24, 25 
 
1.3 
Overview of Clofarabine 
 
Clofarabine (2-chloro-9-[2’-deoxy-2’-fluoro-β-D-arabinofuranosyl]adenine; Cl-F-ara-A; 


 
 
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CAFdA) is a rationally designed, second generation purine nucleoside analogue. 
Clofarabine was designed as a hybrid molecule to overcome the limitations and 
incorporate the best qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA) 
both of which are currently approved by various regulatory authorities for treatment of 
hematologic malignancies. Because clofarabine has a chloro-group at the 2-position of 
adenine,  its  chemical  structure  is  more  closely  related  to  2-CdA  than  to  F-ara-
A.26  Halogenation at the 2-position of adenine renders this class of compounds resistant 
to intracellular degradation by the enzyme adenosine deaminase. Substitution of a 
fluorine at the C-2’-position of the arabinofuranosyl moiety of clofarabine increases its 
stability in gastric acid27 and decreases its susceptibility to phosphorolytic cleavage by 
the bacterial enzyme Escherichia coli purine nucleoside phosphorylase in the 
gastrointestinal tract,28 both of which may lead to enhanced oral bioavailability. 
Clofarabine was approved in December 2004 by the United States Food and Drug 
Administration (US FDA) for the treatment of pediatric patients with relapsed or 
refractory acute lymphoblastic leukemia (ALL) after at least 2 prior regimens based on 
the induction of complete responses. 
 
Mechanism of Action: The precise mechanism of action of clofarabine on dividing and 
non-dividing cells is unknown. Like the other nucleoside analogues (cytarabine, ara-A 
[vidarabine],   cladribine,   fludarabine),   clofarabine   must   be   converted   to the 5’-
triphosphate form by deoxycytidine kinase (dCK) to be active within cells. Clofarabine 
is more efficient as a substrate for purified recombinant dCK, exceeding cladribine and 
the natural substrate, deoxycytidine.29 Evidence suggests that the primary cytotoxic 
effect of clofarabine is due to its inhibition of DNA synthesis.  The triphosphate form of 
clofarabine is an inhibitor of both DNA polymerase α and ribonucleotide reductase.30  
These effects lead to depletion of intracellular deoxynucleotide triphosphate pools, and 
inhibition of elongation of DNA strands during synthesis.26 
With respect to inhibition of 
ribonucleotide reductase, clofarabine and cladribine are superior to fludarabine.30 With 
respect to inhibition of DNA polymerase α, clofarabine and fludarabine are similar and 
both are superior to cladribine.28 Thus, in comparison to cladribine and fludarabine, 
clofarabine more completely inhibits both ribonucleotide reductase and DNA polymerase 
α, versus one or the other. Clofarabine is active in non-dividing cells and in cells with a 
low proliferation rate.  Clofarabine has been shown to disrupt the integrity of 
mitochondria in primary chronic lymphocytic leukemia (CLL) cells. The damage leads 
to release of pro-apoptotic mitochondrial factors.31 These effects are postulated to induce 
apoptosis in indolent, non-dividing CLL cells. This result was not seen with fludarabine 
and may explain, at least in part, the enhanced cytotoxicity of clofarabine30 though the 
physiologic and clinical implications of these observations remain uncertain and under 
continued investigation. 
 
Experience With Clofarabine in Pediatric Leukemia  
 
Phase 1 Clofarabine Studies:  In  the  initial  Phase  1 study  in  pediatric  patients  with  
hematologic  malignancies,  25 patients were treated in cohorts of escalating doses up to 
70 mg/m2, a dose at which 1 patient had grade 4 hyperbilirubinemia and grade 3 elevated 
transaminases, and 1 had a grade 3 skin rash. The MTD was determined to be 52 
mg/m2.27 Of the 13 patients treated at 52 mg/m2, grade 2 to grade 3 increases in bilirubin 
and liver transaminases were observed. A total of 5 patients achieved a CR and 3 
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were generally lower in the pediatric population than the adult population when 
administered the same dose, but there did not appear to be much difference in 
intracellular 
clofarabine triphosphate concentrations. Thus, the MTD and the 
recommended Phase 2 dose was determined to be 52 mg/m2 and the recommended Phase 
2 dose.  The Phase 1 studies in pediatric patients with hematologic malignancies led to the 
initiation of 2 parallel Phase 2 trials in 2002 for patients with either relapsed or refractory 
ALL or relapsed or refractory AML.29 
 
Both studies evaluated clofarabine 52 mg/m2. In the 61 patients enrolled in the 
relapsed or refractory ALL study (61% males: 39% females, 1 to 20 years old), the 
overall remission rate (CR + CRp) was 20%; 30% (18/61) of patients showed a 
response (7CR, 5CRp, 6PR). Responses were noted in 15 of 50 (30%) patients with B-
lineage ALL, 2 of 6 (33%) with T-cell ALL. Responders received a median of 3 prior 
induction regimens; 50% (9/18) had prior HSCT and 50% (9/18) were refractory to the 
preceding induction regimen.  Response rate in refractory patients was 26% (9/35).  
After clofarabine treatment, 10 patients proceeded to transplant (including 8 responders). 
Six of 10 patients who received a transplant were alive at last follow up (survival 
range: 30.1+ to 145.1+ weeks). Response duration in 6 patients with CR or CRp who 
did not receive a transplant ranged from 4.3 to 58.6 weeks; 2 patients maintained CR for 
47.9 and 58.6 weeks after clofarabine therapy. Median overall survival for the patients 
who achieved at least a PR was 66.6 weeks compared to 12.9 weeks for all patients.29 In 
42 pediatric patients with relapsed or refractory AML, the response rate was 26% (1 
CRp, 10 PR). Responders had received a median of 2 prior induction regimens, 36% 
(4/11) had prior HCT and 55% (6/11) patients were refractory to the preceding 
induction regimen. Response rate in refractory patients was 21% (6/28). One patient who 
had received 5 prior induction regimens achieved CRp. 13 (31%) patients (1CRp, 6PR, 
3NE, 3TF) underwent HSCT after completing clofarabine therapy, 5 of whom were 
alive at last follow-up (survival range: 62.7+ to 160.1+ weeks). Many patients 
proceeded to HSCT as soon as a donor was identified without waiting for the patient to 
go into remission, making remission difficult to assess. Median overall survival for 
patients who achieved at least a PR was 32.1 weeks compared to 23.4 weeks for all 
patients.32 
 
Among the 113 pediatric patients with ALL and AML, the most frequently reported 
drug-related AEs were vomiting (66% ALL and 65% AML) and nausea (58% ALL and 
70% AML).32 Other drug-related AEs reported by at least 10% of the pediatric patients 
overall included febrile neutropenia (31% ALL and 28% AML), pyrexia (21% ALL and 
26% AML), pruritus NOS (24% ALL and 20% AML), dermatitis NOS (24% ALL and 
17% AML), headache NOS (18% ALL and 35% AML), diarrhea NOS (21% ALL and 
22% AML), anxiety (16% ALL and 7% AML), fatigue (15% ALL and 13% AML), 
mucosal inflammation NOS (16% ALL and 15% AML), and flushing (12% ALL and 
11% AML). Anorexia occurred in 12% ALL and 9% AML and palmar-plantar 
erythrodysesthesia syndrome in 12% ALL and 9% AML. 
 
Phase 2 Clofarabine Studies: A Phase 2 trial of clofarabine in combination with 
cyclophosphamide and etoposide in pediatric patients with refractory/relapsed acute 
lymphoblastic leukemia was recently reported by Hijiya et al.25 The efficacy and safety 
of intravenous clofarabine 40 mg/m2 per day, cyclophosphamide 440 mg/m2 per day, 
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refractory or relapsed ALL was evaluated in this Phase 2 study. The primary endpoint 
was overall response  rate  (complete  remission  [CR]  plus  CR  without  platelet  
recovery  [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; 
≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response 
rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored 
at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) 
received HCT. Six patients (24%) died because of treatment-related adverse events 
associated with infection, hepatotoxicity, and/or multi-organ failure. The study protocol 
was amended to exclude patients with prior hematopoietic stem cell transplantation after 
4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive 
disease.  No additional cases of veno-occlusive disease occurred. 
 
 
 
Experience With Clofarabine in Adult Patients 
 
Clofarabine activity has been evaluated in children and adults with acute leukemia and 
found to have no difference in activity between these two age groups.33 Based on this 
finding as well as the known clinical activity using clofarabine in relapsed pediatric ALL 
and AML,25,29 it is reasonable to further evaluate the clinical efficacy of clofarabine in 
combination with chemotherapy in adult patients with acute leukemia. 
 
Phase 1 Clofarabine Studies:  Clofarabine  was  evaluated  in  a  Phase 1 study  in  
patients  with  both  hematologic malignancies and solid tumors. In patients with solid 
tumors, the starting dose level was 15 mg/m2 daily for 5 days. Grade 4 
myelosuppression occurred and the clofarabine dose was reduced by several dose 
levels with the MTD defined at 2 mg/m2 in patients with solid tumors. In patients with 
leukemia, the starting dose level was 7.5 mg/m2. This dose was escalated by several dose 
levels until 55 mg/m2 was achieved. At the 55 mg/m2 dose level, grade 3 hepatic 
toxicity was observed in 2 of 4 patients, which caused dose de-escalation to 40 mg/m2 
and became the recommended Phase 2 dose. This cohort was expanded to include 12 
patients. Of the 12 patients treated at 40 mg/m2, 2 patients achieved CR (1 AML and 1 
ALL) suggesting some efficacy and safety at this dose level in patients with acute 
leukemia Based on in vitro data suggesting synergism between clofarabine and 
cyclophosphamide, Karp et al designed a Phase 1study with escalating doses of both 
agents34. Of the 18 patients enrolled, 12 and 6 had relapsed or refractory AML and ALL 
respectively. The median age was 51. Dose Level 1 was cyclophosphamide 200 
mg/m2 on Days 0 and 1, cyclophosphamide 400 mg/m2 on Days 2, 3, and 8-10, and 
clofarabine 20 mg/m2 Days 1-3 and 8-10. The total cyclophosphamide and clofarabine 
dose was 2400 mg/m2 and 120 mg/m2 respectively. In our study, the total 
cyclophosphamide and clofarabine dose is 1500 mg/m2 and 100 mg/m2 respectively. At 
that dose level, 2 of the 6 patients experienced prolonged bone marrow suppression 
which led to the reduction of the clofarabine dose to 10 mg/m2. At this dose level, one 
death occurred at Day 14 and that cohort was expanded to include 12 patients and 
was defined as the DLT. Overall 4 patients died on the study, 2 in each dose cohort. 
The median time to bone marrow recovery was decreased from 45 days to 35 days from 
Dose Level 1 to Dose Level 0. Of the 12 patients enrolled at Dose Level 0, 3 patients 
achieved a CR suggesting activity of this combination in adult relapsed/refractory 
leukemia. 
 
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patients with a median age of 71 years.35 Unfavorable cytogenetics were present in 55%.  
Clofarabine at 30 mg/m2 IV was administered daily for 5 days for induction followed by 
20 mg/m2 for 5 days as consolidation. The ORR was 46% with 38% of patients achieving 
a CR or CRp. The median overall survival for all patients, patients in CR/CRp and those 
in CR was 41, 59 and 72 weeks respectively. Overall clofarabine was well tolerated with 
a 60-day mortality rate of 16% (from any cause). 
 
Study and Dose Rationale 
 
The safety profile of clofarabine appears acceptable within the target populations studied 
to date in the clinical studies summarized above. Clofarabine has demonstrated anti- 
cancer activity through inhibition of DNA synthesis and repair, induction of 
apoptosis, and possibly through other mechanisms. Numerous responses have been 
observed after treatment with clofarabine in heavily pre-treated relapsed/refractory 
patients with ALL or AML. Additionally there have been responses in several adult 
studies of lower dose clofarabine  in  combination  with  a  variety of  agents.31, 36, 37The  
patient  population selected, MRD positive prior to transplantation would be an ideal 
patient population to investigate the role of a “bridge” chemotherapy combination prior 
to HCT and potentially improve the event-free survival (EFS) of this group of patients 
who historically have had inferior outcomes but are ineligible for most current relapsed 
studies. 
 
Experience With Clofarabine/Cyclophosphamide/Etoposide as Bridging Therapy 
in Pediatric ALL 
 
Investigators at the University of Minnesota have been using this combination of lower 
dose clofarabine and cyclophosphamide with etoposide as “bridging therapy” for 
patients with B-precursor ALL who were in a morphologic remission (< 5% leukemia 
blasts in the marrow) but with evidence of MRD   (> 0.01% leukemia blasts) via flow 
cytometry and awaiting HCT. To date, they have treated three pediatric patients with this 
regimen and in all three achieved MRD reduction (2/3 becoming MRD-negative) after a 
single course of therapy and experienced no Grade III/IV toxicities with both rapid 
neutrophil and platelet recovery. All three patients successfully proceeded to HCT after 
completion of this bridging therapy without further delay or toxicity and have 
experienced no increase in post-HCT toxicity. 
 
Based  on  the  success  using  this  clofarabine-based  regimen  at  the  University  of 
Minnesota, five additional patients were treated at four pediatric centers across the 
US, all with MRD-positive ALL (ages ranging 23 months to 20 years). All 5 patients had 
reduction in MRD after a single course of therapy with 4/5 achieving MRD-
negativity. All 5 patients proceeded to HCT with 4/5 alive and free of disease at the 
time of this report and one case of TRM. 
 
Reporting the results of all 8 patients treated with this bridging regimen across all centers 
provides 1-year EFS of 44% (95% CI 6-81) with two relapses occurring.38 One relapse 
occurred in a patient with Philadelphia chromosome positive B-ALL who received 
the bridging therapy, but remained with persistent MRD prior to HCT, which 
incidentally was a reduced intensity conditioning regimen and the patient’s 2nd HCT. The 
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MRD-negativity post-bridging therapy but subsequently relapsed 106 days post-HCT. 
This patient then received another course of the clofarabine-based bridging regimen 
resulting in  elimination  of  his  disease  becoming  MRD-negative  (4% → < 0.01%  
by  flow cytometry) and proceeded to chimeric antigen receptor T-cell (CART) therapy. 
 
Experience With Clofarabine as Bridging Therapy in Adult Patients With AML  
 
Clofarabine when given immediately prior to HCT was found to be safe in the setting 
of haploidentical HCT. In a study by Tischer et al, 18 patients with relapsed leukemia 
were enrolled, 15 having the diagnosis of AML.39 All patients had active leukemia at 
time of HCT and received cytoreductive chemotherapy with clofarabine at a dose of 30 
mg/m2 IV over 5 days followed by 3 days of rest prior to starting their HCT 
conditioning regimen. Conditioning consisted of five doses of fludarabine at 30 
mg/m2/day IV and two doses of cyclophosphamide at 14.5 mg/kg/day IV. The estimated 
OS, RFS and NRM was 55.5%, 39% and 23% respectively. Five patients died from 
NRM with 4 patients dying from infectious complications and one patient dying from 
liver toxicity, and GVHD. 
 
2. 
STUDY DESIGN 
 
This is a Phase 2 study designed for the purpose of estimating various parameters 
surrounding the efficacy  of  Clofarabine,  Cyclophosphamide  and  Etoposide  in  
eliminating  minimal  residual disease (MRD) in acute leukemia patients otherwise in 
remission and without causing significant delay of HCT due to treatment related 
toxicity. A single course of “bridge” chemotherapy is given prior to the transplant 
procedure as an approach to improved disease-free survival in a patient group who 
historically has had inferior outcomes. 
 
The following parameters will be monitored. 
 
 
Primary Objectives 
 
 The effect of Clofarabine, Cyclophosphamide and Etoposide in eliminating the 
presence of MRD without causing a significant delay of HCT due to treatment 
related toxicity, defined as greater than 56 days from completion of bridging 
therapy to start of HCT 
 The proportion of any toxicities associated with Clofarabine, Cyclophosphamide 
and Etoposide 
 
 
Secondary Objectives 
 
 The proportion of pre-transplant chemotherapy-induced aplasia (defined as 
greater than 42 days after infusion of chemotherapy) 
 The proportion of infectious complications following bridging therapy and before 
HCT 
 Treatment–related mortality at Day 100 after HCT 
 One year disease-free survival after HCT 
 The proportion of relapse within one year of HCT 
 


 
 
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3. 
SELECTION OF PATIENTS 
 
Study entry is open to patients regardless of gender or ethnic background.  While 
there will be every effort to seek out and include females and minority patients, the 
patient population is expected to be no different than that of other acute leukemia 
studies at the Medical College of Wisconsin. 
 
3.1  
Inclusion Criteria 
 
3.1.1   Diagnosis of ALL or AML with < 5% blasts in the bone marrow (M1) by 
 
morphology and that meets one of the following criteria: 
 
a. Flow cytometric evidence of MRD (≥ 0.01% leukemic blasts for ALL or         
≥ 0.5% leukemic blasts for AML detected in the bone marrow) 
 
OR 
 
b. Molecular/cytogenetic evidence of disease (FISH or PCR methodology) 
performed within 14 days 
 
AND with the intent of going on to an allogeneic hematopoietic cell 
transplantation (HCT) independent of this study 
 
3.1.2 Patients must have an available donor and have intention of proceeding directly to 
ALL-HCT after completion of 1 cycle of Bridging therapy. 
 
3.1.3  Age 0 to 39 years 
 
3.1.4 Karnofsky Performance Status ≥ 50% for patients 16 years and older and 
Lansky Play Score ≥ 50 for patients under 16 years of age (see Appendix 2) 
 
3.1.5 Patients  must  have  a  life  expectancy  ≥  8  weeks  as  determined  by  the 
enrolling investigator 
 
3.1.6 Have acceptable organ function as defined within 7 days of study registration: 
 
Renal: creatinine clearance ≥ 60 mL/min/1.73m2 or 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 year to < 2 years 
0.6 
0.6 
2 years to < 6 years 
0.8 
0.8 
6 years to < 10 years 
1.0 
1.0 
10 years to < 13 years 
1.2 
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Age 
Maximum Serum 
Creatinine (mg/dl) 
13 years to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
 
Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x upper 
limit of normal (ULN) for age 
 
Cardiac: left ventricular ejection fraction ≥ 40% by ECHO/MUGA 
 
3.1.7 Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At 
least 7 days must have elapsed from prior chemotherapy. 
 
Hematopoietic Growth Factors: At least 7 days since the completion of 
therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) 
administration. 
 
3.1.8 Sexually  active  females  of  child  bearing  potential  must  agree  to  use 
adequate contraception (diaphragm,  birth  control  pills,  injections,  
intrauterine  device  [IUD], surgical sterilization, subcutaneous implants, or 
abstinence, etc.) for the duration of treatment and for 2 months after the last 
dose of chemotherapy.   Sexually active men must agree to use barrier 
contraceptive for the duration of treatment and for 2 months after the last dose 
of chemotherapy. 
 
3.1.9 Voluntary written consent before performance of any study-related procedure 
not part of normal medical care, with the understanding that consent may be 
withdrawn by the subject at any time without prejudice to future medical care. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Acute Promyelocytic Leukemia (APL) 
 
3.2.2 Active extramedullary disease (CNS ≥ CNS2 and/or testicular leukemia) or 
presence of chloromatous disease 
 
3.2.3 Receiving concomitant chemotherapy, radiation therapy; immunotherapy or 
other anti-cancer therapy other than is specified in the protocol 
 
3.2.4 Systemic fungal, bacterial, viral, or other infection not controlled (defined as 
exhibiting ongoing signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment) 
 
3.2.5 Pregnant or lactating. The agents used in this study are known to be teratogenic 
to a fetus and there is no information on the excretion of agents into breast 
milk. All females of childbearing potential must have a blood test or urine study 
within 2 weeks prior to registration to rule out pregnancy. 
 


 
 
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3.2.6 Known allergy to any of the agents or their ingredients used in this study 
 
3.2.7 Participating in a concomitant Phase 1 or 2 study 
 
 
4. 
REGISTRATION PROCEDURES 
 
Registration will occur after eligibility is confirmed and the patient/parent has signed 
the subject consent, but before any treatment has been administered. 
 
The eligibility checklist will be completed at the time of study enrollment. 
 
4.1 
Registration 
 
Upon completion of the screening evaluation, eligibility confirmation and obtaining 
written consent, the patient will be registered in the study file by the Department of 
Pediatrics Division of Hematology/Oncology/BMT MACC Fund Center Clinical Trials 
Office (CTO).  When the Research Electronic Data Capture (REDCap) Database is 
fully functioning for this study, the MARCH Consortium will use this program for 
patient registration. 
 
4.2 
Patients Who Do Not Begin Study Treatment 
 
If a patient is registered on the study, and is later found not able to begin the planned 
study treatment, for whatever reason, the patient will be removed from study and 
treated at the physician’s discretion.  Study data will be collected until the time of study 
removal. The reason for removal from study will be clearly indicated on the case report 
forms. 
 
If a patient begins treatment, and then is discontinued for whatever reason, the patient 
must be followed per Section 5.4. 
 
5. 
TREATMENT PLAN 
 
The administration of the study drugs will follow institutional drug and supportive care 
guidelines.  Refer to Section 5.2 for additional therapy based on specific disease features. 
 
Only 1 treatment course is permitted. 
 
5.1 
Treatment Plan Regardless of Diagnosis 
 
Day 
Agent/Procedure 
Baseline 
Peripheral blood draw and bone marrow aspirate (within 14 days of enrollment) 
Day 1 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 2 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 


 
 
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Day 
Agent/Procedure 
Day 3 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 4 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 5 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
Day 30* 
Perform bone marrow biopsy/aspirate (*Or upon adequate blood count recover 
(ANC > 0.5 AND plt > 50,000) whichever comes first 
Between Day 28 & 42 
Proceed to HCT independent of this study 
 
Pretreatment stress doses of steroids (i.e. hydrocortisone 50-100 mg/m2/dose IV daily) 
during clofarabine administration for prophylaxis against SIRS is allowed on study. 
 
A bone marrow evaluation to determine study response and remission status will be 
performed on study Day 30 or upon adequate blood count recovery (ANC > 0.50 and 
platelet > 50,000), whichever occurs first.  If the marrow is hypocellular and without 
evidence of normal tri-lineage hematopoiesis the marrow should be repeated at Day 42. 
 
5.2 
Supportive Care Guidelines 
 
All supportive measures consistent with optimal patient care will be given throughout 
the study. 
 
Venous Access: A central venous access device, preferably a double lumen, is 
strongly recommended for this study. 
 
Anti-emetics will be used according to standard medical practice. Growth factor use is 
allowed on this study. 
 
Antimicrobial Prophylaxis: Patients should be placed on standard of care prophylaxis 
during this time period at the discretion of the treating physician according to 
institutional guidelines for PCP, HSV, bacterial and fungus. 
 
5.3 
Duration of Therapy 
 
Treatment will be limited to one course.  Patients will receive protocol therapy unless: 
 
 Patient withdraws consent or is non-compliant 
 Disease progression 
 Inter-current illness that prevents further administration of treatment 
 Unacceptable toxicity 
 
5.4 
Follow-Up 
 
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for 60 days from the first dose of study drug or until the start of the transplant prep 
regimen (or other therapy), whichever occurs earlier. 
 
For  patients  who  go  on  to  transplant  (the  intent  of  this  study),  routine  outcomes 
(treatment related mortality, disease free survival) will be abstracted from the Blood and 
Marrow Transplantation (BMT) database through the 3rd year post-transplant follow-up. 
 
6. 
DOSE MODIFICATION 
 
The intent of this study design is for all patients to receive and complete one course of 
therapy.  Patients who exhibit signs of disease progression or experience an unacceptable 
toxicity will be discontinued from treatment. 
 
There will be no dose delays or dose reductions of study drugs for hematologic toxicity 
during Consolidation “Bridging” therapy (Day 1 through Day 30); however, 
prolonged hematopoietic recovery or bone marrow aplasia during the first 42 days may 
meet a study stopping rule per Section 11.4. 
 
6.1 
Clofarabine  
 
Cardiac Dysfunction (Grade 3-4): Discontinue clofarabine administration for Grade 3-4 
left ventricular systolic dysfunction.  
 
Hyperbilirubinemia (Grade 3-4): Hold clofarabine administration if Grade 3 or higher 
increase in bilirubin is noted. If the patient‘s condition stabilizes and organ function has 
returned to baseline, clofarabine administration may be continued at a 25% dose 
reduction.  
 
Pancreatitis (Grade 3-4): Discontinue clofarabine in the presence of hemorrhagic 
pancreatitis or severe pancreatitis. In the case of mild pancreatitis, clofarabine should be 
held until symptoms and signs subside, and amylase levels return to normal and then 
resumed at a 25% dose reduction.  
 
Renal Dysfunction (Grade 3-4): Hold clofarabine administration if Grade 3 or higher 
increase in creatinine is noted. Adjust clofarabine as follows:  
 
 GFR/CrCl 30 < 60 mL/min/1.73 m2: Decrease dose by 50%  
 GFR/CrCl < 30 mL/min/1.73 m2: Do NOT administer clofarabine. Resume only 
when ≥ 30 mL/min/1.73 m2 
 
Systemic Inflammatory Response (SIRS)/Capillary Leak Syndrome: Hold 
clofarabine administration if signs of SIRS develops (tachypnea or other evidence of 
respiratory distress, unexplained hypotension and/or unexplained tachycardia). Although 
clofarabine has been associated with systemic inflammatory response, other causes of 
SIRS, such as infection, should be investigated. If the patient‘s condition stabilizes or 
improves, clofarabine administration may be continued at a 25% dose reduction with the 
addition of pretreatment stress doses of steroids (e.g. hydrocortisone 50-100 mg/m2/dose 
IV daily during clofarabine administration).  
 


 
 
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6.2 
Cyclophosphamide  
 
Hematuria: Omit in the presence of macroscopic hematuria. If there is a history of 
previous significant hematuria, hydrate before cyclophosphamide until specific gravity is 
< 1.010 and hydrate at 125 mL/m2/hr for 24 hours after dose. Monitor for adequate urine 
output as per institution guidelines. Give IV mesna at a total dose that is 60% of the 
cyclophosphamide dose divided to 3 doses (i.e. if the cyclophosphamide dose is 1000 
mg/m2, the total mesna dose is 600 mg/m2 or 200 mg/m2/dose). Give the first mesna dose 
15 minutes before or at the same time as the cyclophosphamide dose and repeat 4 and 8 
hours after the start of cyclophosphamide. This total daily dose of mesna can also be 
administered as IV continuous infusion. The continuous infusion should be started 15-30 
minutes before or at the same time as cyclophosphamide and finished no sooner than 8 
hours after the end of cyclophosphamide infusion.  
 
Renal Dysfunction: If creatinine clearance or radioisotope GFR is < 10 mL/min/1.73 m2, 
reduce dose of cyclophosphamide by 50%. Prior to dose adjustment of 
cyclophosphamide, the creatinine clearance should be repeated with good hydration. 
 
6.3 
Etoposide (VP-16)  
 
Allergic Reaction: Pre-medicate with diphenhydramine (1-2 mg/kg slow IV push, 
maximum dose is 50 mg). If symptoms persist, add hydrocortisone 100-300 mg/m2. 
Continue to use premedication before etoposide in future. Also consider substituting an 
equimolar amount of etoposide phosphate, in the face of significant allergy and/or 
hypotension. Etoposide phosphate is a water soluble prodrug that does not contain 
polysorbate 80 and polyethyleneglycol, the solubilizing agent in etoposide that may 
induce allergic reactions and hypotension. Etoposide phosphate is rapidly converted to 
etoposide in vivo and provides total drug exposure, as represented by AUC (0-infinity) 
that is statistically indistinguishable from that measured for etoposide at equimolar doses.  
 
Hypotension: If diastolic or systolic blood pressure (BP) falls 20 mmHg during infusion, 
reduce infusion rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to 
recover or falls further. Stop infusion if BP does not recover, continue NS. If the patient 
has had any episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 
hours prior to any subsequent infusion.  
 
Renal Insufficiency: If renal function decreases, adjust etoposide as follows: CrCl 10-50 
mL/min/1.73 m2, decrease dose by 25%; if CrCl < 10 mL/min/1.73 m2, decrease dose by 
50%.  
 
Hyperbilirubinemia: If direct bilirubin is > 2 mg/dL, decrease dose by 50%. If direct 
bilirubin is > 5 mg/dL, hold etoposide. 
 
 
 
 


 
 
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7. 
Study Calendar 
 
7.1 
Standard of Care 
Evaluations 
Pre-
Study 
Day 
1-5 
Day 
6-29 
Day  
30-604 
Clinical history 
X 
 
 
 
Physical exam 
X 
X 
Weekly 
Weekly 
Vital exam 
 
X 
X 
Weekly 
Weekly 
Weight 
X 
 
Weekly 
Weekly 
Height 
X 
 
 
 
Performance status 
X 
 
Weekly 
Weekly 
Adverse event, toxicity notation 
X 
X 
Weekly 
Weekly 
Laboratory 
WBC, Hgb, platelets, diff 
X 
X 
Twice Weekly Twice Weekly 
Electrolytes including Ca++, PO4, Glucose 
X 
X 
Weekly 
Weekly 
BUN, Creatinine, ALT, AST, LDH, 
Alkaline Phosphatase, bilirubin 
X 
X 
Weekly 
Weekly 
Albumin and Total Protein 
X 
 
 
 
Serum amylase and lipase 
X 
 
 
 
Urinalysis 
X 
 
 
 
Creatinine clearance1 
X 
 
 
 
Echocardiogram/MUGA 
X 
 
 
 
Pregnancy test2 
X 
 
 
 
Bone marrow aspirate (within 14 days of 
enrollment for pre-study sample)6 
X 
 
 
X3 
Lumbar puncture5 
X 
 
 
 
Treatment 
Clofarabine 
 
Daily 
 
 
Etoposide 
 
Daily 
 
 
Cyclophosphamide 
 
Daily 
 
 
1 Optional for eligibility, see Section 3.5 
2 For females of childbearing potential only 
3 A bone marrow evaluation to determine study response and remission status will be performed 
on study Day 30 or upon adequate blood count recovery (ANC > 0. 5 and plt > 50,000), 
whichever occurs first.  If the marrow is hypocellular and without evidence of normal tri-lineage 
hematopoiesis the marrow should be repeated at Day 42 
4 Follow-up for safety continues until the start of a new therapy (i.e. transplant preparative 
regimen) or Day 60 whichever occurs earlier (transplant related endpoints will be abstracted 
from the BMT database through the 1 year follow-up) 
5 Intrathecal chemotherapy prophylaxis is allowed at the discretion of the treating physician. 
6 Bone marrow must be sent for morphology, flow cytometry, standard cytogenetics, FISH and 
molecular testing for routine AML analysis. 
 
 
 


 
 
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8. 
DRUG FORMULATION AND PROCUREMENT 
 
8.1 
Clofarabine 
 
8.1.1     Other Names:  CLOLAR, clofarabine; CAFdA; Cl-F-ara-A 
 
8.1.2    Classification:  Antineoplastic 
 
8.1.3   Mode of Action:  Clofarabine is sequentially metabolized intracellularly to the 5’-
monophosphate metabolite by deoxycytidine kinase and mono- and di-
phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high 
affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to 
or greater than that of the natural substrate, deoxycytidine.  Clofarabine inhibits    
DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through 
an inhibitory action on ribonucleotide reductase, and by terminating DNA chain  
elongation  and  inhibiting  repair  through incorporation into the DNA chain by 
competitive inhibition of DNA polymerases. The affinity of clofarabine 
triphosphate for these enzymes is similar to or greater than that of deoxyadenosine 
triphosphate. In preclinical models, clofarabine has demonstrated the ability to 
inhibit DNA repair by incorporation into the DNA chain during the repair process.  
Clofarabine 5’-triphosphate  also  disrupts  the  integrity  of  mitochondrial 
membrane, leading to the release of the pro-apoptotic mitochondrial proteins, 
cytochrome C and apoptosis-inducing factor, leading to programmed cell death. 
Clofarabine is cytotoxic to rapidly proliferating and quiescent cancer cell types in 
vitro. The population pharmacokinetics of clofarabine were studied in 40 
pediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or 
refractory ALL or AML. At the given 52 mg/m2 dose, similar concentrations were 
obtained over a wide range of BSAs. Clofarabine was 47% bound to plasma 
proteins, predominantly to albumin. Based on non-compartmental analysis, 
systemic clearance and volume of distribution at steady-state were estimated to be 
28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was estimated to 
be 5.2 hours. No apparent difference in pharmacokinetics was observed 
between patients with ALL and AML or between males and females. Based on 
24-hour urine collections in the pediatric studies, 49-60% of the dose is excreted 
in the urine unchanged. In vitro studies using isolated human hepatocytes indicate 
very limited metabolism (0.2%), therefore the pathways of non-renal elimination 
remain unknown. Although no clinical drug-drug interaction studies have been 
conducted to date, on the basis of the in vitro studies, cytochrome p450 inhibitors 
and inducers are unlikely to affect the metabolism of clofarabine. The effect of 
clofarabine on the metabolism of cytochrome p450 substrates has not been 
studied. The pharmacokinetics of clofarabine have not been evaluated in patients 
with renal or hepatic dysfunction. 
 
8.1.4   Storage and Stability:  Clofarabine is a white to off-white solid with a melting 
point of 228°C to 230°C and a molecular weight of 303.5. The drug substance is 
very stable in the dry state, and aqueous solutions are stable to heat treatment. 


 
 
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Clofarabine is freely soluble in water (1.5 mg/mL) or buffered solutions at room 
temperature. Clofarabine is not less than 97% pure on a dried basis by high 
performance liquid chromatography (HPLC) analysis. Clofarabine is formulated at 
a concentration of 1 mg/mL. Clofarabine is supplied in 1 vial size: a 20-mL clear, 
glass vial with gray stopper and blue flip-off seal. The 20-mL vials contain 20 mL 
(20 mg) of sterile solution. The pH range of the solution is 4.5 to 7.5. The 
solution is clear and practically colorless, preservative free, and free from 
foreign matter. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
 
Vials containing undiluted clofarabine for injection should be stored at controlled 
room temperature. 
 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). The 
commercial expiry period for clofarabine is 24 months at room temperature. 
Ongoing stability studies will continue to confirm the appropriate quality of drug 
product used for clinical trials beyond 24 months. Clofarabine for injection 
should be diluted with 0.9% sodium chloride injection USP or European 
Pharmacopeia (EP) normal saline (NS) or 5% dextrose injection (D5W) USP or 
EP prior to IV infusion. The resulting admixture may be stored at room 
temperature, but must be used within 24 hours of preparation. 
 
8.1.5   Dose Specifics:  For the purposes of this study, clofarabine will be administered 
at the dose of 30 mg/m2 for patients 0-30 years (20 mg/m2 for patients > 30 years) 
IV over 2 hours (given at Hours 0 to 2) on Days 1 through 5. 
 
8.1.6  Administration:  USP  or  0.9%  sodium  chloride  injection  USP  to  a  
convenient  volume  such  as  the maximum final concentration should be 
between 0.15 mg/mL and 0.4 mg/mL, and infuse over 2 hours. The resulting 
admixture may be stored at room temperature, but must be used within 24 hours 
of preparation. To prevent drug incompatibilities, no other medications should be 
infused concurrently through the same IV lines as clofarabine. Also, no blood 
products should be administered at the same time as clofarabine. 
 
To reduce the effects of tumor lysis and other adverse events it is recommended 
that continuous IV fluids be given throughout the 5 days of clofarabine 
administration. Since clofarabine is primarily excreted through the kidneys, 
drugs with known renal toxicity should be avoided during the 5 days of 
clofarabine administration. In addition, since the liver is a known target organ for 
clofarabine toxicity, concomitant use of medications known to induce hepatic 
toxicity should be avoided. 
 
Pretreatment stress doses of steroids with hydrocortisone (50-100 mg/m2/dose IV 
daily) during clofarabine administration is allowed on this study. 
 
8.1.7    Availability:  Commercially available by prescription. 
 
8.1.8    Side Effects:  Refer to Appendix 4. 
 
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a pregnant woman. Women of childbearing  potential  should  be  advised  to  
avoid  becoming  pregnant  while  using Clofarabine. Men should be advised not 
to father a child while receiving treatment with Clofarabine, and for 2 months 
afterwards. 
 
8.2 
Cyclophosphamide 
 
8.2.1  Other Names:  Cytoxan, CTX 
 
8.2.2    Classification:  Alkylating agent 
 
8.2.3  Mode of Action:  Cyclophosphamide is an alkylating agent related to nitrogen 
mustard. Cyclophosphamide is inactive until it is metabolized by P450 
isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active compounds. 
The initial product is 4-hydroxycyclophosphamide (4-HC) which is in equilibrium 
with aldophosphamide which spontaneously releases acrolein to produce 
phosphoramide mustard. Phosphoramide mustard, which is an active bifunctional 
alkylating species, is 10 times more potent in vitro than is 4-HC and has been 
shown to produce interstrand DNA cross-link analogous to those produced by 
mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted 
in the urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. 
The plasma half-life ranges from 4.1 to 16 hours after IV administration. 
 
 
8.2.4 Storage and Stability:  Cyclophosphamide  for  injection  is  available  as  
powder  for  injection  or  lyophilized powder for injection in 500 mg, 1 g, and 2 g 
vials. The powder for injection contains 82 mg sodium bicarbonate/100 mg 
cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is 
recommended. The product will withstand brief exposures to temperatures up to 
30ºC (86ºF). 
 
8.2.5  Dose Specifics:  For  the  purposes  of  this  study,  cyclophosphamide  300  
mg/m2 will be  administered intravenously over 30 to 60 minutes on Days 1 
through 5. 
 
8.2.6 Administration Cyclophosphamide for Injection: Reconstitute with Sterile 
Water or Bacteriostatic Water for Injection to a concentration of 20 mg/mL. 
Solutions reconstituted with preservative should be used within 24 hours if stored 
at room temperature or within 6 days if stored under refrigeration. If administered 
as undiluted drug at the 20 mg/mL concentration, reconstitute with NS only to 
avoid a hypotonic solution. Cyclophosphamide may be further diluted in dextrose 
or saline containing solutions for IV use. 
 
8.2.7 Availability:  Cyclophosphamide is commercially available by prescription.  
Cyclophosphamide for Injection, USP contains cyclophosphamide monohydrate 
and is supplied in vials for single dose use. 
 
8.2.8  Side Effects:  Refer to Appendix 4. 
 


 
 
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Pregnancy Category D:  Cyclophosphamide can cause fetal harm when 
administered to a pregnant woman. 
 
8.3 
Etoposide 
 
8.3.1     Other Names:  VP-16, Etopophos; Toposar; VePesid. 
 
8.3.2   Classification:  A semisynthetic derivative of podophyllotoxin that forms a complex 
with topoisomerase II and DNA which results in single and double strand DNA 
breaks. Its main effect appears to be in the S and G2 phase of the cell cycle. The 
initial t½ is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily 
excreted in the urine. In children, approximately 55% of the dose is excreted in 
the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 
10 mL/min/m² or about 35% of the total body clearance over a dose range of 80 to 
600 mg/m². Etoposide, therefore, is cleared by both renal and non-renal processes, 
i.e., metabolism and biliary excretion. The effect of renal disease on plasma 
Etoposide clearance is not known. Biliary excretion appears to be a minor route of 
etoposide elimination. Only 6% or less of an intravenous dose is recovered in the 
bile as etoposide. Metabolism accounts for most of the non-renal clearance of 
etoposide. The maximum plasma concentration and area under the concentration 
time curve (AUC) exhibit a high degree of patient variability. Etoposide is highly 
bound to plasma proteins (~ 94%), primarily serum albumin.  Pharmacodynamic 
studies have shown that etoposide systemic exposure is related to toxicity. 
Preliminary data suggests that systemic exposure for unbound etoposide correlates 
better than total (bound and unbound) etoposide. There is poor diffusion into the 
CSF < 5%. Cmax and AUC values for orally administered etoposide capsules 
consistently fall in the same range as the Cmax and AUC values for an intravenous 
dose of one-half the size of the oral dose. The overall mean value of oral capsule 
bioavailability is approximately 50% (range 25-75%). Etoposide phosphate is a 
water soluble ester of etoposide which is rapidly and completely converted to 
etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that 
etoposide phosphate is bioequivalent to etoposide when it is administered in molar 
equivalent doses. 
 
8.3.3   Dose Specifics:  For the purposes of this study, etoposide 100 mg/m2 will be 
administered intravenously over 2 hours on Day 1 through 5. 
 
8.3.4  Administration:  Dilute etoposide to a final concentration ≤ 0.4 mg/mL in 
Dextrose or Normal Saline containing IV solutions. Etoposide infusions are 
stable at room temperature for 96 hours when diluted to concentrations of 0.2 
mg/mL; stability is 24 hours at room temperature with concentrations of 0.4 
mg/mL. The time to precipitation is highly unpredictable at concentrations > 
0.4 mg/mL. Administer over 30 to 60 minutes; slow rate of administration if 
hypotension occurs. Do not administer etoposide by rapid intravenous 
injection. Use in-line filter during infusion secondary to precipitate formation 
risk. To avoid leaching of DEHP from PVC bags and tubing, prepare the 
etoposide solution as close as possible preferably within 4 hours to the time of 
administration or alternatively as per institutional policy, non-PVC containers and 
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8.3.5    Availability:  Commercially available by prescription. 
 
8.3.6   Storage and Stability:  Etoposide for Injection is available in sterile multiple 
dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each 
mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 
percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened vials of 
etoposide are stable until expiration date on package at room temperature (25°C).  
Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent 
to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. 
Etoposide phosphate must be stored under refrigeration 2°-8°C (36°-46°F). 
Unopened  vials  of  Etoposide  phosphate  are  stable  until  the  expiration  date  
on  the package. 
 
8.3.7   Side Effects:  Refer to Appendix 4. 
 
Pregnancy Category D:  Etoposide may cause fetal harm when administered to a 
pregnant woman. Women of childbearing  potential  should  be  advised  to  
avoid  becoming  pregnant  while  using Etoposide. Men should be advised not 
to father a child while receiving treatment with Etoposide, and for 2 months 
afterwards. 
 
9. 
ADVERSE EVENT MONITORING, DOCUMENTATION, AND REPORTING 
 
Toxicity and adverse events will be classified according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE) and reported on the schedule 
below.  A copy of the CTCAE can be downloaded from the CTEP home page: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
9.1 
Definitions 
 
The following definitions are based on the Code of Federal Regulations Title 21 
Part 312.32 (21 CFR 312.32(a)). 
 
Adverse Event:  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected Adverse Reaction:  Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. 
 
Life-Threatening  Adverse  Event Or  Life-Threatening  Suspected  Adverse 
Reaction: An  adverse event  or  suspected  adverse  reaction  is  considered  “life-
threatening”  if,  in  the  view  of  either  the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. 
 
Event Attribution Categories:  CTCAE does not define an AE as necessarily ‘caused by 
a therapeutic intervention.’ The clinical investigator must assign attribution for an adverse 


 
 
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event after naming and grading of the event. 
 
 
Attribution 
Description 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
Unanticipated (unexpected) adverse event or unexpected suspected adverse reaction 
as defined by the Medical College of Wisconsin IRB are those that are not already 
described as potential risks in the consent form, not listed in the Investigator’s Brochure 
or not part of an underlying disease. 
 
Expedited (Rapid) Reporting: Certain events may require rapid notification to entities 
providing patient safety oversight (i.e. IRB) as detailed in Section 9.3. 
 
9.2 
Adverse Event Documentation 
 
Adverse events occurring after the initiation of any study treatment must be documented. 
Refer to Appendix 4 for a list of expected toxicities. 
 
Since a key endpoint of this study is to characterize the toxicities of clofarabine, 
cyclophosphamide and etoposide when used in combination, adverse event 
documentation requirements will be determined based on grade, expectedness and 
relationship to study therapy as follows: 
 
 
 
Stopping Rule Events: The following events count toward a study stopping rule per 
Section 11.4 and must be reported to the MCW Study Coordinator and Dr. Burke using 
the SAE Form found in REDCap which is also immediately reported (within 24 hours of PI 
notification) to the MCW DSMC: 
 
 Any Grade 4 non-hematologic treatment related event 
 Any death, regardless of cause during the reporting period for this study (from 
initiation of study treatment through the start of a new treatment (i.e. transplant 
preparative regimen), or Day 60, whichever occurs earlier) 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 and 5 
 
Expected or 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
Not 
Required 
Required 
Required 
Possible 
Probable 
Definite 
Not required 
Not 
required 
Not Required Not 
Required 
Required 
(Non 
hematologic 
only) 
Required 


 
 
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All patients will be monitored until the start of a new treatment (i.e. transplant 
preparative regimen) or Day 60, whichever occurs earlier, as it is expected that most 
treatment related adverse events will occur during this period. 
 
For patients who go on to transplant, transplant related endpoints will be collected by 
record review. 
 
9.3 
Adverse Event Reporting Requirements 
 
The reporting period for this study is from initiation of study treatment through the start 
of a new treatment (i.e. transplant preparative regimen), or D ay 60, whichever occurs 
earlier; however after this time point, the investigator must report upon knowledge any 
study treatment related event meeting the expedited reporting criteria listed in the 
following table. 
 
Agency 
Criteria for Reporting 
Timeframe 
Form to 
Use 
Copy AE 
To: 
MCW 
IRB 
UPIRSO: Any event which is unanticipated, 
involved new or increased risk to subjects, 
and was at least possibly related to study 
procedures through Day 60 or the start of a 
new treatment whichever is earlier 
5 calendar 
days after 
PI 
Notification 
SAE Found 
in REDCap 
Dr. Michael 
Burke & 
MCW Study 
Coordinator 
Other Problems or Events meeting the 
definition of UPIRSO 
MCW 
DSMC 
Any event that counts toward a study 
stopping rule (see Section 11.4) 
Within 24 
hours of PI 
notification 
SAE Found 
in REDCap 
Dr. Michael 
Burke & 
MCW Study 
Coordinator 
 
Serious adverse events are reported directly to Dr. Michael Burke and the MCW Study 
Coordinator within 72 hours of the event via the REDCap database (Section 10.1).  The 
adverse event report is reviewed by Dr. Michael Burke and Causality/Attribution 
assigned, as applicable. 
 
MCW CC DSMC Reporting:  The MCW Cancer Center DSMC is responsible for the 
global oversight and review of patient safety on this clinical trial. The DSMC meets twice 
a year (at a minimum) and all submitted outcome data is reviewed including all adverse 
events reported to the MCW IRB.  The DSMC reserves the right to meet more frequently 
on an as needed basis based on the events submitted. 
 
The DSMC semi-annual review confirms that the trial has not met any stopping rules and 
reviews any patient safety problems necessitating discontinuation of the trial. A report 
from the DSMC is submitted to the MCW IRB as well as the trial coordinators/local PIs 
of this protocol.  
 
Grade 3 Unexpected (non-hematological only), and all Grade 4 and 5 events will be 
submitted to the DSMC within 24 hours of PI (Dr. Michael Burke) Notification.  The 
DSMC will acknowledge the submission with a responding email.   
 


 
 
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MCW IRB Reporting:  Serious adverse events are reported directly to the PI and the 
MCW Study Coordinator within 72 hours of the event via the REDCap database 
(Section 10.1).  The adverse event report is reviewed by Dr. Michael Burke and 
Causality/Attribution assigned, as applicable. If the adverse event meets the MCW IRB 
criteria for expedited reporting, an official signed report is submitted to the MCW 
Institutional Review Board. All deaths, regardless of the cause, are reported to the MCW 
IRB.  
 
An official report of a serious adverse event is faxed or emailed to the MARCH 
coordinating center within five days of occurrence. 
 
9.4  
Event Notification, Deviations, or Patient Complaints 
 
Any event, protocol deviation, or patient complaint, not meeting the criteria for serious 
adverse event reporting, should be reported to the MCW Study Coordinator via the 
REDCap database (Section 10.1). The report is reviewed by the PI and any further action, 
if deemed necessary, is discussed with the reporting site. 
 
10. 
STUDY DATA COLLECTION AND MONITORING 
 
10.1 
Data Management 
 
Data management will be performed utilizing an electronic data capture system called 
REDCap. REDCap (Research Electronic Data Capture) is a secure, web-based 
application designed exclusively to support data capture for research studies.  
 
Security is provided through a table based authentication system where users are added to 
a project and are granted specific rights within the project(s) they have access to. These 
specific access rights consist of access to the study calendar, 3 levels (no access, de-
identified, full data set) of access to the Data Export Tool, access to the Data Import 
Tool, the Data Comparison tool (used when double-data entry is utilized), access to the 
complete logging records, the File Repository, User Rights (ability to add users and grant 
rights), access Data Access Groups, access to reports and the report builder, access for 
project setup and design, and a few more. Users can only access the specific projects they 
have been granted access to.  
 
The CTSI of Southeast Wisconsin’s REDCap installation is housed on a CTSI-owned 
server located in the TBRC Data Center at the Medical College of Wisconsin, and all 
traffic between the user’s browser and the server is encrypted with a 128-bit Digicert SSL 
certificate. The server OS is incrementally backed up nightly and rotated off-site. The 
database (MySQL) is backed up 4 times daily and is also part of the incremental nightly 
OS back up. 
 
The Data Access Groups feature within REDCap will be enabled for this project. This 
feature allows users to be designated into groups (sites), after which any user in the Data 
Access Group may only see records created by another person in that group. Thus, sites 
may enter patient data but not be allowed to see other site’s data/records. Only the CDCC 
will be able to view and analyze data entered from all site records. The data export 
function is included as part of the website. Once data has been successfully entered into 


 
 
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the database, the investigator and his/her staff can extract this data for different analysis 
software programs. 
 
Once an institution consents a patient, they will enter the patient demographics into the 
REDCap system which will assign a study ID. Centers will be required to upload the 
signed informed consent to the CDCC office via the REDCap database. Subsequent data 
will be entered via REDCap for review by the CDCC in the same manner.  The study 
coordinator will review the data reports with Dr. Burke within 24-72 hours  The overall 
study coordinator will follow-up with the institution if there are missing or delinquent 
data forms, and request submission within a timely manner. 
 
Any paper data (i.e. safety reports, reports generated from REDCap) will be kept in a 
locked and secure location within the Clinical Trials Office of the Pediatric 
Hematology/Oncology and Bone Marrow Transplant Program.  The Clinical Trials 
Office has secure, electronic employee badge access only. Any paper data that is 
generated and pertinent to the conduct of study, will be kept for 10 years after the study 
file is closed with the IRB.  
 
REDCap training will be provided by the MCW Clinical and Translational Science 
Institute (CTSI) to each participating site. 
 
For patients going on to transplant, the transplant related endpoints for this study will 
be collected by record review for 3 years post-transplant. 
 
10.2 
Case Report Forms 
 
Initial Plans:  Participant data will be collected using protocol specific case report 
forms developed by the MACC Fund Center CTO.   The CRFs will be approved by 
the study’s Principal Investigator and the Biostatistician prior to release for use.  The 
Study Coordinator or designee will be responsible for registering the patient at time of 
study entry, completing CRFs based on the patient specific calendar or roadmap, and 
updating the patient record until the end of required study participation. 
 
Implementation of REDCap:  Participant data will be collected using protocol specific 
electronic case report forms (e-CRFs) developed within REDCap based on its library of 
standardized forms.  The e-CRF will be approved by the study’s Principal Investigator 
and the Biostatistician prior to release for use.  The Study Coordinator or designee will be 
responsible for registering the patient into REDCap at time of study entry, completing e-
CRFs based on the patient specific calendar, and updating the patient record until the end 
of required study participation. 
 
10.3 
Data and Safety Monitoring Plan (DSMP) 
 
The study’s Data and Safety Monitoring Plan will be in compliance with the Medical 
College of Wisconsin Cancer Center's Data & Safety Monitoring Plan (DSMP), which 
can 
be 
accessed 
at 
http://www.mcw.edu/FileLibrary/Groups/HumanResearchProtectionOffice/IRB/Newan
d DraftPolicies/IRBSOPDSMP.pdf 
 


 
 
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This study will be reviewed by the Medical College of Wisconsin Cancer Center Data 
Safety Monitoring Committee (MCW CC DSMC). A summary of the MCW CC DSMC 
activities are as follows: 
 
 Review the clinical trial for data integrity and safety 
 Review all Grade 3 unexpected adverse events, all Grade 4 and 5 adverse events, 
and all events requiring expedited reporting as defined per protocol 
 Review all DSM reports 
 Submit a summary of any recommendations related to study conduct 
 Terminate the study if deemed unsafe for patients 
 
A copy of the MCW CC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee 
will review reports from the study PI twice annually (or more frequently if needed) and 
provide recommendations on trial continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required.  
 
For the purposes of data and safety monitoring, this study is classified as moderate 
risk. Therefore the following requirements will be fulfilled: 
 
 The PI will complete and submit a semi-annual Trial Progress Report to the MCW 
Cancer Center Data and Safety Monitoring Committee (DSMC) with the 
understanding the MCW DSMC may require more frequent reporting. 
 The PI will oversee the submission of all reportable events per the definition 
of reportable in Section 9.3 to the MCW Cancer Center’s DSMC and the MCW 
IRB. 
 
10.4    Monitoring 
 
The PI at each participating center is responsible for monitoring this study for accuracy of 
data and protocol compliance at their institution.  Patient eligibility will be confirmed by 
Dr. Michael Burke before each patient is enrolled. 
 
The PI, data coordinators, and research nurses are responsible for review and 
maintenance of all patient records at their individual institution to ensure data integrity 
and protocol adherence. 
 
The site PI will permit study-related monitoring, audits, and inspections by the 
MCW compliance groups, as necessary.  The investigator will make available all study 
related documents (i.e. source documents, regulatory documents, data collection 
instruments, study data, etc.).  The investigator will ensure the capability for inspections 
of applicable study-related facilities (i.e. pharmacy, diagnostic laboratory, etc.) will be 
available for trial related monitoring, audits, or regulatory inspections. 
 
10.5    Record Retention 
 
The investigator will retain study records including source data, copies of case report 
forms, consent forms, HIPAA authorizations, and all study correspondence in a secured 


 
 
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facility for 10 years after the study file is closed with the IRB. 
 
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the medical 
records for that patient.  Please contact the CTO before destroying any study related 
records. 
 
11. 
STATISTICAL CONSIDERATIONS 
 
This is a Phase 2 study designed for the purpose of estimating the key parameters for use 
in future studies and for estimating whether there is a difference between adult and 
pediatric response. 
 
11.1  Statistic Endpoints 
 
The following parameters will be monitored and used to estimate the effect sizes with 
their 95% confidence intervals. 
 
 The effect of Clofarabine, Cyclophosphamide, and Etoposide in eliminating the 
presence of persistent disease without causing a significant delay of HCT due to 
treatment related toxicity, defined as greater than 56 days from completion of 
bridging therapy to start of HCT.  The proportion of any toxicities associated 
with Clofarabine, Cyclophosphamide, and Etoposide 
 The proportion of pre-transplant chemotherapy-induced aplasia (defined as 
greater than 42 days after infusion of chemotherapy) 
 The proportion of infectious complications following bridging therapy and 
before HCT 
 The  proportion  of  patients  who  do  not  proceed  to  HCT  after  receiving  
bridging therapy due to disease status or treatment related morbidity/mortality 
 Treatment–related mortality at Day 100 after HCT 
 One year disease-free survival after HCT 
 One year overall survival after HCT 
 The proportion of relapse within one year of HCT 
 
11.2    Statistical Analysis 
 
SAS 9.4 (Cary, NC, USA) will be used for the statistical analyses.  The summary 
statistics including 95% confidence intervals for MRD negative conversion rate will be 
calculated. All toxicity and safety assessments will be presented in the data listings and 
summarized with point estimates and 95% confidence intervals. Proportions will use 
exact binomial confidence intervals. Overall survival and disease free survival estimates 
after HCT will use the Kaplan-Meier method.  The Nelson-Aalen counting process 
method will be used to estimate cumulative survival/relapse and the intensity of the 
process.  Relapse and treatment-related mortality after HCT will be estimated by 
competing risk analysis using the counting process approach. 
 
11.3 
Sample Size Justification 
 
This is a Phase 2 study designed for the purpose of estimating the following key 


 
 
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parameters for use in future studies and for estimating whether there is a difference 
between young adult and pediatric response: 1) The effect of CCE in eliminating the 
presence of MRD; 2) Whether CCE will significantly delay time to HCT due to treatment 
related toxicity; 3) The proportion of any toxicities associated with CCE; 4) The 
proportion of pre-transplant chemotherapy-induced aplasia (defined as greater than 42 
days after infusion of chemotherapy); 5) The proportion of infectious complications 
following bridging therapy and before HCT; 6) The proportion  of  patients  who  do  
not  proceed  to  HCT  after  receiving  bridging therapy due to disease status or treatment 
related morbidity/mortality; 7) Treatment–related mortality at Day 100 after HCT; 6) One 
year DFS after HCT; 7) One year OS after HCT; and 8) The proportion of relapse within 
1-year of HCT. Post-HCT outcomes (OS, EFS and Relapse) will be compared to 
historical controls for children, adolescent and young adults (separated by age; 0-18 and 
19-39 years) receiving a HCT for ALL or AML with pre-HCT MRD, using national and 
international data. 
 
11.4 
Early Stopping Rule for Excessive Toxicity (pre-HCT) and TRM (post-HCT) 
 
The complications and adverse events will be closely monitored in this study. Rates of 
grade 3 or greater non hematologic toxicity that does not resolve by day 56 following 
bridging therapy, such that patients are not able to proceed to HCT on time, that exceed 
10% will be considered unacceptable. The trial will be stopped for review if the Grade 3 
non-hematologic toxicity rate statistically exceeds 10%. Similarly, a pre-HCT toxic 
death rate attributed to the bridging therapy that exceeds p0=5% will be considered 
unacceptable. No formal statistical rule will be employed. Rather, if the crude proportion 
of patients experiencing a toxic death exceed 5% at any time (using the Kaplan-Meier 
curve and log-rank comparisons)  prior to HCT, the cause and circumstances of these 
deaths will be reviewed with the study committee and with the Data and Safety 
Monitoring Committee to determine whether modifications to or termination of the study 
is warranted..  As well, if we see a lack of efficacy in the ability of this regimen to 
eliminate MRD at 1/3 or 2/3 the total number of patients, the study will be suspended to 
consider dose escalation of clofarabine.   
 
Nth 
Patient 
Stopping 
Number 
Mortality 
Stopping 
Number 
Toxicity 
Nth 
Patient 
Stopping 
Number 
Mortality 
Stopping 
Number 
Toxicity 
1 
- 
- 
14 
3 
4 
2 
- 
- 
15 
3 
5 
3 
2 
2 
16 
3 
5 
4 
2 
2 
17 
4 
5 
5 
2 
3 
18 
4 
5 
6 
2 
3 
19 
4 
5 
7 
2  
3 
20 
4 
6 
8 
3 
3 
21 
4 
6 
9 
3 
3 
22 
4 
6 
10 
3 
4 
23 
4 
6 
11 
3 
4 
24 
4 
6 


 
 
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12 
3 
4 
25 
4 
7 
13 
3 
4 
 
 
 
 
12. 
CONDUCT OF THE STUDY 
 
12.1 
Good Clinical Practice 
 
The   study   will   be   conducted   in   accordance   with   the   appropriate   
regulatory requirement(s).  The investigator will be thoroughly familiar with the 
appropriate use of the drug as described in the protocol and Investigator’s Brochure.  
Essential clinical documents will be maintained to demonstrate the validity of the study 
and the integrity of the data collected.  Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according 
to the appropriate regulations. 
 
12.2 
Ethical Considerations 
 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients.  The study will 
only be conducted at sites where IRB approval has been obtained.  The protocol, 
informed consent, written information given to the patients, safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB by the 
investigator. 
 
12.3 
Informed Consent 
 
All potential study participants will be given a copy of the MCW IRB approved consent 
to review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant (or 
parents/guardians for a minor) decides to participate in the study, he/she will be 
asked to sign and date the consent document. Patients who refuse to participate or 
who withdraw from the study will be treated without prejudice. 
 
12.4 
Clinical Trial Registration 
 
A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as 
required by U.S. Law. This web site will not include information that can identify you. At 
most, the web site will include a summary of the results. You can search this web site at 
any time.  NCI Number:  NCT02349178 
 
 
 
 
 
 
 
 
 


 
 
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Tischer J, Stemmler HJ, Engel N, Hubmann M, Fritsch S, Prevalsek D et al. Feasibility of 
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APPENDIX 1 
Eligibility Checklist 
 
Eligibility Checklist – Page 1 of 2 
Patient Initials 
  
 
 
 
 
Patient ID 
 
 
Date Consent Form Signed: 
/
/
 
Diagnosis 
 ALL or 
 AML 
 
Inclusion Criteria 
A “NO” response to any of the following disqualifies the patient from study entry. 
 
 
 
Yes 
No 
1 
Diagnosis of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) with < 5% blasts in the 
bone marrow (M1) by morphology and that meets the following criteria: 
 Flow cytometric evidence of PD (≥ 0.01% leukemic blasts for ALL or ≥ 0.5% leukemic blasts for AML 
detected in the bone marrow) 
OR 
 Molecular/cytogenetic evidence of disease (FISH or PCR methodology) performed within 7 days and with the 
intent of going on to an allogeneic hematopoietic cell transplantation (HCT) independent of this study 
 
 
2 
Age 0 to 39 years 
 
 
3 
Karnofsky ≥ 50% for patients 16 years and older and Lansky status ≥ 50 for patients under 16 years of age               
Score - 
 
 
 
4 
Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator 
 
 
5 
Adequate organ function defined as within 7 days of the start of study treatment, unless otherwise noted 
 
Test 
Required Value 
Patient’s Result 
Date Performed 
Creatinine 
Creatinine clearance ≥ 60 mL/min/1.73m2 
OR serum creatinine based on age: 
 
Age (Yrs) 
Maximum Serum 
Creatinine (mg/dl) 
2 to < 6  
0.8    0.8 
6 to < 10  
1.0   1.0 
10 to < 13  
1.2    1.2 
13 to < 16  
1.5    1.4 
≥ 16  
1.7   1.4 
.
 
mL/min/1.73 m2 
 
OR 
 
.
 mg/dl 
/
/
 
Total 
Bilirubin 
≤ 1.5 x ULN for age 
.
 
/
/
 
ALT 
< 5 X ULN 
 
/
/
 
Cardiac 
Left ventricular ejection fraction ≥ 40% by 
ECHO/MUGA   
% 
/
/
 
 
 
6 
Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or 
radiotherapy prior to entering this study. At least 7 days must have elapsed from prior chemotherapy.  
Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor and at least 14 
days since pegfilgrastim (Neulasta®) administration. 
 
 
7 
Sexually active females of child bearing potential must agree to use adequate contraception (diaphragm, birth 
control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, 
etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy.  Sexually active men 
must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of 
chemotherapy. 
 
 


 
 
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8 
Voluntary written consent before performance of any study-related procedure not part of normal medical care, 
with the understanding that consent may be withdrawn by the subject/guardian at any time without prejudice to 
future medical care. 
 
 
 
APPENDIX 1 
Eligibility Checklist - Continued 
 
Eligibility Checklist – Page 2 of 2 
Patient Initials 
  
 
 
 
 
 
 
Exclusion Criteria 
A “Yes” response to any of the following disqualifies the patient from study entry. 
 
 
Yes 
No 
9 
Acute Promyelocytic Leukemia (APL) 
 
 
10 Active CNS leukemia or presence of chloromatous disease 
 
 
11 Receiving concomitant chemotherapy, radiation therapy; immunotherapy or other anti-cancer therapy other than 
is specified in the protocol 
 
 
12 Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms 
related to the infection and without improvement, despite appropriate antibiotics or other treatment) 
 
 
13 Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no 
information on the excretion of agents into breast milk. All females of childbearing potential must have a blood 
test or urine study within 2 weeks prior to registration to rule out pregnancy. 
 
 
14 Known allergy to any of the agents or their ingredients used in this study. 
 
 
 
Patient Given Copy of Consent:   
  Yes, Date ________________ 
 No 
 
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that 
this patient is:  
 
   _____  Eligible 
____ Ineligible 
Date Registered ____________ 
 
____________________________________________ 
Signature of Person Completing This Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX 2 
Performance Status Criteria 
 
 
For patients 16 years of age and older: 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 
 
For patients less than 16 years of age: 
 
Lansky Performance Scale 
Lansky 
Score 
Play Score 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play but able to 
participate in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX 3 
Response Criteria 
 
Modified RECIST 
 
Complete Remission (CR) 
CR requires that all of the following be present: 
 Peripheral Blood Counts 
o ANC count > 1,000/mm3 
o Platelet count > 100,000/mm3 
o Reduced hemoglobin concentration or hematocrit has no bearing on remission status 
o Leukemic blasts must not be present in the peripheral blood 
 Marrow Aspirate and Biopsy 
o Bone marrow biopsy must demonstrate tri-lineage hematopoiesis with maturation of 
all cell lines. 
o < 5% blasts 
 Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present. 
 
Morphological Remission (MR) 
MR requires that the following be present: 
 Patient meets all peripheral blood and bone marrow criteria for CR, except that platelet 
count is < 100,000/mm3 but > 50,000/mm3 
 
Minimal Residual Disease (MRD) Negativity 
 MRD negativity for ALL requires the following be present: 
o < 0.01% leukemic blasts by flow cytometry 
o Absence of cytogenetic and/or molecular evidence of disease if applicable 
 
 MRD negativity for AML requires the following be present: 
o < 0.5% leukemic blasts by flow cytometry 
o Absence of cytogenetic and/or molecular evidence of disease if applicable 
 
Relapse 
Relapse following CR is defined as: 
 Peripheral Blood Counts 
o Presence of peripheral blasts. A bone marrow examination must be performed to 
confirm relapse. However, please note that the date of relapse is the first date at 
which the relapsed patient had: leukemic blasts in the peripheral blood smear, or 
>5% blasts in the bone marrow. 
 Bone Marrow Aspirate or Biopsy 
o Presence of more than 5% blasts, not attributable to another cause (i.e. bone 
marrow regeneration). 
 
 
 
 


 
 
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APPENDIX 4 
Known and Expected Toxicities of Study Treatment 
 
Known Risks and Side Effects Related to the Clofarabine Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 A fast heartbeat which may 
cause pain in the chest 
 A feeling of extreme tiredness 
not relieved by sleep 
 A decrease in blood pressure  
 Pain in the abdomen (belly) 
 Constipation 
 Diarrhea 
 Nausea and/or vomiting 
 Headache 
 Fever which may also come 
with shaking chills 
 Anxiety 
 Fever with a low white blood 
cell count which could mean 
that you have an infection and 
might require hospitalization 
and treatment with antibiotics 
 Loss of appetite 
 Elevation in the blood of certain 
enzymes found in the liver 
which may mean the liver is not 
working as well as normal 
 Damage to the sac around the 
heart which can lead a build-up 
of fluid around the heart which 
may be painful and affect the 
ability of the heart to work 
normally but in most cases is 
only mild and temporary 
 Temporary change to the heart 
such that it does not pump the 
blood as well which may make 
you tired, weak, feel short of 
breath, and retain fluid 
 Skin rash with itching and 
redness or inflammation 
 Infections including those 
caused by bacteria, virus, and 
fungus and can be found in the 
lung, the blood, the skin and 
 Fluid build-up in the tissues 
 Pain or burning at the site of 
the injection 
 Dizziness 
 Sleepiness 
 Tremor (shakiness usually 
of the hands) 
 Changes to your emotions 
such that you feel 
depressed, anxious, irritable 
or confused 
 High blood pressure 
 Cough or shortness of 
breath 
 Reddening of the face with 
feelings of warmth when the 
drug is infusing 
 Sore throat 
 Inflammation and/or sores 
in the mouth (and/or throat 
and /or esophagus, the tube 
that leads from the mouth to 
the stomach) that may make 
swallowing difficult and are 
painful (painful mouth 
sores) 
 Pain including back or arm 
or leg pain 
 Enlarged liver which could 
lead to an elevation in the 
blood of bilirubin which is 
found in the liver and if 
present in large amounts can 
lead to a yellow appearing 
skin (jaundice) 
 Weight loss 
 Aches and pains in the 
muscles and joints 
 Bleeding from the bladder 
or gums 
 Fluid build-up in the lungs 
 The rapid death of large 
numbers of tumor cells 
which can cause the 
potassium and 
phosphate salts and the 
uric acid in the blood to 
rise quickly and this 
could lead to a life-
threatening irregular 
heart beat or damage to 
the kidneys. 
 Severe loss of water 
from the body 
(dehydration) which if 
untreated may cause low 
blood pressure and 
severe loss of salts such 
as sodium and 
potassium from the body 
and could lead to the 
kidneys failing which 
could be life-threatening 
 Capillary leak 
syndrome: A condition 
in which fluid and 
proteins leak out of tiny 
blood vessels and flow 
into surrounding tissues, 
resulting in dangerously 
low blood pressure. 
Capillary leak syndrome 
may lead to multiple 
organ failure such as 
kidney, heart or liver 
failure and shock. 
 Inflammation of the 
pancreas (an organ in 
the abdomen which 
produces insulin and 
certain digestive 
chemicals) which may 
affect the function of the 


 
 
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Known Risks and Side Effects Related to the Clofarabine Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
other places in the body 
 Bloody nose 
 Fewer white blood cells, red 
blood cells and platelets in the 
blood  
o a low number of white 
blood cells can make it 
easier to get infections 
o a low number of red blood 
cells can make you feel tired 
and weak 
o a low number of platelets 
causes you to bruise and 
bleed more easily 
that can make you feel short 
of breath 
 Severe rash with redness 
and pain on the palms of the 
hand and soles of the feet 
 Red spots on the skin from 
low platelets 
 High levels of uric acid in 
the blood which could 
damage the kidneys  
 Increased levels of a 
chemical (creatinine) in the 
blood which could mean 
kidney damage 
pancreas and which may 
cause pain in the 
abdomen (belly) which 
can be severe and may 
increase the blood sugar 
 
 
Known Risks and Side Effects Related to Cyclophosphamide Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 Loss of appetite 
 Nausea  
 Vomiting 
 Fewer white blood 
cells in the blood. 
○ a low number of 
white blood 
cells may make 
it easier to get 
infections. 
 Hair loss 
 Decreased ability of 
the body to fight 
infection  
 Absence or 
decrease in the 
number of sperm 
which may be 
temporary or 
permanent which 
may decrease the 
ability to have 
children 
 Abnormal hormone function which 
may lower the level of salt in the blood  
 Abdominal pain 
 Diarrhea 
 Fewer red blood cells and platelets in 
the blood 
○ a low number of red blood cells 
may make you feel tired and weak. 
○ a low number of platelets may 
cause you to bruise and bleed more 
easily. 
 Bleeding and inflammation of the 
urinary bladder 
 Absence or decrease monthly periods 
which may be temporary or permanent 
and which may decrease the ability to 
have children 
 Temporary blurred vision 
 Nasal stuffiness with IV infusions 
 Skin rash 
 Darkening of areas of the skin and 
finger nails 
 Slow healing of wounds 
 Infections  
 
Heart muscle damage 
which may occur with 
very high doses and 
which may be fatal 
 
Abnormal heart rhythms 
 
Damage and scarring of 
lung tissue which may 
make you short of breath 
 
A new cancer or leukemia 
resulting from this 
treatment. 
 
Damage or scarring of 
urinary bladder tissue 
 
Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure, rapid heart rate 
chills and fever 
 
Infertility which is the 
inability to have children 
 
 
Known Risks and Side Effects Related to Etoposide Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 Nausea and vomiting 
 
Loss of appetite 
 Damage to the liver 


 
 
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Known Risks and Side Effects Related to Etoposide Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 Hair loss 
 A feeling of weakness or 
tiredness 
 Fewer red and white 
blood cells and platelets 
in the blood  
o a low number of red 
blood cells can make 
you feel tired and 
weak 
o a low number of 
white blood cells can 
make it easier to get 
infections 
o a low number of 
platelets causes you 
to bruise and bleed 
more easily 
 
Decreased blood pressure 
during the infusion which 
may require treatment 
 
Rashes 
 
Diarrhea 
 
Pain in the abdomen 
 
Mouth sores 
 
Tingling sensation or loss 
of sensation in fingers or 
toes 
 
A feeling of  extreme 
tiredness or weakness 
 
The finger or toe nails may 
loosen from their nail beds 
 
Inflammation of the vein 
through which the 
medication was given 
 
Chest pain 
 Severe allergic reaction which can 
be life threatening with shortness 
of breath, low blood pressure, 
rapid heart rate, chills and fever 
 A new cancer or leukemia 
resulting from this treatment 
 Severe rashes which can result in 
loss of skin and damage to 
mucous membranes 
 Absence or decrease monthly 
periods which may be temporary 
or permanent and which may 
decrease the ability to have 
children 
 Damage to the heart muscle 
which may make you feel tired, 
weak, feel short of breath, and 
retain fluid 
 
There also may be other side effects that we cannot predict.  Many side effects go away 
shortly after the drugs are stopped, but in some cases side effects can be serious, long-
lasting, or permanent.  Other drugs may be given to make side effects less serious and 
uncomfortable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX 5 
 
Bridging Therapy Roadmap 
 
Drug 
Route 
Dosage 
Days 
Clofarabine  
IV over 2 hours 
20 mg/m2 
1-5 
Etoposide (ETOP) 
IV over 2 hours 
100 mg/m2 
1-5 
Cyclophosphamide (CYCLO) 
IV over 30 to 60 mins 
300 mg/m2 
1-5 
 
Drugs Given In This Order: 
Clofarabine 20 mg/m2 IV over 2 hours followed by 
Etoposide 100 mg/m2 IV over 2 hours followed by 
 
Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion 
 
Ht ____________ 
Wt. ___________ 
BSA ___________ 
Date 
Due 
Date 
Given 
Day 
Clofarabine 
______mg 
ETOP 
______mg 
CYCLO 
______mg 
 
 
1 
______mg 
______mg 
______mg 
 
 
2 
______mg 
______mg 
______mg 
 
 
3 
______mg 
______mg 
______mg 
 
 
4 
______mg 
______mg 
______mg 
 
 
5 
______mg 
______mg 
______mg 
 
 
6-28 
No Chemotherapy 
 
 
 

ICF_001.pdf: 
Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 1 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Medical College of Wisconsin and Froedtert Hospital 
PARENTAL CONSENT/CHILD ASSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
Bridging Study:  A Phase 2 Study Investigating Clofarabine, Cyclophosphamide and 
Etoposide for Children, Adolescents, and Young Adults (AYA) with Acute Leukemia and 
Minimal Residual Disease  
 
 
 
Michael J. Burke, MD 
Department of Pediatrics 
Division of Hematology/Oncology/BMT 
414-955-4570 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
 
Child/Adult Subject: You are invited to take part in this research study. This form tells you why 
this research study is being done, what will happen in the research study, possible risks and 
benefits to you, your choices, and other important information. If there is anything that you do 
not understand, please ask questions. Then you can decide if you want to join this study or not. If 
you are under 18, your parent or guardian also needs to give their permission for you to join this 
study. 
 
Parent/Guardian: Your child is invited to take part in this research study. This form tells you 
why this research study is being done, what will happen in the research study, and possible risks 
and benefits to your child. If there is anything you do not understand, please ask questions. Then 
you can decide if you want your child to join this study or not. 
The word “you” in this form refers to your child.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
 
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) remain two of the 
most common forms of leukemia diagnosed in both children and adults, as well as two of the 
most common hematological diseases for which allogeneic hematopoietic cell transplantation 
(HCT) is currently used. 
 
There is mounting evidence to support that for patients in hematological remission, the presence 
of minute amounts of leukemia (known as minimal residual disease (MRD), identified 
immediately prior to HCT is associated with higher rates of ALL and AML relapse following 
HCT. 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 2 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
We are asking if you want to participate in a research study of an experimental treatment 
intended to reduce pre-transplant disease burden by achieving a pre-transplant MRD negative 
state.  You are being asked to take part in this research study for the following reasons: 
 
 You have been diagnosed with high risk acute lymphoblastic leukemia (ALL) or acute 
myelogenous leukemia (AML); 
 Your planned treatment involves receiving an allogeneic hematopoietic cell 
transplantation (HCT); and 
 You have evidence of minimal residual disease (MRD) 
 
A total of about 50 people are expected to participate in this study at the following institutions: 
 
 Medical College of Wisconsin/Froedtert Hospital, Milwaukee, WI 
 Children’s Hospital of Wisconsin, Milwaukee, WI 
 Nationwide Children’s Hospital, Ohio 
 University of Wisconsin, Madison, WI 
 
We are expecting to treat about 25 children and adults at the Medical College of 
Wisconsin/Froedtert Hospital/Children’s Hospital of Wisconsin.  
 
The Director of the study is Michael J. Burke, MD in the Department of Pediatric Oncology, 
Hematology, and Bone Marrow Transplant.  A study team works with Dr. Burke. You can ask 
who these people are.  
 
A2. DO I HAVE TO BE IN THIS STUDY? 
 
You can decide whether to take part in this study or not. You are free to say yes or no. If you say 
no, your regular medical care will not change. Even if you join this study, you do not have to 
stay in it. You may stop at any time.  
 
A research study is different from routine medical care in three ways: 1) there are extra risks that 
we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) the 
study procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
 
The goal of this Phase 2 study is to assess the combination of Clofarabine, Cyclophosphamide, 
and Etoposide in their ability to lower MRD without causing toxicities which could possibly 
delay HCT.  We also want to learn if this treatment will prevent relapse and whether it will help 
high risk ALL/AML patients with MRD prior to HCT to live longer. 
 
Everyone in this study will receive a combination of Clofarabine, Cyclophosphamide, and 
Etoposide which are approved by the U.S. Food and Drug Administration for use in patients but 
not with your condition.  We don’t know if this study will help you. Your condition may get 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 3 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
better but it could stay the same or even get worse. We hope the information from this study will 
help us develop a better treatment for MRD prior to HCT in the future. 
 
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
 
Screening Procedures 
  
If you decide to join the study, you will need to have the following exams, tests or procedures to 
find out if you can be in the study.  These exams, tests or procedures are part of regular cancer 
care and may be done even if you do not join the study.  If you have had some of them recently, 
they may not need to be repeated.  This will be up to your study doctor.   
 
 A medical history 
 Physical exam including height and weight 
 Vital signs (blood pressure, pulse, temperature) 
 Blood tests to check various organ functions 
 Urine tests 
 Echocardiogram/MUGA 
 Pregnancy test (if you are a woman who could have children) 
 Performance status (Karnofsky or Lansky) 
 Bone marrow aspirate 
 
Note:  If you have recently had any of the required screening exam tests or X-rays as part of 
your routine medical care, your doctor will, whenever possible, use the results of the previously 
performed studies in determining your eligibility for this study. 
 
Tests on the Bone Marrow 
 
Examinations of the bone marrow will be performed routinely and may be done at the discretion 
of your study doctor.  You have already had many tests of your bone marrow for your previous 
treatment of AML or ALL.  Many children receive some form of sedation or anesthesia during 
this procedure.  A small area over your hip bone on the back will be cleaned and numbed with 
lidocaine and/or with an anesthetic cream.  Approximately 2 teaspoons of bone marrow will be 
withdrawn through a needle inserted into the bone.  The test is painful, especially when the bone 
marrow is withdrawn.  There is also a small risk of bleeding or infection from this procedure. 
 
If the screening information shows that you meet the requirements, then you will be able to start 
the study. If the screening information shows that you cannot be in the research study, the study 
doctors will discuss other options with you and/or refer you back to your regular doctor.  
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 4 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Summary of Study Procedures 
 
During the Study:  If the exams, tests and procedures show that you can be in the study, and 
you choose to take part, the administration of the study drugs will follow institutional drug and 
supportive care guidelines.   
 
Treatment Plan (Regardless of Diagnosis): A treatment cycle lasts about 28 days with the actual 
drugs all being given on Days 1 through 5.  Only 1 treatment course is permitted.  The treatment 
is summarized in the following table: 
 
Drug 
How The Drug Will Be Given? 
Day 
Clofarabine 
IV over 2 hours (given at Hours 0 to 2)  
1-5 
Etoposide 
IV over 2 hours (given at Hours 2 to 4) 
1-5 
Cyclophosphamide 
IV over 30-60 minute infusion (given at Hours 4 to 5) 
1-5 
 
The intent of this study design is for all patients to receive and complete one course of therapy.  
Patients who exhibit signs of disease progression or experience an unacceptable toxicity will be 
discontinued from treatment. 
 
Methods For Giving Drugs 
 
Various methods will be used to give drugs to subjects. 
 
 PO – Drug is given by tablet or liquid swallowed through the mouth. 
 IV – Drug is given using a needle or tubing inserted into a vein.  It can be given by IV 
push over several minutes or by infusion over minutes or hours. 
 IM – Drug is given using a needle injected into the muscle. 
 SQ – Drug is given by injecting a needle into the tissue just under the skin. 
 IT – Intrathecal - Drug used to treat the brain and spinal cord is given using a needle 
inserted into the fluid surrounding the spinal cord. 
 
Drugs given for this study will all be given by IV or through your Central Line as described 
below. 
 
Central Line 
 
For drugs to be given by vein, your doctor will likely recommend that you have a central venous 
line placed.  A central line is a type of tubing inserted into a large vein in the chest by a surgeon 
during a short operation.  The central line is used to administer chemotherapy drugs and to 
withdraw small amounts of blood for testing during treatment.  How the tubing is inserted and all 
the risks associated with central lines will be explained to you, and all of your questions about 
the central line will be answered, when you sign a separate consent for the central line.  A 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 5 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
description of the types of central lines is available at your local institution or in the COG Family 
Handbook for Children with Cancer.  
 
Medical Tests During Treatment 
 
While you are on study treatment the following standard medical tests will be done to monitor 
for response to therapy as well as side effects related to treatment.  These include the following 
and may be done more frequently because you are in the study. 
 
Daily Assessments and Labs (Day 1-5) 
 Physical exams with vital signs  
 Blood tests to check your organ function 
 
You will have regular medical appointments throughout treatment. 
 
Study Tests and Procedures 
 
The following tests will be done even if were not in this study because you are going on to 
HSCT.  You may have these tests done more frequently because you are in the study.   
 
Weekly Assessments and Labs (Day 6-30)  
 Physical exams with vital signs  
 Blood tests to check your organ function 
 
Bone Marrow Test:  A bone marrow evaluation to determine study response and remission 
status will be performed on study Day 30 or upon adequate blood count recovery, whichever 
occurs first.  If the marrow results show low cell counts, you may need to repeat this test at Day 
42.  Your doctor will let you know if you should repeat this test. 
 
Final Study Visit 
 
If you begin protocol therapy, you will be followed for safety monitoring until the start of a new 
therapy (i.e. transplant preparative regimen) or until Day 60, whichever occurs earlier.  Your 
doctor will need to check to see how you are doing.  The doctor will ask you how you feel, if you 
have trouble doing your daily routine, and what drugs you are taking.  You will also have the 
following tests done:  
 
Weekly Assessments and Labs (Day 30-60)  
 Physical exams with vital signs 
 Blood tests to check your organ function 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 6 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
B2. HOW LONG WILL I BE IN THE STUDY? 
 
Subjects in this clinical trial may receive one treatment course on this study.  After treatment, 
subjects will have follow-up examinations and medical tests.  
 
After completing the treatment on this study we would like to continue to collect some medical 
information about how you are doing for as long as you are willing to let us or until the study is 
closed to enrollment and all study activities have been completed.  We will collect information 
on how your AML or ALL and transplant care are doing, and what kind of therapy you may be 
getting.  By keeping in touch with you after you complete treatment, we can better understand 
the long-term effects of the study treatments. 
 
B3. CAN I STOP BEING IN THE STUDY?   
 
You are free to withdraw from the study at any time. If you leave, your regular medical care will 
not change. If you are thinking about leaving, please tell the study doctor.  
 
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 researcher may decide to take you off this study under the following 
circumstances: 
 
 
If he/she believes that it is in your best interest 
 Your disease does not improve or gets worse during treatment 
 You experience side effects from the treatment that are considered too severe 
 You need a treatment that is not allowed on this study 
 If new information becomes available that shows that another treatment would be better 
for you 
 You are not able to follow study-related treatment instructions 
 If the whole study is stopped 
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drugs can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE STUDY?  
 
If you become pregnant or father a child during this study, contact your doctor 
immediately to discuss the requirements for pregnancy outcome follow-up.   
 
Female subjects will be given instructions for discontinuation of study medication. 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 7 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
 
There are risks to taking part in any research study. There is a risk that the treatment plan will not 
cure the cancer or that the cancer can go away after the treatment and then come back at a later 
date. There also may be problems (side effects) we do not know about yet from the drugs given 
in this therapy, or how they combine with other drugs you are taking. If we learn about new 
important side effects, we will tell you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study doctor 
or a member of the study team immediately if you experience any problems, side effects, or 
changes in your health.   
 
C2. RISKS OF STUDY DRUGS 
 
The research drugs themselves may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.  Many go away soon after you stop 
taking the drug.  
 
Each drug may have a unique set of side effects.  Side effects related to drugs occur in people at 
different rates or frequencies.  The following tables (drug monographs) provide details of the 
known and expected side effects associated with the drugs given in this therapy.   
 
Risks and Side Effects Related to the Clofarabine Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 A fast heartbeat which may 
cause pain in the chest 
 A feeling of extreme tiredness 
not relieved by sleep 
 A decrease in blood pressure  
 Pain in the abdomen (belly) 
 Constipation 
 Diarrhea 
 Nausea and/or vomiting 
 Headache 
 Fever which may also come 
with shaking chills 
 Anxiety 
 Fever with a low white blood 
cell count which could mean 
that you have an infection and 
might require hospitalization 
and treatment with antibiotics 
 Loss of appetite 
 Fluid build-up in the 
tissues 
 Pain or burning at the site 
of the injection 
 Dizziness 
 Sleepiness 
 Tremor (shakiness usually 
of the hands) 
 Changes to your emotions 
such that you feel 
depressed, anxious, 
irritable or confused 
 High blood pressure 
 Cough or shortness of 
breath 
 Reddening of the face 
with feelings of warmth 
when the drug is infusing 
 Sore throat 
 The rapid death of large 
numbers of tumor cells 
which can cause the 
potassium and phosphate 
salts and the uric acid in 
the blood to rise quickly 
and this could lead to a 
life-threatening irregular 
heart beat or damage to 
the kidneys. 
 Severe loss of water from 
the body (dehydration) 
which if untreated may 
cause low blood pressure 
and severe loss of salts 
such as sodium and 
potassium from the body 
and could lead to the 
kidneys failing which 
could be life-threatening 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 8 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Risks and Side Effects Related to the Clofarabine Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 Elevation in the blood of certain 
enzymes found in the liver 
which may mean the liver is not 
working as well as normal 
 Damage to the sac around the 
heart which can lead a build-up 
of fluid around the heart which 
may be painful and affect the 
ability of the heart to work 
normally but in most cases is 
only mild and temporary 
 Temporary change to the heart 
such that it does not pump the 
blood as well which may make 
you tired, weak, feel short of 
breath, and retain fluid 
 Skin rash with itching and 
redness or inflammation 
 Infections including those 
caused by bacteria, virus, and 
fungus and can be found in the 
lung, the blood, the skin and 
other places in the body 
 Bloody nose 
 Fewer white blood cells, red 
blood cells and platelets in the 
blood  
o a low number of white 
blood cells can make it 
easier to get infections 
o a low number of red blood 
cells can make you feel tired 
and weak 
o a low number of platelets 
causes you to bruise and 
bleed more easily 
 Inflammation and/or sores 
in the mouth (and/or 
throat and /or esophagus, 
the tube that leads from 
the mouth to the stomach) 
that may make 
swallowing difficult and 
are painful (painful mouth 
sores) 
 Pain including back or 
arm or leg pain 
 Enlarged liver which 
could lead to an elevation 
in the blood of bilirubin 
which is found in the liver 
and if present in large 
amounts can lead to a 
yellow appearing skin 
(jaundice) 
 Weight loss 
 Aches and pains in the 
muscles and joints 
 Bleeding from the bladder 
or gums 
 Fluid build-up in the lungs 
that can make you feel 
short of breath 
 Severe rash with redness 
and pain on the palms of 
the hand and soles of the 
feet 
 Red spots on the skin 
from low platelets 
 High levels of uric acid in 
the blood which could 
damage the kidneys  
 Increased levels of a 
chemical (creatinine) in 
the blood which could 
mean kidney damage 
 Capillary leak syndrome: 
A condition in which fluid 
and proteins leak out of 
tiny blood vessels and 
flow into surrounding 
tissues, resulting in 
dangerously low blood 
pressure.  Capillary leak 
syndrome may lead to 
multiple organ failure 
such as kidney, heart or 
liver failure and shock. 
 Inflammation of the 
pancreas (an organ in the 
abdomen which produces 
insulin and certain 
digestive chemicals) 
which may affect the 
function of the pancreas 
and which may cause pain 
in the abdomen (belly) 
which can be severe and 
may increase the blood 
sugar 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 9 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Risks and Side Effects Related to Cyclophosphamide Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 Loss of appetite 
 Nausea  
 Vomiting 
 Fewer white blood cells 
in the blood. 
○ a low number of 
white blood cells 
may make it easier 
to get infections 
 Hair loss 
 Decreased ability of the 
body to fight infection  
 Absence or decrease in 
the number of sperm 
which may be 
temporary or 
permanent which may 
decrease the ability to 
have children 
 Abnormal hormone function which 
may lower the level of salt in the blood 
 Abdominal pain 
 Diarrhea 
 Fewer red blood cells and platelets in 
the blood 
○ a low number of red blood cells 
may make you feel tired and weak 
○ a low number of platelets may 
cause you to bruise and bleed more 
easily 
 Bleeding and inflammation of the 
urinary bladder 
 Absence or decrease monthly periods 
which may be temporary or permanent 
and which may decrease the ability to 
have children 
 Temporary blurred vision 
 Nasal stuffiness with IV infusions 
 Skin rash 
 Darkening of areas of the skin and 
finger nails 
 Slow healing of wounds 
 Infections  
 
Heart muscle damage 
which may occur with 
very high doses and 
which may be fatal 
 
Abnormal heart 
rhythms 
 
Damage and scarring 
of lung tissue which 
may make you short 
of breath 
 
A new cancer or 
leukemia resulting 
from this treatment. 
 
Damage or scarring of 
urinary bladder tissue 
 
Severe allergic 
reaction which can be 
life threatening with 
shortness of breath, 
low blood pressure, 
rapid heart rate chills 
and fever 
 
Infertility which is the 
inability to have 
children 
 
Risks and Side Effects Related to Etoposide Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
 Nausea and vomiting 
 Hair loss 
 A feeling of weakness or 
tiredness 
 Fewer red and white blood 
cells and platelets in the blood  
o a low number of red blood 
cells can make you feel 
tired and weak 
o a low number of white 
blood cells can make it 
easier to get infections 
o a low number of platelets 
causes you to bruise and 
 
Loss of appetite 
 
Decreased blood 
pressure during the 
infusion which may 
require treatment 
 
Rashes 
 
Diarrhea 
 
Pain in the abdomen 
 
Mouth sores 
 
Tingling sensation or 
loss of sensation in 
fingers or toes 
 
A feeling of  extreme 
tiredness or weakness 
 Damage to the liver 
 Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure, rapid heart rate, 
chills and fever 
 A new cancer or leukemia 
resulting from this treatment 
 Severe rashes which can 
result in loss of skin and 
damage to mucous 
membranes 
 Absence or decrease 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 10 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Risks and Side Effects Related to Etoposide Include Those Which Are: 
Likely 
Less Likely 
Rare But Serious 
bleed more easily 
 
 
 
The finger or toe nails 
may loosen from their 
nail beds 
 
Inflammation of the vein 
through which the 
medication was given 
 
Chest pain 
monthly periods which may 
be temporary or permanent 
and which may decrease the 
ability to have children 
 Damage to the heart muscle 
which may make you feel 
tired, weak, feel short of 
breath, and retain fluid 
 
There also may be other side effects that we cannot predict.  Many side effects go away shortly 
after the drugs are stopped, but in some cases side effects can be serious, long-lasting, or 
permanent.  Other drugs may be given to make side effects less serious and uncomfortable.  
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
 
Risks of Blood Drawing  
 
Risks associated with drawing blood are slight, but some risks include: pain, excessive bleeding, 
and bruising around the needle stick site, fainting or feeling lightheaded, infection (a slight risk 
any time the skin is broken), and multiple punctures to locate veins.  If you do not have an 
indwelling venous catheter (i.e. an IV), a topical anesthetic cream (numbing cream/lotion) can be 
used to decrease the discomfort of blood drawing.  The procedure will be performed with sterile 
preparation (clean the skin with alcohol or iodine wipes) at the site of the blood draw and a band 
aid will be applied at this site to prevent any additional bleeding. 
 
Bone Marrow Examination Risks 
 
The test may be painful.  There is also a small risk of infection or bleeding.  The pain normally 
lessens within minutes to hours. 
 
C4. REPRODUCTIVE RISKS 
 
Risks to Women Who Could Become Pregnant:  The drugs in this study might affect a baby, 
before or after the baby is born. We do not know if the drugs cause harm to a baby, so we do not 
want anyone who might be pregnant to enter the study. You should not become pregnant or 
nurse a baby while in this study. You will be asked to have a pregnancy test to be sure you are 
not pregnant at the start of the study.  
 
If you become pregnant or father a child during this study, contact your doctor 
immediately to discuss the requirements for pregnancy outcome follow-up.   
 
Female subjects will be given instructions for discontinuation of study medication. 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 11 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Risks of Fathering a Child:  You should not father a baby while taking part in this study 
because it is unknown if the drugs in this study could affect a baby. If your partner is able to 
become pregnant, one or both of you must use some form of effective birth control.  You must 
tell the study doctor right away if you think your partner is pregnant. 
 
Birth Control Methods for all Subjects:  Check with the study doctor about the birth control 
methods needed for this study and how long to use them. Some methods might not be good 
enough for this study. If you are having sex that could lead to pregnancy, you should use birth 
control while you are in this study.  This may include: 
 
 Not having vaginal sex (abstinence) 
 Taking birth control pills orally 
 Having birth control shots or patches such as Depo-Provera 
 Surgical sterilization (hysterectomy or tubal ligation) 
 Use of an intrauterine device (IUD) 
 Use of diaphragm with contraceptive jelly 
 Use of condoms with contraceptive foam 
 Use of diaphragm with condoms (“double barrier”) 
 Limiting sexual activity to a male partner who has had a vasectomy 
 
You should continue using birth control for 2 months after stopping the study treatment. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
We don’t know if this study will help you. Your condition may get better but it could stay the 
same or even get worse. We hope the information from this study will help us remove MRD 
prior to going on to HCT but this is not guaranteed.  Your cancer may not have any response to 
the therapy received while participating in this study. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
 
Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  Some third party payers (insurance companies, HMOs, etc.) 
may not pay for hospitalization, treatments or procedures which are determined to be 
experimental or research related.  The study has no plans to pay for medical treatment.   
 
The health care costs during your participation in this study that are considered part of the 
standard treatment of your disease will be billed to your insurance or other third-party payer.  
This includes blood tests, hospitalizations, procedures that will be done, and medications.  All 
costs not paid by your insurance will be your financial responsibility.  Please ask about any 
expected added costs or insurance problems.  Financial Counselors are available to discuss 
insurance, costs and other issues.   
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 12 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout.  You can print a copy 
of the Clinical Trials and Insurance Coverage information from this Web site.   
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy of Clinical Trials and Insurance Coverage. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
 
There are no plans for you to receive payment for participating in this study.   
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
 
You do not have to join this study. You are free to say yes or no. If you do not join this study, 
your doctor can discuss other healthcare choices with you. Most treatment plans have used drugs 
similar to those used in this protocol, although these drugs may be given in different 
combinations, and at different times.  You can receive other combinations of chemotherapy 
without participating in this study.   
 
As an alternative to this study, you may decide you don’t want additional treatment for your 
relapsed leukemia.  You will always receive medicines to help you feel more comfortable and 
deal with problems caused by your cancer or treatment whether you participate in this study or 
not. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 
 
If we learn any important new information about the drugs used in this study that might change 
your mind about being in the study, we will tell you about it right away.  You can then decide if 
you want to stay in the study. 
 
D5. WHAT HAPPENS IF I AM HARMED BECAUSE I TOOK PART IN THE STUDY?  
 
No funds have been set aside to pay any costs if you become ill or are harmed because of this 
study. If you think that you have become ill or were harmed because of this study, let the study 
doctors know right away by calling the Principal Investigator at your participating institution.  
The institutions and their responsible investigators are listed below.  By signing this form, you 
do not give up your right to seek payment for harm you receive while participating in this study. 
 
Institution 
 
 
 
 
 
 
Contact Information 
 
Children’s Hospital of Wisconsin 
 
 
 
Dr. Michael Burke 
Milwaukee, WI 
 
 
 
 
 
414-955-4170 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 13 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
Froedtert Lutheran Memorial Hospital 
 
 
Ehab L. Atallah, MD 
Milwaukee, WI 
 
 
 
 
 
414-825-4600 
 
University of Wisconsin, Madison 
 
 
 
Neha J. Patel, MD 
Madison, WI  
 
 
 
 
 
608-263-8554 
 
Nationwide Children’s Hospital 
 
 
 
Susan Vear, MD 
Columbus, OH 
 
 
 
 
 
614-722-3583 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
 
If you have more questions about this study at any time, you can call the Principal 
Investigator at your participating institution at the same contact information given in the 
previous section (Section D5). 
 
If you have questions about your rights as a study participant, want to report any problems 
or complaints, obtain information about the study, or offer input, you can call the 
MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
 
To do this research study, we need your permission to collect and use some of your health 
information, or you cannot be in the study. This information may come from questions we ask, 
forms we ask you to fill out, or your medical record, as described below. We will only collect 
and use information needed for the study.  
 
The health information to be collected and used for this study is:  
 
 Medical records of the care you receive for this study and the results of previous tests, 
exams, and procedures relating to the condition you are being treated for. 
 
E2. Who will see the health information collected for this study? 
 
The only MCW/Froedtert Hospital/Children’s Hospital of Wisconsin employees allowed to 
handle your health information are those on the study team, those on the Institutional Review 
Board (IRB) and those who check on the research activities to make sure the hospital’s rules are 
followed. 
 
The study team may share your information with people who don’t work at MCW/Froedtert 
Hospital/Children’s Hospital of Wisconsin because they planned, pay for, or work with us on this 
study.  The federal Privacy Rule may no longer protect your health information once it leaves 
MCW/Froedtert Hospital/Children’s Hospital of Wisconsin.  For this study, we plan to share 
information with those doctors, researchers or government representatives working with us on 
this study at the institutions or companies listed here: 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 14 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
 
 U.S. Food and Drug Administration, Rockville, MD     
 Multisite Coordinating Center - MCW/Froedtert Hospital Research/Children’s Hospital 
of Wisconsin, Milwaukee, WI 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record or your 
applicable treating institution such as:  
 
 Children’s Hospital of Wisconsin 
 Nationwide Children’s Hospital  
 University of Wisconsin, Madison, medical record.   
 
As a result, this research information may be seen by people allowed to see your medical records 
for healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 
We will not use your personal health information for a different study without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed, the information might be used or released for other purposes without asking you. 
Results of the study may be presented in public talks or written articles, but no information will 
be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
 
One risk of taking part in a research study is that more people will handle your personal health 
information collected for this study. The study team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
 
If you sign this form, we plan to keep your information for 10 years after the research study ends 
and the study file is closed with the IRB in case we need to check it again for this study. 
 
E5. Can I cancel my permission to share this health information? 
 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to the Principal Investigator at your treating institution. The letter must say 
that you have changed your mind and do not want the researcher to collect and share your health 
information. At that time, we may decide that you cannot continue to be part of the study. We 
may still use the information we have already collected.  
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 15 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
F1. FOR MORE INFORMATION ABOUT THE STUDY 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
You can look up this study by referring to the ClinicalTrials.gov number (NCT02349178) or by 
asking the study team for a printed copy.    
 
CONSENT/ASSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
 
 I have read (or had read to me) this entire consent document.  All of my questions have been 
answered to my satisfaction. 
 The study’s purpose, procedures, risks and possible benefits have been explained to me.   
 I agree to let the study team use and share the health information and other information 
gathered for this study. 
 I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
Date or Date & Time: Time on subject’s line is optional to include; if included in template, 
must be completed by each subject. 
 
 
 
Child/Subject's Name please print 
Child/Subject's Signature
Date    
 
 
 
Parent’s/Guardian’s Name please print  
Parent’s/Guardian’s Signature 
Date    
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 
 
 
 
Name of Witness (if applicable) please 
print  (for short form consent process, or 
consent of blind or illiterate subject) 
Signature of Witness 
 
Date 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A (Consent/Assent) - Version: September 04, 2015  
IRB Protocol Number: PRO 22848  
IRB Approval Period: 9/12/2016 – 9/11/2017  
Consent – Froedtert/Children’s Hospital of Wisocnsin 
Page 16 of 16 
Protocol v5 – 02/08/2016 
EFFECTIVE 
 
9/12/2016 
 
MCW/FH IRB
 
 
 
 
 
* Name of Person Discussing/ 
Obtaining Consent please print  
Signature of Person 
Discussing/Obtaining Consent
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study. 
 
 
 
 
Name of Principal Investigator              
please print  
__ I participated in consent process 
__ I acknowledge enrollment of this 
subject into the study 
Signature of Principal Investigator 
Date