Conditions: Leukemia Acute Myelogenous Leukemia Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The purpose of the first part of this study is to establish the maximum tolerated dose (MTD) of oral ciprofloxacin when given in combination with a fixed dose of oral etoposide in patients with resistant acute myeloid leukemia (AML). The purpose of the second part of this study is to determine if the established dose of oral ciprofloxacin in combination with oral etoposide is effective in the treatment of patients with resistant AML.

Detailed description:
This study will look at: any side effects that occur, the effectiveness of the study drug, and how your disease reacts to ciprofloxacin in combination with etoposide. This study will try to find the highest tolerated dose of ciprofloxacin without causing serious side effects.

Ciprofloxacin is a commonly used antibiotic drug that is approved for use by the United States Food and Drug Administration (FDA). The FDA has not approved ciprofloxacin to treat AML. Etoposide is an anticancer chemotherapy drug that is approved for use by the FDA for the treatment of small cell lung cancer and testicular cancer. Etoposide is also used for treatment of various blood cancers.

There is laboratory research that has shown that ciprofloxacin can make leukemia cells more sensitive to etoposide chemotherapy. This observation indicates that ciprofloxacin may help improve the effectiveness of etoposide in the treatment of resistant AML.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Ciprofloxacin 750 MG intervention 2: Etoposide intervention 3: Ciprofloxacin 1000 MG intervention 4: Ciprofloxacin 500 mg
Intervention descriptions: intervention 1: 750 mg ciprofloxacin will be taken orally twice daily on Days 1 to 10 of each 28-day cycle. intervention 2: Etoposide 200 mg will be taken orally once daily on Days 2 to 8 of each 28-day cycle. intervention 3: 1000 mg ciprofloxacin will be taken orally twice daily on Days 1 to 10 of each 28-day cycle. intervention 4: 500 mg ciprofloxacin will be taken orally twice daily on Days 1 to 10 of each 28-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
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Version 6.1 
 
A Phase Ib/II Clinical Trial of Oral Ciprofloxacin and Etoposide in Subjects with Resistant 
Acute Myeloid Leukemia (AML) 
 
 
Protocol Number: 
 
 
UF-HEM-005 
Principal Investigator:  
 
Randall A. Brown, M.D. 
University of Florida 
1600 SW Archer Road 
Box 100278 
Gainesville, FL 32610-0278 
Email: randy.brown@medicine.ufl.edu 
Office: 352-273-7832 
Statistical Support:                           Ji-Hyun Lee 
                                                            Director, Division of Quantitative Sciences  
University of Florida Health Cancer Center 
Professor, Department of Biostatistics 
University of Florida  
Gainesville, FL 
Email: jihyun.lee@ufl.edu 
Phone: 352-273-9079 
 
Clinical Phase: 
 
 
Ib/II 
 
Date of Original Protocol:  
April 5, 2016 
 
Date of Current Protocol:  
January 30, 2020 
 
Version of Current Protocol: 
6.1  
 
Protocol Management: 
      
UFHCC Project Management Office 
 
 
 
 
      
PMO@cancer.ufl.edu 
     
IND:                                     
#130395  
 
Investigational Agent(s):  
            Etoposide (VP-16), Ciprofloxacin  
             
PROTOCOL REVISION   
Version 6.0 dated 08NOV2019 
RECORD:  
 
 
 
Version 5.0 dated 28MARCH2019 
 
 
 
 
 
Version 4.0 dated 07JAN2019 
 
 
 
 
 
Version 3.0, dated 08MAY2018 
 
 
 
 
 
Version 2.0, dated 19JUNE2017 
 
 
 
 
 
Version 1.0, dated 05APR2016 
                                                                              
 


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Keywords: 
Etoposide (VP-16), Ciprofloxacin, Metnase inhibitor, 
Resistant AML, Maximum Tolerated Dose, changes in 
chromosomal karyotype, somatic mutations  
 
 
 
 
 
 
 
 
 
 


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 Table of Contents 
1. 
BACKGROUND AND RATIONALE ................................................................................. 14 
1.1 
Management of Resistant Acute Myeloid Leukemia (AML) ........................................ 14 
1.2 
Etoposide (VP-16) in AML ............................................................................................ 14 
1.3 
Metnase: A DNA Repair Component Mediates Resistance to Topo II Inhibitors ......... 14 
1.4 
Proposal: Treatment of Resistant AML with Etoposide and Ciprofloxacin .................. 15 
2. 
OBJECTIVES ....................................................................................................................... 15 
2.1 
Primary ........................................................................................................................... 15 
2.2 
Secondary ....................................................................................................................... 15 
3. 
STUDY DESIGN.................................................................................................................. 16 
3.1 
Overview ........................................................................................................................ 16 
3.2 
Rationale for Drug Doses and Schedule ........................................................................ 16 
3.2.1 
Etoposide................................................................................................................. 16 
3.2.2 
Ciprofloxacin .......................................................................................................... 16 
3.3 
Phase Ib .......................................................................................................................... 17 
3.3.1 
Dose Escalation and De-Escalation ........................................................................ 17 
3.3.2 
Dose Limiting Toxicity ........................................................................................... 18 
3.4 
Phase II ........................................................................................................................... 18 
3.5 
Study Duration ............................................................................................................... 19 
3. 
SELECTION OF SUBJECTS............................................................................................... 19 
3.1 
Number of Subjects ........................................................................................................ 19 
3.2 
Inclusion Criteria ............................................................................................................ 19 
3.3 
Exclusion Criteria ........................................................................................................... 20 
4. 
STUDY TREATMENT ........................................................................................................ 20 
4.1 
Etoposide and Ciprofloxacin .......................................................................................... 20 
4.2 
Treatment Duration ........................................................................................................ 21 
4.3 
Supportive Care .............................................................................................................. 22 
4.4 
Management of Toxicity ................................................................................................ 22 
4.4.1 
Non- Hematologic Toxicity .................................................................................... 22 
4.4.2 
Hematologic (Blood/Bone Marrow) Toxicity ........................................................ 23 
5. 
PRIOR AND CONCOMITANT MEDICATIONS .............................................................. 23 
5.1 
Prior Medications and Therapy ...................................................................................... 23 
5.2 
Concomitant Medications and Therapy ......................................................................... 23 
6. 
STUDY PROCEDURES ...................................................................................................... 25 


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6.1 
Screening Procedures ..................................................................................................... 25 
6.2 
On-Study Evaluations .................................................................................................... 26 
6.3 
Treatment Discontinuation ............................................................................................. 28 
6.4 
Follow up/Survival ......................................................................................................... 28 
7. 
DATA MEASUREMENTS AND METHODS OF COLLECTION ................................... 29 
7.1 
Data Measurements ........................................................................................................ 29 
7.1.1 
Safety Data .............................................................................................................. 29 
7.1.2 
Efficacy Data .......................................................................................................... 29 
7.2 
Collection Methods ........................................................................................................ 29 
7.2.1 
Bone Marrow Samples ............................................................................................ 29 
7.2.2 
Safety Measurements .............................................................................................. 29 
7.2.3 
Adverse Events ....................................................................................................... 29 
7.2.4 
Clinical laboratory assessments .............................................................................. 30 
7.2.5 
Physical Examination, Vital Signs and ECG .......................................................... 30 
8. 
ADVERSE EVENTS ............................................................................................................ 30 
8.1 
Definitions ...................................................................................................................... 30 
8.1.1 
Adverse Event ......................................................................................................... 30 
8.1.2 
Serious Adverse Event ............................................................................................ 31 
8.1.3 
Non-Serious Adverse Event .................................................................................... 32 
8.2 
Period of Observation..................................................................................................... 32 
8.3 
Documenting and Reporting of Adverse Events by Investigator ................................... 32 
8.3.1 
Assessment of Causal Relationship of Study Drug ................................................ 32 
8.3.2 
Intensity of Adverse Events .................................................................................... 33 
8.3.3 
Action Taken with Study Drug ............................................................................... 33 
8.3.4 
Definition of Outcome ............................................................................................ 34 
8.4 
Immediately Reportable Events ..................................................................................... 34 
8.4.1 
Serious Adverse Events .......................................................................................... 34 
8.4.2 
Other Events Requiring Immediate Reporting ....................................................... 34 
9. 
DISCONTINUATION .......................................................................................................... 35 
9.1 
Discontinuation of Subjects ........................................................................................... 35 
9.2 
Replacement of Subjects ................................................................................................ 35 
9.3 
Study Stopping Rules ..................................................................................................... 35 
10. 
DATA AND SAFETY MONITORING ............................................................................ 35 
11. 
STATISTICAL METHODS .............................................................................................. 37 


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11.1 Determinations of Sample Size ...................................................................................... 37 
11.2 Analysis Populations ...................................................................................................... 37 
11.2.1 Safety Population .................................................................................................... 37 
11.2.2 Dose Limiting Toxicity Evaluable Population (Phase Ib) ...................................... 37 
11.2.3 Efficacy Evaluable Population ................................................................................ 38 
11.3 Analysis Methods ........................................................................................................... 38 
11.3.1 Safety ...................................................................................................................... 38 
11.3.2 Efficacy ................................................................................................................... 38 
12. 
EMERGENCY PROCEDURES ........................................................................................ 38 
12.1 Emergency Contact ........................................................................................................ 38 
12.2 Emergency Identification of Investigational Products ................................................... 38 
12.3 Emergency Treatment .................................................................................................... 39 
13. 
ADMINISTRATIVE CONSIDERATIONS ...................................................................... 39 
13.1 Good Clinical Practice ................................................................................................... 39 
13.2 Delegation of Investigator Responsibilities ................................................................... 39 
13.3 Subject Information and Informed Consent ................................................................... 39 
13.4 Confidentiality ................................................................................................................ 39 
13.5 Protocol Amendments .................................................................................................... 40 
13.6 Record Retention ............................................................................................................ 40 
14. 
APPENDIX ........................................................................................................................ 41 
14.1 Appendix A: AML Response Criteria According to IWG ............................................. 42 
14.2 Appendix B: ECOG Performance Status ....................................................................... 43 
14.3 Appendix C: Medications That Can Prolong QTc (Non-Comprehensive) .................... 44 
14.4 Appendix D: Statistical Characteristics of the “3+3” Design ........................................ 45 
15. 
REFERENCES .................................................................................................................. 46 
 
 
 


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ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine transaminase (also SGPT) 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
AST 
aspartate transaminase (also SGOT) 
AUC 
area under curve 
AUC(0-t) 
area under the plasma concentration-time curve from time zero to time t 
AUC(0-∞) 
area under the plasma concentration-time curve from time zero to infinity 
AUC(0-Tlast) 
area under the plasma concentration-time curve from time zero to the last 
measurable time point 
BAD 
biologically active dose 
BSA 
body surface area 
BUN 
blood urea nitrogen 
C 
cycle 
CBC 
complete blood count 
CL 
clearance 
CLBoralB 
apparent clearance after oral administration 
CBmaxB 
maximum plasma concentration 
CMP 
comprehensive metabolic panel 
CR 
complete remission 
CRi 
complete remission (with incomplete blood counts) 
CRp 
complete remission (with incomplete platelet recovery) 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
DISC 
Data Integrity and Safety Committee 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMD 
extramedullary disease 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GI 
gastrointestinal  
HI 
HMA 
hematologic improvement (see Appendix D) 
Hypomethylating agent  
ICF 
informed consent form 


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ICH 
International Conference on Harmonization 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IV 
intravenous 
IWG 
International Working Group 
Ke 
elimination rate constant 
LC-MS/MS 
high performance liquid chromatography/tandem mass spectrometry 
LDH 
lactic dehydrogenase 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS 
myelodysplastic syndromes 
mg 
milligram  
MTD 
maximum tolerated dose 
NOAEL 
no observed adverse effect level 
OS 
overall survival 
PCR 
polymerase chain reaction 
PFS 
progression free survival 
PI 
principal investigator 
PML 
promyelocytic leukemia 
PR 
partial remission 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
RBC 
red blood cells 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
serum glutamic pyruvate transaminase (also ALT) 
t½ 
terminal elimination half-life 
Tmax 
time to maximum plasma concentration 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell  
WHO 
World Health Organization 
 
 
 


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PROTOCOL SYNOPSIS 
 
Title: 
A Phase Ib/II Clinical Trial of Oral Ciprofloxacin and Etoposide in 
Subjects with Resistant Acute Myeloid Leukemia (AML) 
Rationale: 
There is a paucity of treatment options for subjects with resistant AML. 
Recently AML has been shown to be a multi-genetic disease with sub-
clonal architecture that evolves spontaneously and in response to 
treatment. Chemotherapy-resistant leukemic clones can quickly gain 
dominance by “survival of the fittest” dynamics. One way of targeting 
minor yet resistant clones is to augment the effectiveness of current 
chemotherapy drugs. Hromas et al. discovered the importance of the 
Metnase complex in repairing chemotherapy related DNA damage in 
leukemia and other cancers (1-3). Screening studies identified 
ciprofloxacin as a Metnase inhibitor that chemosensitizes leukemic 
myeloblasts to etoposide chemotherapy (4). The non-overlapping 
toxicity profiles of ciprofloxacin and etoposide, and their additive 
effectiveness in this model, make these agents attractive candidates for 
use in combination in subjects with resistant AML.  
Primary 
Objective: 
In subjects with resistant AML, to  
• Phase 1b: 
Establish the maximum tolerated dose (MTD) of oral ciprofloxacin 
when given in combination with a fixed dose of oral etoposide to 
subjects with resistant AML.   
• Phase II:   
Determine the complete response (CR, CRi, and CRp, see Appendix A) 
rate to treatment with ciprofloxacin and etoposide at the MTD in adults 
with resistant AML.  
Secondary 
Objectives: 
In subjects with resistant AML, to 
• Determine the safety and feasibility of treatment with oral 
ciprofloxacin and etoposide;   
• Measure duration of complete response, of progression free 
survival and of overall survival following treatment with oral 
ciprofloxacin and etoposide; and  
• Estimate the incidence of Grade ≥ 3 adverse events following 
treatment with ciprofloxacin and etoposide.  
Study Design: 
This is an open-label, single arm, Phase Ib/II study of oral 
ciprofloxacin and etoposide in subjects with resistant AML. This study 
is designed to evaluate the complete response rate, the safety profile, 
and biologic activity of the combination of oral ciprofloxacin and 
etoposide in subjects with resistant AML. For both study phases, all 
subjects will receive 1 cycle of induction.  At the end of Cycle 1, 
subjects who demonstrate progressive disease will have completed 
study treatment.  For any subject who demonstrates stable disease or a 


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partial response, a second cycle of induction will be given.  No subject 
will receive more than 2 cycles of induction. 
Phase Ib: 
In the Phase Ib portion of the study, subjects will be enrolled in 
cohorts of three (3) in a traditional 3+3 study design (5). The starting 
dose is level “0” and includes: ciprofloxacin 750 mg orally twice daily 
on Days 1 - 10 and etoposide 200 mg orally once daily on Days 2 – 8.  
During the first cycle of treatment, subjects will be individually 
assessed for safety and dose limiting toxicity (DLT) for the purpose of 
determining the MTD of ciprofloxacin.  The MTD will be defined as 
the highest dose of ciprofloxacin at which < 33% of the subjects treated 
at a given dose level experience a DLT (See Figure 1). The Phase Ib 
portion of this study ends when a MTD is identified among the three 
planned dose levels (See Table 2).  
Subjects withdrawn before Cycle 1 Day 1 (C1D1) will not be evaluable 
for dose escalation decisions and will be replaced in their treatment 
cohort.  A subject is evaluable for dose-escalation decisions provided: 
they receive all drug doses and remain on study until evaluation at 
Cycle 1 Day 28 without a DLT; or they experience a DLT during Cycle 
1.  Subjects who miss any etoposide or ciprofloxacin doses or withdraw 
from study without a DLT and prior to Cycle 1 Day 28 are not 
evaluable for dose escalation decisions and will be replaced in their 
cohort of treatment.   
During dose escalation no more than 3 subjects will be treated 
simultaneously at any given dose level.  The Phase Ib portion of this 
study will not be complete until > 28 days after accrual of the last 
subject. 
Phase II: 
Enrollment in the Phase II portion of the study will begin once the 
MTD has been determined. After Cycle 1, subjects with progressive 
disease will be removed from the study.  Other study participants will 
continue to receive a second 28-day cycle of ciprofloxacin and 
etoposide at the MTD or until one of the following occurs: disease 
progression, unacceptable toxicity, consent withdrawal, completion of 
Cycle 2, or termination of the study.   
Dose Limiting Toxicity (DLT) 
DLT will be defined as any of the following events that are considered 
to be related to treatment with ciprofloxacin and etoposide. For the 
purpose of dose-escalation and MTD determination, only DLTs that 
occur during the first cycle of oral ciprofloxacin and etoposide will be 
considered.  These include:    
1. Any Grade > 3 non-hematologic toxicity, except alopecia; and 
vomiting or nausea uncontrolled by medical management;  


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2. Any treatment-related effect that results in a subject missing 
more than 25% of ciprofloxacin or etoposide doses; 
3. Any non-hematologic toxicity considered to be related to 
ciprofloxacin or etoposide that results in a delay of Cycle 2 by > 
14 days; 
4. Grade 4 neutropenia (absolute neutrophil count < 500/mm3) in 
subjects with baseline  ANC levels > 500/mm3 persisting up to 
Day 42 after the start treatment, in the absence of leukemia;  
5. Grade 3 or greater QTc prolongation developing after the start 
of therapy with oral ciprofloxacin; and/or   
6. Any episode of tendon rupture.  
Prior to commencement of Phase II, DLT’s and records of toxicity will 
be reviewed by the Data Integrity and Safety Committee (DISC).   
Inclusion/ 
Exclusion  
Criteria: 
Inclusion criteria - All of the following must apply:   
A. Age ≥ 18 years. 
B. Diagnosis of AML confirmed by review of bone marrow pathology 
at the University of Florida. 
C. Patients with relapsed and or refractory AML  
• who failed to achieve CR or CRi after at least one cycle of 
induction chemotherapy and not suitable for second cycle 
of standard intensive chemotherapy,  
• who have progressed after 1 cycle of HMA or intolerant to 
HMA  therapy and not suitable for standard induction 
chemotherapy regimens.   
• who have relapsed after any duration of response, 
D. Per the treating physician, the subject must have a life expectancy 
of > 4 weeks.  
E. Subject performance status must be ECOG 0, 1, or 2 (See 
Appendix B). 
F. Subject must have a total bilirubin ≤ 2 mg/dL and AST and ALT ≤ 
2.5 times upper limit of normal.   
G. Subject must have serum creatinine < 2 mg/dL. 
H. Females of child-bearing potential (i.e., women who are pre-
menopausal or not surgically sterile) may participate, provided they 
meet the following conditions: 
o Must agree to use physician-approved contraceptive methods 
throughout the study and for 6 months following the last dose 
of ciprofloxacin and/or etoposide. Adequate forms of 
contraception are abstinence, double barrier methods (e.g., 
condoms with spermicidal jelly or foam and diaphragm with 
spermicidal jelly or foam), oral, depot, or injectable 
contraceptives, intrauterine devices, and tubal ligation.   
o Must have a negative serum pregnancy test within 7 days prior 
to beginning treatment on this study.   


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I. Males with female partners of child-bearing potential must agree to 
use physician-approved contraceptive methods (e.g., abstinence, 
condoms, vasectomy) throughout the study and should avoid 
conceiving children for 6 months following the last dose of 
ciprofloxacin and/or etoposide. 
J. Subjects must have provided written informed consent, and 
demonstrated the willingness and ability to comply with all study-
related procedures.   
Exclusion criteria - None of the following can apply:   
A. History of allergic or significant adverse reaction (e.g., 
anaphylaxis, prolonged QTc, or severe tendonitis) to ciprofloxacin 
or etoposide. 
B. Acute promyelocytic leukemia (APL) with t(15;17). 
C. Prolonged baseline QTc, defined as QTc interval > 470 msec in 
women and > 450 msec in men, or > 480 msec for subjects with a 
bundle branch block. 
D. Uncontrolled clinically significant infection.  Subjects with fever 
(temperature > 38.30C) thought to be related to leukemia are 
eligible assuming that blood cultures are negative during the 7 days 
prior to Cycle 1 Day 1 and there is no clinical evidence of active 
infection (e.g., negative or stable radiographs and negative physical 
examination). 
E. Ongoing, symptomatic Clostridium difficile infection.  Subjects 
who are asymptomatic with negative stool for C. difficile may 
participate. 
F. Pregnant and/or nursing. 
G. History of Myasthenia Gravis.  
H. Treatment with any anticancer therapy (standard or investigational) 
within 14 days prior to the first dose of ciprofloxacin or less than 
full recovery (< CTCAE Grade 1) from the clinically significant 
toxic effects of that treatment. The use of hydroxyurea is allowed 
only during the first 14 days of cycle 1.  
Study Duration 
and Dates: 
• It is estimated that the subject recruitment period will be 
approximately 48 months. No subject will receive more than 2 
cycles of therapy from Day 1 of Cycle 1. 
• Data regarding disease status and overall survival will be collected 
monthly until disease progression, death or until 3 years from the 
on-study date. 


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Safety 
Assessments: 
 
Subjects will be evaluated weekly during and for at least 28 days 
following the last cycle of chemotherapy. Assessments will include 
(See Table 1):  
• Interval history, review of systems, medications, new allergies, and 
physical examination with vital sign measurements;  
• Weekly laboratory assessments, including a CBC with differential 
and CMP; and 
• Toxicity assessment per the NIH Common Toxicity Criteria 
Adverse Event (CTCAE) version 4.   
Efficacy 
Assessments: 
Efficacy parameters used to assess response include hemoglobin, ANC, 
platelet count, circulating blasts, and bone marrow aspirate and/or 
biopsy. 
Sample Size 
Estimation 
In prior clinical trials of oral etoposide in resistant AML the CR rate 
has been approximately 20%. It is expect that the combination of 
etoposide with ciprofloxacin will improve CR to 40%. In order to 
detect this difference with type I error rate of 0.10 and power of 80%, 
when the true response rate is 40%, a minimum of 24 evaluable 
subjects will be treated in Phase II based on the Simon’s two-stage 
MiniMax design. Accounting for 15-20% drop out rate, a total of 30 
subjects will need to be recruited to this phase. 
 
 


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Table 1. Study Events Schedule  
 
Assessment 
Screen 
( ≤ 21 
days 
prior to 
Day 1) 
Cycle 1 
Cycle 2  
End of 
Treat-
ment12 
± 7days 
Long-
Term 
Follow 
Up13 
Day 
1 
Day 
8±2 
Day 
15±2 
Day 
22±2 
 
Day 
28±2 
 
Days 
1, 8, 
15, 
22±2 
 
Day 
28±2 
 
 
Signed Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical /Treatment History 
X 
 
 
 
 
 
 
 
 
 
Medication History1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interval History/Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity Assessment  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of Systems  
 
X 
X 
X 
X 
X 
X 
X   
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead electrocardiogram (ECG)2 
X 
 
X 
 
 
X 
 
 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology Laboratory Evaluations4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Chemistry Laboratory 
Evaluations5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Pregnancy Test (females)6 
X 
 
 
 
 
X 
 
X 
X 
 
Administer Ciprofloxacin7 
 
X 
X 
 
 
 
X 
 
 
 
Administer Etoposide8 
 
 
X 
 
 
 
X 
 
 
 
Bone Marrow Aspirate and/or 
Biopsy9 
X 
 
 
 
 
X 
 
X 
X 
 
Adverse Events Assessments11 
X 
X 
X 
X 
X 
X13 
X 
X 
X 
 
Survival Assessment 
 
 
 
 
 
 
 
 
 
X 
1 Document all medications taken during the two (2) weeks prior to screening and throughout and for 28 days after last treatment.  
2 Includes: rhythm, rate, and PR, QRS, and QTc intervals. 
3 Includes: systolic and diastolic blood pressure, pulse rate, respiratory rate, and temperature. 
4 Complete CBC including: hemoglobin, hematocrit, platelet and white blood cell count (WBC) with differential including circulating blasts and 
absolute neutrophil count. 
5 BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, sodium, potassium, calcium, magnesium, phosphorous, 
bicarbonate, chloride, glucose, albumin, and total protein. 
6 Serum pregnancy test within 1 week of Cycle 1 Day 1 for females of childbearing potential. Repeat within one week prior to first day of each 
subsequent cycle.    
  7 Ciprofloxacin will be administered orally twice daily on Days 1 to 10 of a 28-day cycle. 
8 Etoposide 200 mg will be administered orally once daily on Days 2 to 8 of a 28-day cycle. 
9 The screening bone marrow assessment must be performed within 42 days of Cycle 1 Day 1 and must be reviewed at UF. If bone marrow 
analysis results from outside lab is used to confirm diagnosis, slides must be made available to be read by UF pathologist. This must confirm a 
diagnosis of AML, non-M3.  In case of archived marrow used for eligibility or bone marrow inaspirable or slides unavailable to be read by UF 
pathologist, and there is greater than 10% blast present, peripheral blood may be collected for flow cytometry.   
11 Monitoring for SAEs and AEs starts the day patient signs the informed consent form (ICF), continuing throughout the study. Subjects who have 
received at least one dose of study drug and discontinue prematurely (regardless of reason) will be followed for any adverse events that occur 
during the study until 28 days (± 2 days) following the last dose of study treatment (i.e., the Follow-up Visit).  
12 End of treatment visit will occur at C1D28 visit in subjects with progressive disease or at study withdrawal if the date does not correspond to a 
protocol-specified visit.  Additional follow-up will include an assessment for the evaluation of AEs and concomitant medications 28 days (± 7 
days) after the last dose of study medication. Other assessments will be performed as necessary by the treating physician.  
13 All subjects will be followed monthly until: disease progression, death, or until 3 years from the on-study date. 
 
 


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1. BACKGROUND AND RATIONALE 
1.1 
Management of Resistant Acute Myeloid Leukemia (AML) 
Patients with AML who fail induction chemotherapy (refractory) and those who relapse after 
optimal chemotherapy are seldom cured with salvage regimens (6).  While allogeneic stem cell 
transplantation can cure 30-50% of patients with resistant AML who are transplanted in 
complete remission (CR), most patients are not candidates due to failure to achieve CR with 
salvage therapy or due to comorbid conditions or absence of a suitable donor.   
Given that resistance to chemotherapy is the major cause of death for patients with AML, there is 
an urgent need for novel treatment regimens that are well tolerated and capable of overcoming 
disease resistance (7).  Recent advances in molecular genetics have revealed that AML is 
characterized by a complex, sub-clonal architecture that evolves spontaneously and in response 
to treatment.  Chemotherapy-resistant leukemia clones can quickly become dominant by 
“survival of the fittest” dynamics.  In order to target minor, yet resistant clones, one strategy is to 
augment the effectiveness of current chemotherapeutic agents.   
1.2 Etoposide (VP-16) in AML  
Etoposide is a semisynthetic glucoside derivative of podophyllotoxin.  Although the exact 
mechanism of action is uncertain, it is generally accepted that etoposide acts as a Topo II 
inhibitor triggering decatenation checkpoint arrest (2). Although intravenous etoposide has 
activity in a variety of hematologic malignancies and solid tumors, the drug has usually been 
combined with other active agents so that the contribution of etoposide to efficacy or toxicity is 
difficult to assess (8-11).  However, high-dose single-agent etoposide is clearly active in patients 
with hematologic malignancies although toxicity is severe (12).   
Oral etoposide was developed to facilitate outpatient therapy.  In addition, available data 
suggests schedule dependency for etoposide such that administration on multiple consecutive 
days may be more effective than dosing at 6 to 8 day intervals (13). Availability of oral etoposide 
permits prolonged exposure without multiple office visits.  Perhaps the largest experience using 
single agent oral etoposide in patients with hematologic malignancies was reported by Osby et al 
(14) .  In that trial etoposide was given at a fixed dose of 100 mg daily for 14 days in 21 day 
cycles.  As expected, myelosuppression was the major toxicity with approximately 2/3 of all 
patients experiencing grade 3/4 neutropenia.  Of 13 patients with AML (11) or myelodysplasia 
(2), 5 received a single course due to severe, primarily hematologic toxicity.  Non-hematologic 
toxicity included grade 2 hepatic dysfunction in 2/14 evaluable patients, grade 1 renal 
dysfunction in 1/11 patients and grade 3 nausea/vomiting in 2/14 patients.  This toxicity profile is 
similar to that described by others following treatment with multiple daily doses of oral 
etoposide with the exception of mucositis described with 21 day schedules (13) .    
In conclusion, oral etoposide is an active and well tolerated agent for treatment of resistant AML 
and offers the convenience of treatment in the outpatient setting. 
1.3 
Metnase: A DNA Repair Component Mediates Resistance to Topo II Inhibitors 
DNA double strand breaks can be generated by failed decatenation and Topoisomerase IIα (Topo 
II) is the critical decatenating enzyme (2).  Topo II inhibitors, such as etoposide, can trigger 
decatenation checkpoint arrest at either of 2 decatenation mitotic checkpoints.  Metnase (also 


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SETMAR) is a novel DNA repair protein with a SET histone methylase domain and a 
transposase nuclease domain and both are essential for enhancement of DNA double-strand 
break repair.  Hromas et al reported that both AML and ALL cells fail to arrest in mitosis when 
Topo II is inhibited and that Metnase levels mediate progression through mitosis by enhancing 
Topo II function.  Critically, Metanse mediates cell proliferation through and protects Topo II 
from etoposide.  This implies that Metanse is a critical mediator of leukemia resistance to the 
cytotoxic effect of Topo II inhibitors (1).  
Based on these observations, inhibition of Metnase could overcome the resistance of leukemia 
cells to Topo II inhibitors.  Small molecule inhibition of Metnase should show an excellent 
therapeutic index given that it is overexpressed in malignant cells and that there are few other 
human Transposase domain proteins with which to cross-react.  Hromas et al virtually screened a 
large chemical library of small compounds for docking in the into the Metnase nuclease active 
site (4).  It was found that high but clinically achievable concentrations of ciprofloxacin blocked 
the ability of Metnase to cleave DNA, which is essential for its ability to repair DNA double-
strand breaks.  Further, ciprofloxacin enhanced the antiproliferative effects of etoposide on the 
AML cell line KG-1(4).  
In summary, ciprofloxacin is a Metnase inhibitor which enhances the antiproliferative effect of 
etoposide on AML cells in-vitro.  These observations indicate that ciprofloxacin could improve 
the effectiveness of etoposide in the treatment of resistant AML.   
1.4 Proposal: Treatment of Resistant AML with Etoposide and Ciprofloxacin  
This protocol proposes to treat patients with resistant AML using the combination of etoposide 
and ciprofloxacin.  In the Phase Ib portion of this trial, the maximum tolerated dose will be 
determined of ciprofloxacin when given in combination with a fixed dose of etoposide.  The 
protocol will then proceed with the Phase II portion, in which the activity of this combination 
will be determined in patients with resistant AML.   
2. OBJECTIVES  
2.1 
Primary  
In subjects with resistant AML, to  
Phase Ib:  Establish the maximum tolerated dose (MTD) of oral ciprofloxacin when given in 
combination with a fixed dose of oral etoposide.   
Phase II: Determine the rate of CR (See Appendix A) following treatment with the MTD (15).   
2.2 Secondary   
In subjects with resistant AML, to  
• Determine the safety and feasibility of treatment with ciprofloxacin and etoposide;  
• Measure the response duration, progression-free and overall survival (PFS and OS 
respectively);    
• Estimate the incidence of Grade ≥ 3 adverse events following treatment with ciprofloxacin 
and etoposide at the MTD.  


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3. STUDY DESIGN 
3.1 Overview 
This is an open label, single arm, phase Ib/II study of oral ciprofloxacin and etoposide in subjects 
with resistant AML.  In the Phase Ib portion of the study, the MTD of ciprofloxacin will be 
determined using a standard 3+3 design.  In the Phase II portion the rate of CR will be estimated 
following treatment with a fixed dose of etoposide given with the MTD of ciprofloxacin.  For 
both study phases, all subjects will receive 1 cycle of induction.  At the end of Cycle 1, subjects 
who demonstrate progressive disease will have completed study treatment.  For any subject who 
demonstrates stable disease or a partial response, a second cycle of induction will be given.  No 
subject will receive more than 2 cycles of induction. 
3.2 
Rationale for Drug Doses and Schedule  
3.2.1 Etoposide  
 
As discussed in Section 1.2, oral etoposide is an active agent in the treatment of AML.  
Etoposide absorption is saturable at doses > 200 mg/day. Lower doses are associated with 
increased bioavailability but with higher inter- and intra-subject variability (16). In the current 
study etoposide will be administered at a daily dose of 200 mg in order to optimize 
bioavailability.  As discussed above, the use of 14 day cycles of oral etoposide resulted in 
toxicity which limited therapy to a single cycle in over 1/3 of those treated (14). In order to give 
multiple cycles of therapy 7-day courses of etoposide will be administered.   
3.2.2 Ciprofloxacin 
Ciprofloxacin is a quinolone antibiotic which works by inhibiting DNA gyrase (17, 18).  
Ciprofloxacin is a Topo II inhibitor and in-vitro and xenograft tumor models have shown that 
this drug has anti-proliferative and possibly pro-apoptotic activity (19-23) at concentrations 
ranging from 12-800 mcg/ML (19, 20, 23-27) .  The use of ciprofloxacin in the current trial is 
based on the ability of this drug to inhibit Metnase and thereby enhance the activity of etoposide 
in subjects with resistant acute leukemia.  Hromas et al demonstrated that ciprofloxacin 
potentiated the activity of etoposide on AML cell lines at a concentration of 2 µmol/L 
(0.662µg/mL based on its molecular weight of 331) (4). 
Per the prescribing information, a single dose of 250 mg, 500 mg, 750 mg, and 1000 mg of oral 
ciprofloxacin in healthy volunteers achieved a Cmax of 1.2, 2.4, 4.3 and 5.4 µg/mL (28). The 
elimination half-life of ciprofloxacin is 4 hours, and PK studies have shown the mean serum 
concentrations at 12 hours after a single dose of 250 mg, 500 mg, and 750 mg were 0.1, 0.2 and 
0.4 μg/mL, respectively.  
The 750 mg twice daily as a starting dose was chosen because this dose results in sustained 
levels that approximate those shown to augment etoposide effect (See Table 2) (4) . Further, this 
dose is commonly used for treatment of infection and has been well tolerated (28).  To achieve a 
steady state concentration prior to initiation of etoposide, ciprofloxacin will be started 24 hours 
before etoposide is begun.  If the starting dose of ciprofloxacin is tolerated, a higher dose of 
1,000 mg twice daily will be explored in order to further increase ciprofloxacin 12 hour levels.  
Although less commonly used, this dose has also been well tolerated in studies in normal 
volunteers and in subjects with infection (29, 30).   


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3.3 
Phase Ib 
3.3.1 Dose Escalation and De-Escalation 
The dose escalation phase of the study will utilize a standard “3+3” design to establish the MTD 
of oral ciprofloxacin in combination with a fixed dose of etoposide (200 mg daily on days 2-8).  
Ciprofloxacin will be given on days 1-10 at one of three dose levels shown in Table 2.  The 
MTD will be defined as the level associated with a < 1/3 chance of DLT.  To summarize: (See 
Figure 1)  
1) Three subjects are initially treated at dose Level 0 (ciprofloxacin 750 mg twice daily).                                  
 
a) If none of these experience DLT, then dose will be escalated to Level +1.   
 
b) If one of these experiences DLT, then up to three more subjects are treated at Dose 
Level 1.  If one or more of these develops DLT, then the MTD is considered to be 
exceeded and dose will be reduced to Level -1.  If none of these additional subjects 
develop a DLT then the dose will be escalated to Level +1.     
c) If 2/3 of these subjects experience DLT, then the MTD is considered to be exceeded 
and dose is reduced to Dose Level -1.  
2) If the dose is escalated to Dose Level +1, the same process will be followed to determine 
if this is the MTD (no further escalation).   
3) If the dose is reduced to Level -1, then the same process will be followed to determine if 
this is the MTD.  If Dose Level -1 is above the MTD the study will be closed and it will 
be concluded that treatment with this combination at effective doses is not safe.                                         
 
Table 2. Planned Dose Levels  
Dose Level 
Drug 
Dose 
Frequency 
Schedule 
0 
Ciprofloxacin 
Etoposide 
750mg 
200mg 
Twice Daily 
Once Daily 
D1-10 
D2-8 
+1 
Ciprofloxacin 
Etoposide 
1000mg 
200mg 
Twice Daily  
Once Daily 
D1-10 
D2-8 
-1 
Ciprofloxacin 
Etoposide 
500mg 
200mg 
Twice Daily 
Once Daily 
D1-10 
D2-8 
Subjects withdrawn before Cycle 1 Day 1(C1D1) will not be evaluable for dose escalation 
decisions and will be replaced in their treatment cohort.  A subject is evaluable for dose-
escalation decisions provided: they receive all drug doses and remain on study until evaluation at 
Cycle 1 Day 28 without a DLT; or they experience a DLT during Cycle 1.  Subjects who miss 
any etoposide or ciprofloxacin doses or withdraw from study without a DLT and prior to Cycle 
1, day 28 are not evaluable for dose escalation decisions and will be replaced in their cohort of 
treatment.   
No more than 3 subjects will be added simultaneously to a dose cohort during dose escalation.  
The Phase Ib portion of this study ends when the MTD has been identified.  
Subjects entered during Phase 1b who develop DLT with the first cycle will be withdrawn from 
the study.  Subjects who do not develop DLT with the first cycle, will be treated in a second 
repeated 28-day cycle with ciprofloxacin and etoposide at the dose level given during Cycle 1 


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until completion of Cycle 2, disease progression, unacceptable toxicity, consent withdrawal, PI 
decision to discontinue treatment, or termination of the study.  Intra-subject dose escalation will 
not be permitted.  No subject will receive more than 2 cycles of treatment.  
Figure 1. Example of How MTD Will Be Determined in Cycle 1 
 
 
 
Level 0 
 
 
Level +1 
Exceeded 
MTD 
← 
DLT 
2/3 
3 Subjects 
DLT 
0/3 
→ 
3 Subjects 
 
 
 
DLT 
1/3 
 
 
 
 
 
 
↓ 
 
 
 
 
 
 
Level 0 
 
 
Level +1 
Exceeded 
MTD 
← 
DLT 
≥ 2/6 
Add  
3 Subjects 
DLT 
1/6 
→ 
3 Subjects 
 
3.3.2 Dose Limiting Toxicity 
DLT will be defined as any of the following events determined by the PI to be related to 
treatment with ciprofloxacin and etoposide and that constitute a change from baseline 
irrespective of outcome. For the purpose of dose-escalation decisions and MTD determination, 
only DLTs that occur during the first cycle of ciprofloxacin and etoposide treatment will be 
taken into account.   
1. Any Grade > 3 non-hematologic toxicity, except alopecia; and vomiting or nausea 
uncontrolled by medical management; 
2. Any treatment-related effect that results in a subject missing more than 25% of 
ciprofloxacin or etoposide; 
3. Any non-hematologic toxicity considered to be related to ciprofloxacin or etoposide that 
results in a delay of Cycle 2 by > 14 days; 
4. Grade 4 neutropenia (absolute neutrophil count < 500/mm3) in subjects with baseline 
ANC levels > 500/mm3 persisting up to 42 days after the start of treatment, in the absence 
of leukemia;  
5. Grade 3 or greater QTc prolongation developing after the start of therapy with oral 
ciprofloxacin; and/or  
6. Any episode of tendon rupture.  
For the purpose of dose-escalation/de-escalation decisions and MTD determination, only DLTs 
that occur during Cycle 1 of Phase Ib will be considered.  DLT assessment will occur at the 
Cycle 1 Day 28 visit.  Prior to commencement of Phase II, DLT’s and records of toxicity will be 
reviewed by the DISC.   
3.4 
Phase II 
Enrollment in the Phase II portion of the study (dose expansion) will begin once the MTD has 
been determined. After Cycle 1, subjects with progressive disease will be removed from study.  
Others will continue to receive 28-day cycles of ciprofloxacin and etoposide at the same dose 
level until completion of Cycle 2, disease progression, unacceptable toxicity, consent 
3 Subjects 
   Level -1 


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withdrawal, PI decision to discontinue treatment, or termination of the study.  No subject will 
receive more than 2 cycles of therapy. 
3.5 
Study Duration 
The subject recruitment period is approximately 48 months. The study duration encompasses the 
following: 
• Screening period of up to 21 days;  
• Treatment with ciprofloxacin and etoposide until the endpoints defined under Section 3.4 
are met; and   
• Day 28 follow-up after the last cycle of therapy. 
• No subject will receive more than 2 cycles of therapy from Day 1 of Cycle 1. 
 
3. SELECTION OF SUBJECTS 
3.1 
Number of Subjects 
The number of subjects enrolled in Phase Ib to be 8-24 depending upon toxicity, after accounting 
for a 25% drop-out rate during the first 28-day cycle.  In Phase II, up to 44 subjects with relapsed 
and/or refractory AML will be enrolled.  Justification for sample size in phase II is provided in 
Section 11.1. Subjects in this study can be of any race, gender and ethnic group. 
3.2 
Inclusion Criteria  
A. Age ≥ 18 years.  
B. Diagnosis of AML confirmed by review of bone marrow pathology at the University of 
Florida.  
C. Patients with relapsed and or refractory AML  
• who failed to achieve CR or CRi after at least one cycle of induction chemotherapy 
and not suitable for second cycle of standard intensive chemotherapy,  
• who have progressed after 1 cycle of HMA or intolerant to HMA therapy and not 
suitable for standard induction chemotherapy regimens.  
• who have relapsed after any duration of response, 
D. Per the treating physician, the subject must have a life expectancy of ≥ 4 weeks. 
E. Subject performance status must be Eastern Cooperative Oncology Group (ECOG) 0, 1, 
or 2 (see Appendix B). 
F. Subject must have total bilirubin ≤ 2 mg/dL and AST and ALT < 2.5 times the upper 
limit of normal.    
G. Subject must have serum creatinine < 2 mg/dL. 
H. Females of child-bearing potential (i.e., women who are pre-menopausal or not surgically 
sterile) may participate, provided they meet the following conditions: 
o Must agree to use physician-approved contraceptive methods throughout the study 
and for 6 months following the last dose of ciprofloxacin and/or etoposide.   
Adequate forms of contraception are abstinence, double-barrier methods (e.g., 
condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or 
foam), oral, depot, or injectable contraceptives, intrauterine devices, and tubal 
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o Must have a negative serum pregnancy test within 7 days prior to beginning 
treatment on this study. 
I. Males with female partners of child-bearing potential must agree to use physician-
approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the 
study and should avoid conceiving children for 6 months following the last dose of 
ciprofloxacin and/or etoposide. 
J. Subjects must have provided written informed consent and be willing to comply with all 
study-related procedures.  
3.3 
Exclusion Criteria 
Subjects with any of the following will not be eligible for study participation: 
A. History of allergic or significant adverse reaction (e.g., anaphylaxis, prolonged QTc, or 
severe tendonitis) to ciprofloxacin or etoposide.   
B. Acute promyelocytic leukemia (APL) with t(15;17). 
C. Prolonged baseline QTc, defined as QTc interval > 470 msec in women and > 450 msec 
in men, or > 480 msec in subjects with a bundle branch block. 
D. Uncontrolled, clinically significant infection.  Subjects with fever (temperature > 38.3) 
thought to be related to leukemia are eligible assuming that blood cultures are negative 
during the 7 days prior to Cycle 1 Day 1 and there is no clinical evidence of active 
infection (e.g., negative or stable radiographs and negative physical examination). 
E. Ongoing, symptomatic Clostridium difficile infection.  Subjects who are asymptomatic 
with negative stool for C. difficile may participate.   
F. Pregnant and/or nursing. 
G. History of Myasthenia Gravis. 
H. Treatment with any anticancer therapy (standard or investigational) within 14 days prior 
to the first dose of ciprofloxacin or less than full recovery (< CTCAE grade 1) from the 
clinically significant toxic effects of that treatment.  The use of hydroxyurea is allowed 
only during the first 14 days of Cycle 1.   
4. STUDY TREATMENT 
All subjects entering the screening phase will receive a unique subject number. This number will 
be used to identify the subject throughout the study. Subjects withdrawn from the study will 
retain their subject number.  
4.1 
Etoposide and Ciprofloxacin 
Ciprofloxacin will be administered orally twice daily on Days 1 to 10 of each 28-day cycle. 
Whenever possible, doses should be taken at 0800 hours and 2000 hours.  If for some reason the 
doses are not taken at these times, ciprofloxacin can be taken as late as 6 hours after the 
scheduled time.  If > 6 hours elapses, that dose of ciprofloxacin will be held and not made up.  
The starting dose will be 750 mg (dose level 0) with escalation to a maximum of 1000 mg (dose 
level +1) or de-escalation to a minimum of 500 mg (dose level -1).   


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Etoposide at a fixed dose of 200 mg will be administered orally once daily on Days 2 to 8 of 
each 28-day cycle.  Subjects will be instructed to take etoposide with their morning dose of 
ciprofloxacin at 0800 hours on an empty stomach.  If for some reason the dose is not taken at this 
time, it may be taken as late as 6 hours after the scheduled time.  If >6 hours elapses, that dose of 
etoposide will be held and not made up.   
A medication diary will be given to all subjects and they will be instructed to record the actual 
times they take both etoposide and ciprofloxacin.  Doses missed will be recorded as such.  
Subjects will be told to call within 12 hours of missing a dose.  Subjects will be instructed to 
bring the diary and any unused medication with them to all study visits. Any unused medication 
will be disposed of per institutional standard practice. 
Subjects in Cycle 1 of Phase Ib who miss any etoposide or ciprofloxacin doses will be 
considered evaluable only if a DLT occurs.  Otherwise they will be removed from the study on 
Day 28 and replaced in the cohort in which they were treated.  Subjects in Phase Ib beyond the 
first cycle and those in Phase II will be considered evaluable for response if they have received at 
least one cycle in accord with the protocol.  For these subjects non-compliance with dosing will 
be dealt with at the discretion of the PI.   
Standard administration instructions will be given to each subject for ciprofloxacin (e.g., 
separating administration from dairy products, calcium-fortified juices, sucralfate, antacids, or 
other medications that contain aluminum, magnesium, calcium, iron, or zinc).  Subjects will be 
advised not to consume grapefruit or grapefruit juice within 7 days prior to starting ciprofloxacin 
and until 7 days after completion of all doses of ciprofloxacin on study. 
4.2 
Treatment Duration 
Phase Ib subjects who developed a DLT with the first cycle will be taken off study at the Cycle 1 
Day 28 visit.   
For all others, treatment with ciprofloxacin and etoposide will be repeated in 28-day cycles until:   
• In Cycle 2, if the treating physician decides that the subject has rapidly progressive 
disease despite treatment;  
• Subject withdrawal of consent for continued participation in the study;  
• Inter-current illness that prevents further administration of study treatment;  
• Unacceptable toxicity attributed to study treatment with ciprofloxacin and etoposide;  
• Completion of 2 cycles of therapy from Day 1, Cycle 1;  
• Disease progression defined by >25% increase in marrow blasts (Appendix A);  
• If, in the opinion of the PI or treating physician, continuation in the study could be 
detrimental to the subject’s well-being;  
• Significant deviation from inclusion/exclusion criteria in the opinion of the PI;  
• Lost to follow-up (discontinuation date will be recorded as the date of last contact with 
subject); and/or 
• Termination of the study.  
Subjects with an ANC < 500/µL at the Day 28 assessment will be treated unless the Day 28 bone 
marrow shows < 5% cellularity.  In that event, treatment will be held and a CBC will be repeated 
weekly until Day 42.  A bone marrow will be repeated no later than Day 42 for subjects who 


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have treatment held.  In the event that the subject does not show bone marrow recovery with a 
cellularity > 5% by Day 42 of treatment, the subject will be withdrawn from the study.   
Table 3. Dosing Modifications  
 
Event 
Action 
Disease Progression 
Stop Therapy 
ANC > 500/ µL, No progression 
Resume Therapy 
ANC < 500/ µL, Cellularity > 5%, 
No progression 
Resume Therapy 
4.3 
Supportive Care 
Supportive care will be administered to all study subjects per institutional guidelines. 
Subjects should be prescribed and counseled to take an anti-emetic 30 – 60 minutes prior to all 
etoposide doses. Subjects should be counseled to take etoposide capsules on an empty stomach.  
Subjects should be counseled on the expected side effects of ciprofloxacin and etoposide, and 
what to do if/when these occur. 
4.4 
Management of Toxicity 
The National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 4 
(CTCAE) will be used to grade toxicity (http://ctepinfo.nih.gov/).   In Cycle 1 of Phase Ib, any 
patients developing DLT will be permanently withdrawn from the study.   
In Phase Ib and in Phase II, for subjects receiving Cycle 2 or beyond, any toxicity which delays 
treatment beyond day 42 of a cycle will result in permanent withdrawal of the subject from the 
study.  In addition, toxicity which results in missing more than ½ of all doses of etoposide or 
ciprofloxacin will result in permanent withdrawal from the study.   
The following applies to toxicity occurring in Phase Ib or Phase II except as stated:  
4.4.1 Non- Hematologic Toxicity 
For any Grade 3 or greater non-hematologic adverse event (AE), deemed related or possibly 
related to the study intervention and/or the discretion of the investigator, the subject to stop the 
study drugs. 
Management of non-hematologic toxicities such as nausea, vomiting, mucositis, enteritis, and/or 
diarrhea will follow institutional guidelines.   
4.4.1.1 Infection 
For any severe infection, study treatment will be held until the infection is controlled. If the 
infection occurs during the treatment period, missed doses will not be made up.  
Management of infection will follow standard institutional guidelines.  
4.4.1.2 QTc Interval 
Asymptomatic prolonged QTc has been reported with quinolones, although it is not very 
common with ciprofloxacin. If borderline increases (0.43 to 0.45 sec in men, 0.45 to 0.47 sec in 


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women) in QTc are noted during screening and before each new cycle, the following are 
recommended: 
• Maintain serum potassium > 4.0 mmol/L and serum magnesium > 2.0 mg/dL whenever 
possible; and   
• Medications with the potential for QTc prolongation should be avoided when possible 
while on ciprofloxacin. 
12-lead ECG recordings will be obtained during screening, on Cycle 1 Day 8, Cycle 1 Day 28, 
and when clinically indicated. 
CTCAE V4 Grade 3 toxicity criteria for the QTc interval is > 501 msec on at least two separate 
ECGs (Fredericia correction).  If this occurs, the subject will be placed on a cardiac monitor and 
cardiology consultation will be obtained for confirmation.  If confirmed, potassium and 
magnesium supplementation will be given as above.  For subjects in Cycle 1 of Phase Ib, this 
event represents a DLT and the subject will be permanently removed from the study.  For 
subjects beyond Cycle 1 of Phase Ib and for those in Phase II, therapy will be held until 
eligibility criteria are met.   
4.4.2 Hematologic (Blood/Bone Marrow) Toxicity 
Dose delays or dose modifications are not required for hematologic toxicities unless the disease 
assessment shows bone marrow hypoplasia (< 5% cellularity). It is assumed that any cytopenia at 
diagnosis is due to resistant AML.   
Management of neutropenia, neutropenic fever, thrombocytopenia, anemia, or bleeding should 
follow standard guidelines within the institution.  
In the absence of medical indications (surgery, bleeding) platelet transfusions should be given to 
maintain counts > 10,000/µL .  
Erythropoietin, G-CSF, or GM-CSF may not be used during protocol treatment. 
 
5. PRIOR AND CONCOMITANT MEDICATIONS 
5.1 
Prior Medications and Therapy 
Relevant medical history should be obtained at screening and include prior medications and 
treatment history for AML, as well as prior cytotoxic therapy, chemotherapy, or radiation 
therapy for conditions other than AML. All medications taken within 2 weeks prior to screening, 
regardless of indication, should be recorded.  
5.2 
Concomitant Medications and Therapy 
Any therapy or medication (except study drugs), administered from screening until 28 days after 
the last dose of either study drug, is considered a concomitant therapy or medication. However, if 
another course of anti-cancer therapy is initiated prior to the 28-day follow-up period visit, a 
record of concomitant medications will no longer be performed. If the use of any concomitant 
treatments (medications or procedures) becomes necessary, the treatment must be recorded, 
including the name of the drug or treatment, dose, route, date, indication for use, expected 
duration, and frequency of treatment. Assessment and documentation of concomitant 
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Within 14 days of the first dose of ciprofloxacin and throughout this study, subjects may not 
receive any other chemotherapy or any investigational agent.  The use of hydroxyurea is allowed 
only during the first 14 days of Cycle 1.  Concomitant medications should be kept to a minimum 
on Days 1 – 12 of each cycle. Anti-emetics and other supportive medications such as antibiotics 
should be recorded on the CRF.  
No other fluoroquinolone should be administered throughout the study unless mandated by 
resistant infection.  Prophylactic levofloxacin is not allowed. If other fluoroquinolones are 
required, ciprofloxacin must be stopped.  Otherwise, the administration of prophylactic 
antimicrobials is left to the discretion of the treating physician. On study Days 1 – 12 every effort 
should be made to give fluconazole at a dose of no more than 100 mg daily and to avoid 
voriconazole.  
Subjects should receive appropriate treatment prior to, during and after study treatment as 
medically indicated to prevent tumor lysis syndrome. 
Nausea and/or vomiting prophylaxis and control should be administered per institutional 
guidelines.  Anti-emetics should be taken 15-30 minutes prior to each etoposide dose with 
dexamethasone 4-8 mg orally being favored.  The anti-emetic chosen should be based on 
treatment- and subject-related factors, and prior history of control of nausea and/or vomiting. 
Medications that can prolong the QTc interval are relatively contraindicated on Days 1 – 12 of 
each cycle. A non-comprehensive list of these medications is listed in Appendix C. Subjects 
taking one or more of these medications may participate in the clinical study providing that they 
meet QTc eligibility criteria. 
Medications with expected/known drug interactions with ciprofloxacin or etoposide should be 
avoided, if possible. Dose adjustments and/or alternative medications should be made whenever 
possible. Each subject’s medication list should be reviewed at each study visit for any potential 
drug interactions, and any medication adjustment decisions should be made by the treating 
provider.  
Ciprofloxacin is a known inhibitor of human cytochrome P450 1A2. Ciprofloxacin may increase 
the toxicity of medications that are metabolized by this enzyme including theophylline, 
tizantidine, duloxetine, propranolol, and caffeine.  Therapy with these agents should be closely 
monitored.  
Etoposide is a major substrate of human cytochrome P450 3A4 and P-glycoprotein. Medications 
that are strong inhibitors of this enzyme/transporter should be avoided if possible, or dose 
adjustments made. All subjects should be counseled to avoid grapefruit or juices containing 
grapefruit while on treatment with ciprofloxacin and etoposide.  
The following drugs are also excluded: 
• 
filgrastim (G-CSF, Neupogen); 
• 
sargramostim (GM-CSF, Leukine); 
• 
peg-filgrastim (Neulasta); 
• 
erythropoietin (EPO, Procrit); 
• 
darbopoietin (Aranesp); 
• 
concomitant anti-cancer treatment(s); 
• 
revlimid (lenalidomide); 
• 
retinoids; 


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• 
interleukin-11; 
• 
thalidomide; 
• 
interferon; 
• 
azacitidine (Vidaza); 
• 
decitabine (Dacogen); and 
• 
Other investigational drugs. 
6. STUDY PROCEDURES 
Please refer to the Study Events Schedule (Table 1).   
6.1 
Screening Procedures   
Written informed consent must be obtained prior to performing any study-specific evaluations or 
tests. Tests or evaluations performed as standard of care within the specified screening period, 
but prior to informed consent, may be accepted for this study and need not be repeated. 
The following screening assessments are required within 21 days prior to Cycle 1 Day 1 (C1D1), 
unless otherwise specified:  
• Demographic data, including date of birth, gender, race, and smoking status (smoker or 
nonsmoker); 
• Medical history, including major diseases and/or surgeries; 
• Baseline signs and symptoms; 
• Document all medications taken during the 3weeks prior to screening; 
• Physical examination; 
• Weight; 
• Bone marrow aspirate and/or biopsy for clinical classification, flow cytometry, 
cytogenetic classification, and identification of commonly tested mutations in AML, 
(within 42 days of start of treatment (C1D1); 
• ECOG performance status (see Appendix B: ECOG Performance Status); 
• 12-lead electrocardiogram (ECG), including rhythm, heart rate, and PR, QRS, and QTc 
intervals; 
• Vital signs, including systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and temperature; 
• Hematology laboratory evaluations: 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute differential including circulating blasts, and platelet count; 
• Blood chemistry laboratory evaluations:  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, 
sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, chloride, 
glucose, albumin, and total protein; 
• Serum pregnancy test within 7 days of Cycle 1 Day 1 for females of childbearing 
potential; and 
• Adverse event (AE) assessment (starting when the subject provides written informed 
consent). 


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6.2 
On-Study Evaluations  
Cycle 1 Day 1 
All subjects will have the following procedures completed on the Cycle 1 Day 1 visit, unless 
otherwise specified: 
• Document concomitant medications and transfusions; 
• AE assessment; 
• Physical exam;  
• Vital signs, including blood pressure, pulse, respirations, and temperature; 
• Weight;  
• ECOG Performance Score; 
• Hematology laboratory evaluations (unless performed in the 24 hours prior to visit): 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute differential including circulating blasts, and platelet count; and 
• Blood chemistry laboratory evaluations (unless performed in the 24 hours prior to visit):  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, 
sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, chloride, 
glucose, albumin, and total protein. 
Cycle 1 Day 8 
All subjects will have the following procedures: 
• Document concomitant medications and transfusions; 
• AE assessment; 
• Physical exam; 
• 12-lead electrocardiogram (ECG), including rhythm, heart rate, and PR, QRS, and QTc 
intervals;  
• Vital signs, including blood pressure, pulse, respirations, and temperature; 
• Weight;  
• ECOG Performance Score; 
• Hematology laboratory evaluations (unless performed in the 24 hours prior to visit): 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute differential including circulating blasts and platelet count; 
• Blood chemistry laboratory evaluations (unless performed in the 24 hours prior to visit):  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, 
sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, chloride, 
glucose, albumin, and total protein; and  
Cycle 1 Days 15 and 22 
All subjects will have the following procedures: 
• Document concomitant medications and transfusions; 
• AE assessment; 
• Physical exam;  
• Vital signs, including blood pressure, pulse, respirations, and temperature; 
• Weight;  
• ECOG Performance Score; 


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• Hematology laboratory evaluations (unless performed in the 24 hours prior to visit): 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute differential including circulating blasts and platelet count; and 
• Blood chemistry laboratory evaluations (unless performed in the 24 hours prior to visit):  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, 
sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, chloride, 
glucose, albumin, and total protein. 
Cycle 1 Day 28 
The C1D28 visit may occur ± 48 hours from the protocol-specified date. All subjects will have 
the following procedures: 
• Document concomitant medications and transfusions; 
• AE assessment; 
• Physical exam;  
• Vital signs, including blood pressure, pulse, respirations, and temperature; 
• Weight; 
• 12-lead electrocardiogram (ECG), including rhythm, heart rate, and PR, QRS, and QTc 
intervals;  
• ECOG Performance Score; 
• Hematology laboratory evaluations: 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute differential including circulating blasts, and platelet count;  
• Blood chemistry laboratory evaluations:  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, 
sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, chloride, 
glucose, albumin, and total protein;  
• Bone marrow aspirate and/or biopsy for clinical classification (cellularity, blast 
assessment) andcytogenetic testing, ; and 
• Serum or urine pregnancy test – if applicable for females of childbearing potential.   
At C1 D28, the subject will have completed protocol-specified treatment for Cycle 1. For 
subjects in Phase Ib, DLT assessment will occur at this point.  
Cycle 2/Days 1, 8, 15, and 22  
All subjects will have the following procedures completed on the visit, unless otherwise 
specified: 
• Document concomitant medications and transfusions; 
• AE assessment; 
• Physical exam;  
• Vital signs, including blood pressure, pulse, respirations, and temperature; 
• Weight;  
• ECOG Performance Score; 
• Hematology laboratory evaluations (unless performed in the 24 hours prior to visit): 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute differential including circulating blasts, and platelet count; and 


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• Blood chemistry laboratory evaluations (unless performed in the 24 hours prior to visit):  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, LDH, 
sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, chloride, 
glucose, albumin, and total protein. 
Cycle 2 /Day 28 (±2)  and EOT (± 7)  
The Day 28 visit may occur ± 48 hours and EOT may occur within 7 days from the protocol-
specified date. All subjects will have the following procedures: 
• Document concomitant medications and transfusions; 
• AE assessment; 
• Physical exam;  
• Vital signs, including blood pressure, pulse, respirations, and temperature; 
• Weight; 
• ECOG Performance Score; 
• Hematology laboratory evaluations: 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood 
cell (WBC) absolute differential including circulating blasts, and platelet 
count;  
• Blood chemistry laboratory evaluations:  
o BUN, creatinine, uric acid, total bilirubin, AST, ALT, alkaline phosphatase, 
LDH, sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, 
chloride, glucose, albumin, and total protein;  
• Bone marrow aspirate and/or biopsy for clinical classification (cellularity, blast 
assessment) and cytogenetic testing,; and 
• Serum or urine pregnancy test – if applicable for females of childbearing potential 
• 12-lead electrocardiogram (ECG), including rhythm, heart rate, and PR, QRS, and 
QTc intervals (only at EOT)  
If a subject achieves CR, or at end of treatment bone marrow assessments will be performed as 
clinically indicated.  
6.3 
Treatment Discontinuation 
The end of treatment visit will occur at the C1 D28 visit in subjects with progressive disease or 
those in Phase Ib who develop DLT or at study withdrawal, even if the date does not correspond 
to a protocol-specified visits. Other reasons for withdrawal of treatment are given in Section 4.2.  
For subjects completing study stipulated two cycles of treatment (phase II portion of the study) 
will complete end of treatment assessment as described in section 7.2 
6.4 
Follow up/Survival 
Subjects will have a follow-up visit for the evaluation of adverse events and concomitant 
medications 28 days (± 7 days) after the last study medication dose. 
Follow-up evaluations will be performed for clinically significant abnormal physical 
examinations or abnormal laboratory findings, 12-lead ECGs, or vital signs, as deemed necessary 
by the treating physician.. All subjects who have adverse events, whether considered associated 


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with the use of the study drugs or not, must be monitored to determine the outcome. The clinical 
course of the adverse event will be followed according to accepted standards of medical practice, 
even after the end of the period of observation, until a satisfactory explanation is found or the 
Principal Investigator deems it medically justifiable to terminate follow-up.  
 All subjects will be followed monthly until: disease progression, death, or until 3 years from the 
on-study date.  
7. DATA MEASUREMENTS AND METHODS OF COLLECTION 
7.1 
Data Measurements 
7.1.1 Safety Data 
Safety variables for this study include the following: 
• DLTs; 
• Physical examinations; 
• Vital signs; 
• 12-lead ECGs; 
• Clinical laboratory measurements, including hematology and serum chemistry; and 
• Adverse events. 
7.1.2 Efficacy Data 
The efficacy outcomes of interest will be CR (including CRi and CRp) as defined in Appendix 
A.  The efficacy variables, which will be used to assess response, include hemoglobin, ANC, 
platelets, circulating blasts, bone marrow aspirate and biopsy. 
7.2 
 Collection Methods 
 
7.2.1  
Bone Marrow Samples 
Bone marrow aspiration and biopsy will be collected using standard institutional procedures at 
the following time points: 
• Screening: within 42 days prior to Cycle 1 Day 1; 
• Day 28 (± 7 days) after each cycle until CR or progressive disease  
Bone marrow aspirations (6 to 8 mL) and core biopsies will be collected as per standard of care 
for leukemia treatment. As per standard of care, these specimens will also be sent for flow 
cytometry.  Routine cytogenetics, FISH and genetic analysis will be obtained if abnormalities 
were present at the time of study entry.   
.  
7.2.2 Safety Measurements 
Safety measurements for this study include AEs, clinical laboratory measurements (hematology 
and serum chemistry), physical examination findings, vital signs, and 12-lead ECGs. 
7.2.3 Adverse Events 
Adverse events that occur prior to dosing will be collected on Day 1 by questioning the subject 
regarding their occurrence since the screening visit.  Adverse events will be collected at each 


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clinic visit based on observation and spontaneous reporting. 
7.2.4 Clinical laboratory assessments  
Clinical laboratory assessments are outlined in Table 1.  
Hematology assessments will be performed during the Screening period and on Days 1, 8, 15, 
22, and 28 of each cycle. The hematology assessments will include: 
• Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell (WBC) 
absolute differential including circulating blasts, and platelet count.  
Blood chemistry assessments will be performed during the Screening period on Days 1, 8, 15, 
22, and 28 of each cycle. The chemistry assessments will include: 
• Electrolytes: (sodium, potassium, calcium, magnesium, phosphorous, bicarbonate, and 
chloride); 
• Renal function: (BUN, creatinine, and uric acid);  
• Liver function: SGOT (also known as AST), SGPT (also known as ALT), total bilirubin; 
• LDH, and alkaline phosphatase; and  
• Other: (glucose, albumin, and total protein). 
Serum pregnancy tests for females of childbearing potential will be performed during the 
screening period and on day 28 of each cycle.  If delayed, a pregnancy test will be repeated 
within 7 days of the first day of the next cycle.   
Approximately 50 mL of blood will be collected for safety assessments from each subject over 
the course of each 28-day cycle. 
Abnormal, clinically significant results as assessed by the Principal Investigator should be 
repeated to rule out laboratory error. Persistent relevant abnormal changes from baseline must be 
followed up until the cause is determined or until they return to the premedication value. 
Hematology and serum chemistry will be carried out according to the standard operating 
procedures by the validated local laboratory. 
7.2.5 Physical Examination, Vital Signs and ECG 
A physical examination and vital signs (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and temperature) will be conducted during the Screening period and on each 
study visit (Days 1, 8, 15, 22, and 28) of every cycle of CE. A 12-lead ECG (rhythm, heart rate, 
and PR, QRS, and QTc intervals) will be performed during the Screening period, on Cycle 1 Day 
8, Cycle 1 Day 28, and as clinically indicated.  
8. ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 Adverse Event 
The term “adverse event” includes any sign, symptom, syndrome, or illness that appears or 
worsens in a subject during the period of observation in the clinical study and that may impair 
the wellbeing of the subject. The term also covers laboratory findings or results of other 
diagnostic procedures that are considered to be clinically significant (e.g., that require 
unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the 
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The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under treatment, or of a concomitant 
illness/condition; 
• An effect of the study drug; or 
• A combination of 2 or more of these factors. 
No causal relationship with the study drug or with the clinical study itself is implied by the use of 
the term “adverse event.” 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may be an 
adverse event. Planned surgical measures permitted by the clinical study protocol and the 
condition(s) leading to these measures are not adverse events. 
When a clear diagnosis is available that explains the abnormal objective findings, this diagnosis 
will be recorded as an adverse event and not the abnormal objective findings (e.g., viral hepatitis 
will be recorded as the adverse event and not the transaminase elevation). If a definitive 
diagnosis is not available, then the sign(s) (e.g., clinically significant elevation of transaminase 
levels) or symptom(s) (e.g., abdominal pain) will be recorded as the adverse event. 
Adverse events fall into the categories “serious” and “non-serious.” 
8.1.2 Serious Adverse Event 
A serious adverse event is one that at any dose of the study drug or at any time during the period 
of observation: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is medically important. 
Life-threatening means the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused 
death if it were more severe. 
Persistent or significant disability or incapacity means there is a substantial disruption of a 
person’s ability to carry out normal life functions. 
Medical and scientific judgment should be exercised in deciding whether other adverse events 
may be considered serious because they jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. Examples of such events are: 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. “Medically important” should be marked only if no other serious 
criteria are met. 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not consistent 
with the currently known adverse reaction to ciprofloxacin or etoposide 


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Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). Any grade ≥ 3 adverse event per CTCAE is 
generally considered severe AE. This is not the same as “serious,” which is based on the 
outcome or action criteria usually associated with events that pose a threat to life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
8.1.3 Non-Serious Adverse Event 
A non-serious adverse event is any adverse event not meeting any of the serious adverse event 
criteria. 
8.2 
Period of Observation 
For the purpose of this study, the period of observation for adverse events starts on the day the 
subject signs informed consent. For subjects who fail screening, the period of observation ends 
on the date of screening failure. Treated subjects, including those who were prematurely 
discontinued from the study, will be followed for any adverse events that occur during the study 
from the time the subject signs the informed consent form until 28 days (± 7 days) following the 
last dose of study treatment (i.e., the Follow-up Visit). However, if another course of anti-cancer 
therapy is initiated prior to the 28-day follow-up period visit, collection of adverse events will no 
longer be performed, with the exception of events that may be possibly, probably, or definitely 
related to the investigational agent or are clinically significant.  
8.3 
Documenting and Reporting of Adverse Events by Investigator 
All adverse events that occur after the subject has signed informed consent must be documented 
on the pages provided in the case report form. The following approach will be taken for 
documentation: 
• All adverse events (whether serious or non-serious) must be documented on the “Adverse 
Event” page of the case report form. 
• For adverse events classified as serious (see Section 8.4.1) the Investigator must report 
the event within 24 hours to UFHCC PMO. All SAE's must also be reported to the IRB 
and DISC in accordance with the institution's policy.  
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms are 
present, then these should be recorded as separate diagnoses on the pages of the case report form. 
All subjects who have adverse events, whether considered associated with the use of study drug 
or not, must be monitored to determine the outcome. The clinical course of the adverse event will 
be followed according to accepted standards of medical practice, even after the end of the period 
of observation, until a satisfactory explanation is found or the Principal Investigator considers it 
medically justifiable to terminate follow-up. Should the adverse event result in death, a full 
pathologist’s report should be supplied, if possible. 
8.3.1 Assessment of Causal Relationship of Study Drug 
The Investigator will provide an assessment of the potential causal relationship between adverse 


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events and study medication by determining whether or not there is a reasonable possibility that 
the event was caused by the study medication. The relationship or association of the adverse 
event to the study medication will be characterized as not related, probably not related, possibly 
related, probably related, or related:   
Not Related: There is not a temporal relationship to the study drug administration or the 
adverse event is clearly due only to the progression of the underlying disease state, intercurrent 
illness, concomitant medication, concurrent therapy or other known cause. 
Probably Not Related:  There is little or no chance that the study drug administration caused the 
adverse event; the event is most likely due to another competing cause, including intercurrent 
illness, progression or expression of the disease state, or a reaction to a concomitant medication 
or concurrent therapy appearing to explain the reported adverse event.  
Possibly Related:  The association of the adverse event with the study drug administration is 
unknown; however, the adverse event is not reasonably attributed to any other condition.  
Probably Related:  When a reasonable temporal relationship exists between the adverse event 
and the study drug administration; significant symptoms abate upon discontinuation of the study 
drug and there is a reasonable explanation based on known characteristics of the study drug and 
there is no clear association with preexisting disease or therapy, intercurrent illness, concurrent 
therapy or other factor(s). 
Related:  When the adverse event is a known side effect of the study drug or there is a temporal 
relationship to the administration of the study drug; or the adverse event reappears upon re-
administration of the study drug (rechallenge); or the significant symptoms of the adverse event 
abate upon discontinuation of the study drug (dechallenge). 
8.3.2 Intensity of Adverse Events 
The intensity of adverse changes in physical signs or symptoms will be graded according to the 
CTCAE version 4. For all other adverse events not described in the CTCAE, the intensity will be 
assessed by the Investigator using the following categories: 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required. 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible. 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
Death (Grade 5) – the event resulted in death. 
8.3.3 Action Taken with Study Drug 
The action the Investigator took with study drug as a result of the event should be recorded as 
one of the following: 
None – No action was taken with regard to the study drug as a result of the adverse event. 
Interrupted – Study drug was stopped due to the adverse event, but was later resumed at the 


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same dose. 
Dose decreased – The dose of study drug was decreased as a result of the adverse event. 
Permanently discontinued – The subject was withdrawn from the study due to the adverse 
event. 
Only one item should be chosen. If multiple actions apply, the following “worst case” scenario 
hierarchy should be used to determine the preferred entry: 
Discontinued > dose decreased > therapy interrupted. 
8.3.4 Definition of Outcome 
The outcome of the AE should be recorded as one of the following: 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
observable residual effects. 
Resolved with sequelae – The subject recovered from the adverse event with observable 
residual effects. 
Not resolved – The adverse event was present at the time of last observation. 
Death – The subject died as a result of the adverse event. 
8.4 
Immediately Reportable Events 
8.4.1 Serious Adverse Events 
Serious adverse events (SAEs) must be reported to the UFHCC Project Management Office 
(pmo@cancer.ufl.edu) within 24 hours of becoming aware of the event, and reported to the UF 
Health DISC within 5 days of being made aware of the event.  All SAE's must also be reported 
to the IRB in accordance with the institution's policy per 21 CFR part 56.  
The initial report must be as complete as possible, including details of the current illness and 
SAE and an assessment of the causal relationship between the event and study drug. Information 
not available at the time of the initial report (for example, an end date for the adverse event or 
laboratory values received after the report) must be documented and provided to DISC,PMO, 
and IRB in accordance with their reporting guidelines.  
8.4.2 Other Events Requiring Immediate Reporting 
Any overdose of treatment should be reported to the UF Health DISC within 5 days of being 
made aware of the event, and UFHCC Project Management Office (pmo@cancer.ufl.edu) within 
24 hours of becoming aware of the event, regardless of association with a separate adverse event. 
In case the overdose did not result in any adverse event, the Investigator should report this as 
“overdose, no adverse event” and provide the intended amount, as well as the actual amount, of 
drug administered. In the event of overdose or exaggerated response, appropriate supportive 
measures should be employed. Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician. 


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9. DISCONTINUATION 
9.1 
Discontinuation of Subjects 
A subject must be discontinued from protocol-prescribed therapy under the circumstances 
defined in Section 4.2.   
If a female subject or the female partner of a male subject who is required to use defined 
contraceptive methods becomes pregnant after the study, the female subject or pregnant partner 
must be followed until the outcome of the pregnancy is known. 
As far as possible, all end-of-study examinations must be performed on all subjects who receive 
the study drug but do not complete the study according to protocol. All subjects who discontinue 
from protocol-prescribed therapy for any of the reasons above will be followed for at least 28 
days following the last day of study drug administration. 
9.2 
Replacement of Subjects 
Subjects who are withdrawn prior to C1D1 for any reason will be replaced.  
Phase Ib - Subjects who withdraw or are withdrawn from study prior to C1 Day 28 without a 
DLT will be replaced by another subject.   
Phase II - Subjects who withdraw or are withdrawn prior to receiving one full cycle of therapy 
will be replaced by another subject.   
9.3 
Study Stopping Rules 
During Phase Ib the study will be stopped if Dose Level -1 is not tolerated due to excessive 
toxicity.   
 
During Phase II, the stopping rule for efficacy is inherently incorporated by using the Simon two 
stage design. For safety stopping rule, if 35% of the stage I study subjects (i.e., 5 subjects= 14 x 
0.35) experience adverse events, the study will not proceed to the second stage of the study and 
will be terminated, regardless of efficacy result.  
 
Also, as a Level 3 - high risk study as defined by DISC committee the study is subject to semi-
annual review of the safety data. A decision may be made to allow additional subjects to be 
enrolled and treated after consultation with the DISC. 
10. DATA AND SAFETY MONITORING 
This protocol will be reviewed and monitored by the University of Florida Health Cancer Center 
(UFHCC) Data Integrity and Safety Committee (DISC).  This study will have, at a minimum, 
semi-annual monitoring by the UFHCC DISC. Any adverse event fulfilling expedited reporting 
requirements must be reported to the DISC coordinator within 5 working days. The DISC 
coordinator will forward the report to the DISC Chairperson.  Questions about subject safety or 
protocol performance will be addressed with the sponsor-investigator, statistician and study team 
members. Should any major concerns arise, DISC will offer recommendations regarding whether 
or not to suspend the trial.  
UFHCC DISC data and safety monitoring activities include:  


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• Review of clinical trial conducted for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the protocol  
• Review of reports generated by data quality control review process  
• Notification of the sponsor-investigator of recommended action  
• Notification of sites coordinated by the UFHCC of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
In compliance with the UFHCC data and safety monitoring plan, the PI will provide a Data 
Integrity and Safety Committee Report to DISC at the predetermined timelines for the level of 
risk category assigned during the initial SRMC review. 
UFHCC investigator-initiated protocols will be classified into one of the following categories of 
risk: 
 
Level 1 – Low risk non-therapeutic interventional trials. 
 
Level 2 – Moderate risk therapeutic (i.e., drug, biologic, or device) trials using FDA  
    approved or commercially available compounds or interventions. 
 
Level 3 – High risk therapeutic trials (i.e., investigator-sponsored INDs, Phase I trials,  
    studies requiring biosafety approval, or other areas that may be designated by  
   NIH as high risk). 
 
Level 4 – Complex trials involving very high risk to subjects and a high level complexity  
    (i.e., first in human or gene transfer studies). 
The PI will summarize and provide DISC with all pertinent data related to the level of risk 
assigned by SRMC.  This protocol summary will include a minimum of the following: 
• The UF IRB assigned protocol number, UFHCC assigned protocol number, protocol title, 
PI name, data coordinator name or primary study coordinator, regulatory coordinator 
name, and statistician. 
• Date of initial UF IRB approval, date of most recent consent UF IRB approval/revision, 
date of UF IRB expiration, study status, and phase of the study. 
• Study target accrual and study actual accrual. 
• Protocol objectives with supporting data and list of number of study participants who 
have met each objective. 
• Measures of efficacy. 
• Early stopping rules with supporting data and a list of the number of study participants 
who have met the early stopping rules. 
• Summary of toxicities and protocol deviations. 
• Summary of any recent literature which may affect the safety or ethics of the trial. 
As part of the responsibilities assumed by conducting this study, the Principal Investigator (PI) 
agrees to maintain and have available for monitoring adequate case records (accurate source 
documents and CRFs) for the subjects treated under this protocol.  
The PI will be primarily responsible for monitoring of adverse events, protocol violations, and 
other immediate protocol issues. The study coordinator will collect information on subjects 
enrolled through the use of electronic or paper adverse event (AE) forms, CRFs, and Informed 
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Identification of oversight responsibility: 
The PI has primary responsibility. 
The UFHCC DISC will meet at least semi-annually to review accrual, patterns and frequencies 
of all adverse events, protocol violations, and when applicable, internal audit results.  
Description of internal (PI) safety review and monitoring process: 
Adverse events will be reported along with all of the other collected data in the OnCore database. 
The PI or PI designee will report all adverse events to the UFHCC DISC and IRB per reporting 
guidelines.  
11. STATISTICAL METHODS 
The sections below provide an overview of the statistical considerations and analyses. 
11.1 Determinations of Sample Size 
An estimate of 8-24 patients are to be enrolled to Phase Ib portion of the study accounting for a 
25% drop-out rate. Precise sample size cannot be defined, as it is dependent on the observed 
toxicity rate in this phase.  
Subjects will be enrolled in the Phase II portion of the study once the MTD has been determined. 
The primary intention is to determine the complete response rate (CR + CRi, see Appendix A) of 
ciprofloxacin and etoposide given at the MTD to subjects with resistant AML, which is achieved 
at the end of any treating cycle. The CR rate for AML subjects receiving etoposide alone is 
approximately 20% (the null hypothesis). We expect that the combination of ciprofloxacin and 
etoposide will improve the CR rate to 40%. In order to detect this difference with a type I error 
rate of 0.10 and power of 80%,  when the true response rate is 40%, a minimum of 24 subjects 
who are evaluable for response will need to be accrued, based on the Simon’s two-stage 
Minimax design. Specifically, in the first stage, we will enroll 14 evaluable subjects to this 
phase. The accrual will be temporarily suspended once the 14th evaluable subject is enrolled, 
pending response evaluation.  If  2 or fewer respond, in these 14 subjects, the study will be 
stopped. Otherwise, continue to accrue additional 10 evaluable subjects (for a total of 24 
evaluable subjects)., The null hypothesis of 20% CR will be rejected if 8 or more CRs are 
observed in 24 subjects. Assuming 20% drop out rate, the total number of subjects to be enrolled 
to the Phase II portion is 30  
11.2 Analysis Populations 
11.2.1 Safety Population 
The safety population will consist of all subjects who received at least one dose of each study 
drug and had at least one post-dose safety assessment. Safety summaries will include all subjects 
in the safety population. 
11.2.2 Dose Limiting Toxicity Evaluable Population (Phase Ib) 
Subjects withdrawn before C1D1 will not be evaluable for dose escalation decisions and will be 
replaced.  A subject is evaluable for dose-escalation decisions provided: they receive all drug 
doses and remain on study until evaluation at Cycle 1 Day 28 without a DLT; or they 
experienced a DLT during Cycle 1.  Subjects who miss any etoposide or ciprofloxacin doses or 


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withdraw from study without a DLT and prior to Cycle 1 Day 28 are not evaluable and will be 
replaced in their cohort of treatment.  Tabulations of DLTs will only include the DLT-evaluable 
population.  
11.2.3 Efficacy Evaluable Population 
The efficacy population will include all subjects who receive at least 1 cycle of ciprofloxacin and 
etoposide and had at least one post-dose efficacy assessment. 
11.3 Analysis Methods 
11.3.1 Safety 
Safety evaluation will include monitoring for adverse events, scheduled laboratory assessments, 
vital sign measurements, ECGs, and physical examinations. The intensity of adverse changes in 
physical signs or symptoms will be graded according to the CTCAE version 4. For all other 
adverse events not listed in the CTCAE, the intensity of events will be assessed by the PI using a 
5-point scale as described in Section 8.3.2. 
The number of adverse events and the incidence of adverse events will be summarized. Adverse 
events will be summarized by maximum intensity (as described in Section 8.3.2) and relationship 
to study drug for each treatment group. Separate summaries will be provided for all adverse 
events, serious adverse events, treatment-related adverse events, and other significant adverse 
events (e.g., adverse events leading to study discontinuation). 
Clinical laboratory results will be listed by subject or, as appropriate, summarized descriptively 
by treatment group, which will include a display of change from baseline. Laboratory values 
outside of the normal ranges will be identified. Clinically significant hematologic laboratory 
abnormalities (i.e., meet Grade 3, 4, or 5 criteria according to CTCAE) will be listed and 
summarized. 
Physical examination, vital sign, and ECG data will be listed for each subject at each visit. If 
appropriate, descriptive statistics for vital signs, both observed values and changes from baseline, 
will be summarized by treatment group. 
11.3.2 Efficacy 
All efficacy endpoints will be summarized descriptively using frequency distributions. In 
addition, 95% confidence intervals will be provided for the proportion of each 
response/improvement. 
12. EMERGENCY PROCEDURES 
12.1 Emergency Contact 
In emergency situations, the treating physician should contact the Principal Investigator by 
telephone at the number listed on the title page of the protocol. 
12.2 Emergency Identification of Investigational Products 
This is an open-label study; therefore, study drug will be identified on the package labeling. 


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12.3 Emergency Treatment 
During and following a subject’s participation in the study, the treating physician and/or 
institution should ensure that adequate medical care is provided to a subject for any adverse 
events, including clinically significant laboratory values, related to the study. 
13. ADMINISTRATIVE CONSIDERATIONS 
13.1 Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and Co-
Investigators abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined 
in the Declaration of Helsinki. The study will receive approval from an Institutional Review 
Board (IRB) prior to commencement. The Principal Investigator will conduct all aspects of this 
study in accordance with applicable national, state, and local laws of the pertinent regulatory 
authorities. 
13.2 Delegation of Investigator Responsibilities 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
study-related duties and functions. The Principal Investigator will maintain a list of Co-
Investigators and other appropriately qualified persons to whom he has delegated significant 
study-related duties. 
13.3 Subject Information and Informed Consent 
Before being enrolled in this clinical trial, the subject must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to him or her. An informed consent document that includes both information 
about the study and the consent form will be prepared and given to the subject. This document 
will contain all ICH, GCP, and locally required regulatory elements. The document must be in a 
language understandable to the subject and must specify the person who obtained informed 
consent. 
After reading the informed consent document, the subject must give consent in writing. The 
written informed consent will be obtained prior to conducting any study-related procedures or 
tests. The subject’s consent must be confirmed at the time of consent by the personally dated 
signature of the person conducting the informed consent discussions. A copy of the signed 
consent document must be given to the subject. 
The PI will retain the original signed consent document. The PI will not undertake any measures 
specifically required only for the clinical study until valid consent has been obtained. 
13.4 Confidentiality 
Each subject will be assigned a unique acrostic that will contain no protected health information. 
The PI will retain a copy of the acrostic key in a locked office. Only the study number and 
unique acrostic will be recorded in the CRF, and if the patient’s name appears on any other 


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document (e.g., pathologist report), it must be redacted before a copy of the document is placed 
in study files. Study files stored on a computer will be stored in accordance with local data 
protection laws. Subjects will be told that the IRB, UF Health Data Integrity and Safety 
Committee, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection law. 
13.5 Protocol Amendments 
Once the study has started, amendments should be made only in exceptional cases. The changes 
then become part of the study protocol. 
13.6 Record Retention 
Essential documents will be retained by the PI for a minimum of 3 years after study closure at 
IRB. Essential documents include the following: 
• Signed informed consent documents for all subjects; 
• Subject identification code list, screening log, and enrollment log; 
• Record of all communications between the PI and the IRB; 
• Composition of the IRB; 
• Record of all communications between the PI and the DISC; 
• Composition of the DISC; 
• List of Co-Investigators and other appropriately qualified persons to whom the PI has 
delegated significant study-related duties, together with their roles in the study, 
curriculum vitae, start/stop date(s) of participation, and their signatures; 
• Copies of CRFs and of documentation of corrections for all subjects (for electronic case 
report forms [eCRFs], electronic files of the eCRF and audit trails will be utilized and 
provided to the site, as necessary); 
• Drug accountability records; 
• Record of any body fluids or bone marrow samples retained; and 
• Other source documents (subject records, hospital records, laboratory records, etc.). 
 
 


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14. APPENDIX 
 
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14.1 Appendix A: AML Response Criteria According to IWG 
 
Response 
Criterion 
Neutrophils  
(µL) 
Platelets 
(µL) 
Bone 
Marrow 
Blasts 
(%) 
Other 
CR  
>1,000 
>100,000 
<5 
Transfusion  
independent, no 
evidence of  EMD  
CRi (CR with 
incomplete 
blood counts)  
<1,000 
<100,000 
<5 
No evidence of 
EMD  
CRp (CR with 
incomplete 
platelet 
recovery)  
>1,000 
 
<100,000 
<5 
No evidence of 
EMD 
Disease 
Progression 
 
 
> 25% 
increase 
from 
baseline 
 
Key: AML=acute myelogenous leukemia; CR=complete remission; 
EMD=extramedullary disease; IWG=International Working Group;  
 
 
 


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14.2 Appendix B: ECOG Performance Status 
 
ECOG 
Score 
Description 
Karnofsky 
Score 
Description 
0 
Fully active, able to carry 
on all pre-disease 
performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity, 
minor signs or symptoms of 
disease.  
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to 
carry out work of a light or 
sedentary nature, (e.g., 
light house work, office 
work). 
80 
Normal activity with effort, some 
signs or symptoms of disease.  
70 
Cares for self, unable to carry on 
normal activity or do active work.  
2 
Ambulatory and capable of 
all self-care but unable to 
carry out any work 
activities. Up and about 
more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs.  
50 
Requires considerable medical 
assistance and frequent medical 
care.  
3 
Capable of only limited 
self-care, confined to bed 
or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance.  
30 
Severely disabled, hospitalization 
indicated. Death not imminent.  
4 
Completely disabled. 
Cannot carry on any self-
care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indications. Death not imminent.  
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 
Adapted from: Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin 
Oncol. 2003;21(24):4642-4649. 
 
Adapted from: Center For International Blood & Marrow Transplant Research: 
http://www.cibmtr.org/DataManagement/TrainingReference/Manuals/DataManagement/Docume
nts/appendix-l.pdf 
 
 
 
 
 


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14.3 Appendix C: Medications That Can Prolong QTc (Non-Comprehensive) 
 
Generic 
Name 
Brand Name 
Class/Clinical Use 
Amiodarone 
Cordarone®, 
Pacerone® 
Anti-arrhythmic / abnormal heart rhythm 
Arsenic 
trioxide 
Trisenox® 
Anti-cancer / Leukemia 
Astemizole 
Hismanal® 
Antihistamine / Allergic rhinitis 
Bepridil 
Vascor® 
Anti-anginal / heart pain 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
Chlorpromazi
ne 
Thorazine® 
Anti-psychotic/ Anti-emetic / schizophrenia/ nausea 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Clarithromyci
n 
Biaxin® 
Antibiotic / bacterial infection 
Disopyramide Norpace® 
Anti-arrhythmic / abnormal heart rhythm 
Dofetilide 
Tikosyn® 
Anti-arrhythmic / abnormal heart rhythm 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Droperidol 
Inapsine® 
Sedative;Anti-nausea / anesthesia adjunct, nausea 
Erythromycin 
E.E.S.®, 
Erythrocin® 
Antibiotic;GI stimulant / bacterial infection; 
increase GI motility 
Fluconazole 
Diflucan ®  
Anti-fungal 
Halofantrine 
Halfan® 
Anti-malarial / malaria infection 
Haloperidol 
Haldol® 
Anti-psychotic / schizophrenia, agitation 
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal heart rhythm 
Levomethady
l 
Orlaam® 
Opiate agonist / pain control, narcotic dependence 
Mesoridazine 
Serentil® 
Anti-psychotic / schizophrenia 
Methadone 
Methadose®, 
Dolophine® 
Opiate agonist / pain control, narcotic dependence 
Pentamidine 
Pentam®,  
NebuPent® 
Anti-infective / pneumocystis pneumonia 
Pimozide 
Orap® 
Anti-psychotic / Tourette's tics 
Probucol 
Lorelco® 
Antilipemic / Hypercholesterolemia 
Procainamide 
Procan®, 
Pronestyl® 
Anti-arrhythmic / abnormal heart rhythm 
Quinidine 
Cardioquin®,  
Quinaglute® 
Anti-arrhythmic / abnormal heart rhythm 
Sotalol 
Betapace® 
Anti-arrhythmic / abnormal heart rhythm 
Sparfloxacin 
Zagam® 
Antibiotic / bacterial infection 
Terfenadine 
Seldane® 
Antihistamine / Allergic rhinitis 
Thioridazine 
Mellaril® 
Anti-psychotic / schizophrenia 
Voriconazole 
V-Fend ® 
Anti-fungal 
 


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14.4 Appendix D: Statistical Characteristics of the “3+3” Design 
 
Probabilities of Stopping or Continuing Dose Escalation for Given Probabilities of DLT 
Associated with the Dose Level 
 
True Probability of DLT 
at a Dose Level 
0.05 0.1 
0.2 
0.33 0.4 
0.5 
0.6 
0.67 0.7 
0.8 
Probability of Dose 
Escalation Based on 3  or 
6 Subjects (2 or more 
DLTs) 
0.97 0.91 0.71 0.43 0.31 0.17 0.08 0.04 0.03 0.01 
Probability of Ceasing 
Dose Escalation Based 
on 3 or 6 Subjects (2 or 
more DLTs) 
0.03 0.09 0.29 0.57 0.69 0.83 0.92 0.96 0.97 0.99 
Probability Based on 
only 3 Subjects (0 DLT) 
0.86 0.73 0.51 0.30 0.22 0.13 0.06 0.04 0.03 0.01 
    Key: DLT = dose limiting toxicity 
 
The probability that dose escalation will cease is at least 92% when the DLT probability is > 
60%. If the true probability of DLT for a dose level is at least 33%, the probability of stopping 
dose escalation is at least 57%. If the true probability of DLT for a dose level is less than 10%, 
the probability of stopping dose escalation is less than 10%. The probability of dose escalation 
continuing is at least 91% when the DLT probability is < 10%. 
 
 
 
 
 
 
 
 
 


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