Clinical trial NCT02658487
Conditions: Acute Myeloid Leukemia (AML) Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Acute Myeloid Leukemia With Multilineage Dysplasia Myeloid Sarcoma Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia Therapy-Related Myelodysplastic Syndrome
Sponsor: Vanderbilt-Ingram Cancer Center
Start date: 2016-03-01; Completion date: 2024-09-01
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well vosaroxin and cytarabine work in treating patients with untreated acute myeloid leukemia. Drugs used in chemotherapy, such as vosaroxin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the rate of complete remission (CR) after induction therapy with the combination of "7+V" (vosaroxin and standard dose infusional cytosine arabinoside \[ara-C\]) for patients with newly diagnosed, previously untreated acute myelogenous leukemia (AML).

SECONDARY OBJECTIVES:

I. Frequency of grade 3-5 adverse events related to administration of "7+V".

II. To evaluate for the presence of minimal residual disease (MRD) remaining after "7+V" induction and/or re-induction.

III. To determine the CR/CR with incomplete blood count recovery (CRi) rate after one and/or 2 cycles of "7+V" induction.

IV. To determine the time to neutrophil and platelet recovery following "7+V" induction.

V. To assess disease-free survival (DFS) at 1 year (yr) of patients achieving CR/CRi after "7+V" induction.

VI. To assess overall survival (OS) at 1 yr of all patients receiving protocol-defined therapy.

VII. To determine the correlation of hematopoietic stem cell transplant (HSCT) comorbidity index and Wheatley Index scores with disease response, DFS and OS.

TERTIARY OBJECTIVES:

* I. To describe the mutational burden of this cohort of AML patients.
* II. To correlate genomic aberration with response rate, DFS, and OS.
* III. To determine the number of patients treated with vosaroxin who eventually go to allogeneic HSCT.

OUTLINE:

Patients receive vosaroxin intravenously (IV) on days 1 and 4 and cytarabine IV continuously on days 1-7 (Induction-I). Patients with residual leukemia and for whom a second course is indicated in the judgment of the investigator may undergo a second course of treatment (Induction-II) 14-57 days after day 1 of Induction-1

After completion of study treatment, patients are followed every 3 months for 1 year.

Arms: arm 1: Patients receive vosaroxin IV on days 1 and 4 and cytarabine IV continuously on days 1-7 (Induction I). Patients with residual leukemia and for whom a second course is indicated in the judgment of the investigator may undergo a second course of treatment (Induction II) 14-57 days after day 1 of Induction I.
Interventions: intervention 1: Cytarabine intervention 2: Vosaroxin
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
7+V Induction for untreated AML 
 
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PROTOCOL INFORMATION 
 
Study Title:   Phase II trial of vosaroxin in combination with infusional cytarabine in patients 
with untreated AML 
(VITAL Trial … Vosaroxin and Infusional Cytarabine for Frontline Treatment 
of Acute Myeloid Leukemia)   
 
Sponsoring Institution: 
Vanderbilt-Ingram Cancer Center  
Vanderbilt University Medical Center 
 
Study Chairs: 
Stephen A. Strickland, MD, MSCI 
Michael R. Savona, MD, FACP 
stephen.strickland@vanderbilt.edu 
michael.savona@vanderbilt.edu 
 
 
 
Statisticians:  
 
Gregory D. Ayers, MS 
 
 
 
 
Jeffrey D. Blume, PhD 
 
VICC Multi-Institutional Coordinating Center: 
Address: 
 
2141 Blakemore Ave., Nashville, TN 37212 
Email address:  
Coordinating.Center@vanderbilt.edu  
Fax no: 
 
615-875-0040 
Phone no: 
 
615-936-5770 
 
Contracting Authority: 
 
Name:  
 
Amy Griffith 
Address: 
 
2141 Blakemore Avenue 
Phone no: 
 
615-875-0044 
Fax no: 
 
615-936-5850 
Email Address: 
amy.griffith@vanderbilt.edu 
 
Protocol version date: 
18 January 2016 
 


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PROTOCOL ACCEPTANCE PAGE  
Protocol Title: 
Phase II trial of vosaroxin in combination with infusional 
cytarabine in patients with untreated AML  
Protocol Date:   
 
18 January 2016 
Version Number: 
 
1.10 
 
I have received and read the above protocol.  I agree to conduct the study in accordance with the 
current protocol. 
 
 
 
Principal Investigator’s Signature  
 
Date 
 
Principal Investigator’s Name (Print) 
 
Site Name 
 
________________________________________________________ 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
AHD 
Antecedent hematological disorders 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid/ myelogenous leukemia 
AML-MLD 
Acute myeloid/ myelogenous leukemia with multilineage dysplasia 
APL 
Acute promyelocytic leukemia 
ara-C 
Cytosine arabinoside  
ara-CTP 
Arabinosyl-cytosine triphosphate  
AST 
Aspartate aminotransferase 
AQD 
Anticancer quinolone derivative 
ASCO 
American Society of Clinical Oncology 
BSA 
Body surface area 
C 
Celsius 
CBC 
Complete blood count 
CNS 
Central nervous system 
CI 
Confidence interval 
CR 
Complete remission  
CRi 
Complete remission with incomplete blood count recovery 
CRp 
Complete remission with incomplete platelet recovery 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebral Vascular Accident 
DFS 
Disease- free survival 
D5W 
Dextrose in water 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
DSB 
Double-strand breaks  
DSMB 
Data Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee  
Echo 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
Event-free survival 
EKG 
Electrocardiogram 
EOT 
End of treatment 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FISH 
Fluorescence in situ hybridization 
GCP 
Good clinical practice 
GVHD 
Graft versus host disease 
Hgb, 
Hemoglobin 
HP 
Heavily pretreated 
H & P 
Medical history & physical examination 
HR 
Hazard ratio 
HSCT 
Hematopoietic stem cell transplantation 
ICF 
Informed consent form 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device  


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List of Abbreviations 
IUS 
Intrauterine system  
IV 
Intravenous  
IWG 
International Working Group 
LDH 
Lactate dehydrogenase 
LFS 
Leukemia-free survival 
LVEF 
Left ventricular ejection fraction 
LR 
Log-likelihood ratio 
MDS 
Myelodysplasia 
mg 
Milligram 
MI 
Myocardial infarction 
MP 
Minimally pretreated 
MPN 
Myeloproliferative neoplasms 
MRD 
Minimal residual disease 
MTD 
Maximum-tolerated dose  
MUGA  
Multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI  
National Cancer Institute 
OS 
Overall survival  
PE 
Physical examination 
PET 
Positron emission tomography 
Plts  
Platelets 
PK 
Pharmacokinetics 
PO 
“by mouth” 
PR 
Partial remission 
PS 
Performance status 
PT/PTT INR 
Prothrombin time/partial thromboplastin time international normalized ratio 
q 
Every 
RBC 
Red blood cell count 
SAE 
Serious adverse event 
SRC 
Scientific Review Committee 
VITAL Trial 
Vosaroxin and Infusional Cytarabine for Frontline Treatment of Acute Myeloid 
LeukemiaTrial 
7+V 
Vosaroxin and standard dose infusional cytosine arabinoside (ara-C) 
t-AML/t-MDS 
Treatment-related myeloid neoplasms  
TF 
Treatment Failure 
TIA 
Transient ischemic attack 
TK 
Tyrosine kinase 
VICC 
Vanderbilt-Ingram Cancer Center 
WBC 
White blood cell count 
WHO 
World Health Organization 


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PROTOCOL SYNOPSIS 
TITLE: 
Phase II trial of vosaroxin in combination with infusional cytarabine in 
patients with untreated AML 
OBJECTIVES:               
Primary Objective:    
• To assess the rate of complete remission (CR) after induction therapy with the 
combination of “7+V” [vosaroxin and standard dose infusional cytosine 
arabinoside (ara-C)] for patients with newly diagnosed, previously untreated acute 
myelogenous leukemia (AML) 
 
Secondary Objectives: 
• To further evaluate the safety and tolerability of “7+V”  
• To evaluate for the presence of minimal residual disease (MRD) remaining after 
“7+V” induction and/or re-induction 
• To determine the CR/CRi rate after one or 2 cycles of “7+V” induction 
• To determine the time to neutrophil and platelet recovery following “7+V” 
induction 
• To assess disease-free survival (DFS) at 1yr of patients achieving CR/CRi after 
“7+V” induction  
• To assess overall survival (OS) at 1yr of all patients receiving protocol-defined 
therapy  
• To determine the correlation of HSCT comorbidity index, AML-Score, and 
Wheatley Index scores with disease response, DFS and OS 
 
Exploratory Objectives: 
• To describe the mutational burden of this cohort of AML patients 
• To correlate genomic aberration with response rate, DFS, and OS 
• To determine the number of patients treated with vosaroxin who eventually go to 
allogeneic HSCT 
 
 
 
 
 
 
 
 
 


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STUDY DESIGN:  
• Single-arm, open-label, phase II study of vosaroxin in combination with cytarabine in 
patients with newly diagnosed AML.   
• Vosaroxin will be administered intravenously at 90 mg/m2 on days 1 and 4.  Cytarabine 
will be administered in standard fashion as a continuous infusion of 100 mg/m2 daily on 
days 1-7.  
 Patients with evidence of residual leukemia on “Day 14 biopsy” following initial 
induction will be offered re-induction with intravenous vosaroxin at 70 mg/m2 on 
days 1 and 4 in combination with continuous infusion cytarabine at 100 mg/m2 daily 
on days 1-7. 
• Two-stage design.  Forty-one (41) patients will provide 80% power to detect a 20% 
increase in complete remission rates (from 40% to 60%) with a Type I Error rate of 5%. 
The design permits one interim look to examine evidence of futility after the first 17 
patients are evaluable for response.  If ≤ 7 patients achieve CR then the likelihood of 
reaching the goal endpoint of ≥ 60% remission would be diminished.  In this case, the 
VITAL Study DSMB (consisting of a representative from the funding organization, the 
study chairs, a biostatistician, and participating investigator to be selected by the study 
chairs) will review the clinical data to determine the merits of continued enrollment.  If > 
7 CRs are observed then the second stage will open automatically and increase 
enrollment to 41 patients. 
 Stage 1: First 17 patients who are evaluable for response prior to futility analysis 
 Stage 2: Patients 18-41 enrolled after futility analysis   
• Likelihood-based assessment of the statistical evidence be used to monitor the false 
discovery rate as data accrue and will provide the option of adding one or two 
extension cohorts of 10 participants each if the initial trial results are inconclusive. 
• Selected Standard of Care Study Procedures: 
 Pre-enrollment marrow aspirate / biopsy to confirm AML diagnosis in accordance 
with WHO define diagnostic criteria, and to be used for analyses as outlined 
below in correlative analyses section 
 Echo / MUGA to assess LVEF prior to exposure to induction chemotherapy 
 Repeat marrow aspirate / biopsy at day 14 (± 2 days) following initiation of 
induction therapy to assess disease status 
 Recovery marrow assessment to be performed following count recovery (ANC > 
1000, Platelets > 100) following the initiation of induction therapy for formal 
response assessment.  Disease assessment will be performed on day 57 (± 3 days) 
for those failing to demonstrate peripheral count recovery, or per the discretion of 
the investigator. 
 
 
 
 
 


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STUDY POPULATION: 
• Adult patients with newly diagnosed, previously untreated, acute myeloid leukemia  
INCLUSION CRITERIA:  
• Age ≥ 18 years of age 
• Ability to provide informed consent 
• Ability to tolerate intensive therapy with vosaroxin 90mg/m2 and standard dose of 
cytarabine as per the investigator discretion 
• ECOG performance status 0-2 at time of study entry (Appendix A) 
• Morphologically confirmed new diagnosis of AML in accordance with WHO 
diagnostic criteria (Appendix B) 
• Patients who have received hydroxyurea alone or have previously received “non-
cytotoxic” therapies for MDS or MPN (e.g., thalidomide or lenalidomide, 5-
azacytidine or decitabine, histone deacetylase inhibitors, low-dose cytoxan, tyrosine 
kinase or dual TK/src inhibitors) will be allowed  
• Renal function: Serum creatinine ≤ 2.0 mg/dL 
• Hepatic enzymes (ALT, AST) ≤ 2.5 x upper limit of normal  
• Total bilirubin ≤ 1.5 x upper limit of normal unless clearly related to Gilbert’s 
Disease, hemolysis or leukemic infiltrate 
 
• For patients in stage 1 (patients #1-#17).  
 ≥ 55 years of age with AML of any risk classification, OR 
 18-54 years of age with high-risk AML disease based on one of the following: 
o Antecedent hematologic disorder including myelodysplasia (MDS)-related 
AML (MDS/AML) and prior myeloproliferative disorder (MPD)  
o Treatment-related myeloid neoplasms (t-AML/t-MDS) 
o AML with FLT3-ITD  
o Myeloid sarcoma  
o AML with multilineage dysplasia (AML-MLD)  
o Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 
21q or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; complex 
karyotypes (≥ 3 clonal abnormalities); monosomal karyotypes 
 
• For patients in stage 2 (enrolled patient #18 and beyond).   
• ≥ 55 years of age with AML of any risk classification, OR 
• 
18-54 years of age with intermediate or high risk AML as defined by NCCN risk 
assignment (Appendix C) 
 
 
 
 
 
 
 


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EXCLUSION CRITERIA: 
Stage I: 
• Patients 18-54 years of age with “good risk” AML defined as the presence of t(8;21) , 
inv(16), or t(16;16) as diagnosed by morphologic criteria, flow cytometric 
characteristics, and rapid cytogenetics or FISH (Patients with t(8;21), inv(16), 
t(16;16) who are unable to receive anthracycline based induction will be allowed to 
enroll provided the medical reason they are unable to receive anthracyclines is 
clearly documented and provided they fulfill all other eligibility and criteria).     
 
Stage I and Stage II: 
• Patients with Acute Promyelocytic Leukemia (APL) as diagnosed by morphologic 
criteria, flow cytometric characteristics, and rapid cytogenetics or FISH or molecular 
testing 
• Any previous treatment with vosaroxin  
• Concomitant chemotherapy, radiation therapy 
 For patients with hyperleukocytosis with > 50,000 blasts/uL; leukopheresis or 
hydroxyurea may be used prior to study drug administration for cytoreduction at 
the discretion of the treating physician. Hydroxyurea must be stopped 24 hours 
prior to initiation of protocol defined therapy. 
• Active CNS leukemia  
• Active, uncontrolled infection. Patients with infection under active treatment and 
controlled with antibiotics are eligible.  
• Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant 
for non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia). Patients 
with GVHD controlled on stable doses of immunosuppressants are eligible.  
• Known HIV seropositivity 
• Any other medical, psychological, or social condition that may interfere with study 
participation or compliance, or compromise patient safety in the opinion of the 
investigator or medical monitor 
• LVEF < 40% as measured by echocardiogram or MUGA 
• Women who are pregnant or breastfeeding 
• Renal insufficiency requiring hemodialysis or peritoneal dialysis 
 
STUDY TREATMENT: 
• Cytarabine (commercial supply)  
 administered as a continuous infusion with a dose of 100 mg/m2 daily x 7 days 
• Vosaroxin (supplied by Sunesis)   
 Induction: 90 mg/m2 infusion on days 1, 4 
 Re-induction: 70 mg/m2 infusion on days 1, 4  
PRIMARY ENDPOINT: 
• Complete remission 
 
 


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STATISTICAL PLAN: 
The primary objective of this single-arm, phase II clinical trial is to determine if 
vosaroxin in combination with standard dose cytarabine as induction chemotherapy can 
significantly improve the rate of complete remission (CR) in patients with untreated acute 
myeloid leukemia.  Forty-one (41) patients will be enrolled in a two-stage design that permits 
one interim look to examine evidence of futility. As per convention, the study will not be stopped 
early on the basis of preliminary evidence of efficacy observed at the end of the first stage (i.e., 
at the interim look).   
    
Ethical imperatives and resource constraints encourage the exploration of more adaptive 
designs. Hence we propose, in the context of a standard two-stage design, that a likelihood-based 
assessment of the statistical evidence be used.  An important advantage is that, unlike p-values, 
which are binary in nature, likelihood ratios have three evidential zones: evidence favoring the 
null hypothesis, evidence favoring the alternative hypothesis, and weak or inconclusive evidence 
(i.e., favoring neither hypothesis).  
In accordance with our desire to maintain a uniform study design, we set a total sample 
size of 41 participants.  An interim futility analysis will be conducted following enrollment of 17 
evaluable patients.  If ≤ 7 patients achieve CR then the likelihood ratio in support of reaching the 
goal endpoint of ≥ 60% remission would be diminished.  In this case, the DSMB will review the 
clinical data to determine the merits of continued enrollment.   If > 7 CRs are experienced by the 
first 17 evaluable patients, enrollment will automatically proceed to enroll a total of 41 patients.  
Under this two-stage design, a 60% remission endpoint by the “7+V” combination is 3.45 times 
more likely than a 40% response rate if 22 or more patients experience CR.  
In the context of the planned likelihood assessment the option will be provided to add an 
extension cohort of up to 20 participants if the initial trial results are inconclusive. In this 
scenario, the use of a likelihood based extension cohort results in false positive and false 
discovery rates of 3.7% and 3.9%, respectively. 


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PROTOCOL SCHEMA 
 
 
 
 
Recovery  
Biopsy (-) 
Day 14  
Biopsy (-) 
Recovery  
Biopsy (+) 
Recovery  
Biopsy (-) 
Registration 
Newly diagnosed AML  
- ≥18 years of age 
- Intermediate or High Risk 
Induction 
• Vosaroxin 90 mg/m2, Days 1 and 4 
• Cytarabine 100 mg/m2, Days 1-7 
Re-Induction 
• Vosaroxin 70 mg/m2, Days 1 and 4 
• Cytarabine 100 mg/m2, Days 1-7 
Disease assessment upon count 
recovery or on Day 57 (+/-3) in the 
absence or peripheral count 
recovery  
• Recovery defined as:  
ANC > 1000 and Plts > 100  
Re-Induction 
• Vosaroxin 70 mg/m2, Days 1 
and 4 
• Cytarabine 100 mg/m2, Days 1-7 
Disease assessment upon count 
recovery or on Day 57 (+/-3) in the 
absence or peripheral count recovery  
• Recovery defined as:  
ANC > 1000 and Plts > 100  
Patients achieving CR / CRi will 
proceed to consolidation off study 
and/or HSCT at the discretion of 
the treating physician 
• 
Patients will be followed for 
DFS, OS, and HSCT Status
Patients achieving CR / CRi will 
proceed to consolidation and/or 
HSCT at the discretion of the 
treating physician 
• Patients will be followed for 
DFS, OS, and HSCT Status 
 
  
Recovery  
Biopsy (+) 
Patients failing to achieve CR / CRi 
will proceed to EOT visit 
• Additional therapy (off-study) 
will be at the discretion of the 
treating physician 
• Patients will be followed for 
OS and HSCT Status 
Day 14 
Biopsy (+) 


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Table of Contents 
PROTOCOL ACCEPTANCE PAGE .................................................................................................................. 2 
PROTOCOL SYNOPSIS ............................................................................................................................................. 5 
PROTOCOL SCHEMA ............................................................................................................................................ 10 
1. 
BACKGROUND ............................................................................................................................................. 14 
1.1. 
ACUTE MYELOID LEUKEMIA .................................................................................................................... 14 
1.2. 
STUDY RATIONALE ........................................................................................................................... 14 
1.3. 
INVESTIGATIONAL PRODUCT ................................................................................................................... 15 
2. 
OBJECTIVES ............................................................................................................................................ 19 
2.1. 
PRIMARY OBJECTIVES ................................................................................................................. 19 
2.2. 
SECONDARY  OBJECTIVES ............................................................................................................. 19 
2.3. 
EXPLORATORY OBJECTIVES ..................................................................................................... 20 
3. 
STUDY DESIGN ........................................................................................................................................ 20 
3.1. 
OVERALL DESIGN AND PLAN ...................................................................................................... 20 
3.2. 
DURATION OF STUDY .................................................................................................................... 21 
4. 
SELECTION OF STUDY POPULATION ................................................................................................ 21 
4.1. 
INCLUSION CRITERIA ...................................................................................................................... 21 
4.2 
EXCLUSION CRITERIA: .................................................................................................................... 22 
5. 
STUDY PROCEDURES ............................................................................................................................ 23 
5.1. 
SCREENING ......................................................................................................................................... 23 
5.2. 
TREATMENT / HEMATOLOGIC RECOVERY ................................................................................ 24 
5.3. 
END OF TREATMENT ........................................................................................................................ 25 
5.4. 
FOLLOW-UP ........................................................................................................................................ 25 
TABLE 1. 
STUDY CALENDAR .................................................................................................................... 26 
6. 
STUDY DRUG ADMINISTRATION........................................................................................................ 28 
6.1. 
VOSAROXIN FORMULATION .......................................................................................................... 28 
6.2. 
VOSAROXIN STORAGE ..................................................................................................................... 28 
6.3. 
DOSE CALCULATION, PREPARATION, AND ADMINISTRATION ............................................. 28 
7. 
CONCOMITANT MEDICATIONS .......................................................................................................... 30 
TABLE 2. 
INSTRUCTIONS FOR THE USE OF CONCOMITANT MEDICATIONS AND THERAPIES 31 


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8. 
DISCONTINUATION OF TREATMENT ................................................................................................ 32 
8.1. 
DISCONTINUATION CRITERIA FOR INDIVIDUAL PATIENTS .................................................. 32 
8.2. 
PROTOCOL VIOLATIONS AND DEVIATIONS ............................................................................... 33 
9. 
EFFICACY ASSESSMENTS .................................................................................................................... 33 
9.1. 
DETERMINATION OF OVERALL SURVIVAL ................................................................................ 33 
9.2. 
DETERMINATION OF RESPONSE ................................................................................................... 33 
9.3. 
TIME-TO-EVENT ENDPOINTS.......................................................................................................... 33 
TABLE 3. 
VOSAROXIN RESPONSE CRITERIA BASED ON INTERNATIONAL WORKING GROUP 
CRITERIA30 ....................................................................................................................................................... 34 
10. 
SAFETY ASSESSMENTS ..................................................................................................................... 34 
10.1. 
SAFETY MONITORING ...................................................................................................................... 34 
10.2. 
OVERDOSE .......................................................................................................................................... 35 
11. 
ADVERSE EVENT DEFINITIONS AND REPORTING ..................................................................... 36 
11.1. 
ADVERSE EVENT DEFINITIONS ACCORDING TO ICH GUIDELINES AND FDA FINAL RULE 
ON SAFETY REPORTING REQUIREMENTS ............................................................................................... 36 
TABLE 4. 
ADVERSE EVENT DEFINITIONS ............................................................................................. 36 
11.2. 
ELICITING ADVERSE EVENT REPORTS ....................................................................................... 37 
11.3. 
ASSESSMENT AND RECORDING  OF ADVERSE EVENTS ........................................................... 37 
11.4. 
GUIDELINES FOR RECORDING ADVERSE EVENTS ................................................................... 38 
11.5. 
INTENSITY OF THE ADVERSE EVENT ........................................................................................... 38 
11.6. 
ADVERSE EVENT ATTRIBUTION .................................................................................................... 38 
11.7. 
SERIOUS ADVERSE EVENT REPORTING REQUIREMENTS ...................................................... 39 
11.8. 
GENERAL INSTRUCTIONS FOR REPORTING SERIOUS ADVERSE EVENTS TO THE FDA 
AND SUNESIS PHARMACEUTICALS ........................................................................................................... 40 
12. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...................................... 41 
12.1. 
STATISTICAL CONSIDERATIONS ................................................................................................... 41 
12.2. 
SAMPLE SIZE CONSIDERATIONS ................................................................................................... 41 
12.3. 
STUDY DESIGN ................................................................................................................................... 41 
12.4. 
DEFINITION OF ENDPOINTS RESPONSE FOR INTERIM ANALYSIS. ....................................... 46 
12.5. 
STATISTICAL COMPARISONS ......................................................................................................... 47 
12.6. 
SAFETY ANALYSIS ............................................................................................................................. 47 
13. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ...................................................... 47 
13.1. 
COMPLIANCE  WITH LAWS AND REGULATIONS ....................................................................... 47 


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REFERENCES ................................................................................................................................................... 52 
APPENDIX A. 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS37 ......... 55 
APPENDIX B.   WHO DIAGNOSTIC CRITERIA FOR AML ........................................................................ 56 
APPENDIX C. 
AML RISK PROGNOSTICATION ..................................................................................... 57 
APPENDIX D: 
CONTRACEPTIVE GUIDELINES AND PREGNANCY ................................................... 58 
APPENDIX E.  PROPHYLACTIC ANTIMICROBIALS AND MUCOSITIS CARE RECOMMENDATIONS
 ............................................................................................................................................................................ 59 
APPENDIX F.   COMORBIDITY INDEX AND RISK STRATIFICATION SCORING SYSTEMS ............. 61 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. BACKGROUND 
1.1. Acute Myeloid Leukemia  
Data from the American Cancer Society estimate 18,860 new diagnoses of acute myeloid 
leukemia in the United States in 2014 and an alarming 10,460 deaths of patients with this 
diagnosis.1  Although there has been no major change in induction therapy strategy for nearly 
4 decades2, subgroups that respond particularly well or poorly have been identified based on 
their genetic features.3-7 Careful examination of disease characteristics at diagnosis is 
imperative to risk-stratify patients and appropriately apply novel risk-adapted therapies or 
intensified treatment strategies including hematopoietic stem cell transplantation (HSCT).   
 
 
1.2. Study Rationale 
AML is an aggressive and highly fatal disease with a median age of 67 years at diagnosis 
and an unfortunate age-adjusted 5-year survival of 24.2%.8  Given the advanced age of the 
majority of patients with this diagnosis and/or the medical comorbidities often associated 
with their advanced age, many AML patients are not offered the conventional intensive 
strategy of “7+3” (cytarabine + anthracycline).  Many older patients who are deemed 
medically appropriate to receive an intensive induction strategy tend to have AML with poor 
risk cytogenetic or molecular features and only ~40% are expected to achieve complete 
remission.9,10  Because of these features, the 5-year overall survival of patients above the age 
of 55 approaches only 10%.9  While most patients with newly diagnosed AML are over 55 
years of age, adult patients aged 18-55 do develop AML, and have variable success with 
standard therapy of 7+3.  With the exception of favorable risk AML in younger patients, the 
5 year survival for patients less than 55 years of age remains less than 40%.6  The poor long-
term survival of these patients combined with a lack of available novel therapeutic strategies 
in the past 40 years warrants the investigation of newer agents in the frontline setting.    
As vosaroxin ± cytarabine has been successfully administered and tolerated in both AML 
patients of advanced age (≥ 60 years)11 and all patients with relapsed/refractory disease,12,13 
14 we will pursue the investigation of the combination of cytarabine with vosaroxin (“7+V”) 
in newly diagnosed AML patients.        
There is an established, acceptable safety profile of infusional cytarabine 400mg/m2 
given over 5 days concomitantly with vosaroxin. Pharmacokinetic studies from this 
combination have established the rapid, linear elimination of vosaroxin in the presence of 
infusional cytarabine and provide precendent and rationale for vosaroxin with 7 days of 
infusional cytarabine given in the customary fashion at a dose of 100mg/m2/day.  This 
combination will provide the opportunity to expand upon the previously observed efficacy of 
vosaroxin in patients with high-risk (relapsed/refractory) AML14 and has the potential to 


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provide a foundation for a future randomized phase III trial comparing “7+V” to 
conventional “7+3”. 
 
1.3. Investigational Product 
Vosaroxin is a first-in-class anticancer quinolone derivative (AQD) currently in clinical 
development by Sunesis Pharmaceuticals, Inc. as a treatment for acute myeloid leukemia 
(AML). The molecular formula of vosaroxin is C18H19N5O4S and its molecular weight is 
401.45 Daltons. Vosaroxin is administered as a short intravenous (IV) infusion within 10 
minutes. 
Vosaroxin has a unique mechanism of action distinct from other cytotoxic anticancer 
agents. The activity of vosaroxin in mammalian cells appears to parallel the activity of the 
quinolone antibiotics in prokaryotes.15-17 Vosaroxin intercalates DNA and inhibits 
topoisomerase II activity through both enzymatic inhibition and poisoning.18  This leads to 
site-selective DNA double-strand breaks (DSB) in G/C-rich sequences, which are 
characteristic sites of quinolone-induced DNA cleavage.19 Vosaroxin targets actively 
replicating cells, and the extent of DNA damage is cell-cycle dependent, with the damage 
induced in G2/M > S >> G1. The DNA damage results in a delay in S phase, arrest at G2/M 
phase, and cell death by apoptosis. Vosaroxin is minimally metabolized and does not require 
metabolism for cytotoxic activity. 
Vosaroxin and cytarabine have non-overlapping primary molecular mechanisms of 
action.20  In contrast to vosaroxin, cytarabine is a pyrimidine nucleoside analog that requires 
cellular uptake and metabolism to form the active metabolite, arabinosyl-cytosine 
triphosphate (ara-CTP). The activities of ara-CTP, namely inhibition of DNA polymerase and 
DNA ligase, and direct incorporation into DNA, result in DNA damage and termination of 
synthesis. Cytarabine activity is highly specific for the S phase of the cell cycle. 
Phase 1 Studies SPO-0001 & SPO-0002: Relapsed/Refractory Solid Tumors 
The purpose of these studies was to assess the vosaroxin dose-limiting toxicity (DLT), 
maximum-tolerated dose (MTD), pharmacokinetics and clinical activity of vosaroxin in 
patients with relapsed/refractory solid tumors. 21   Two dose-escalation studies evaluated IV 
vosaroxin administered every 3 weeks (SPO-0001) or weekly every 28 days for 3 weeks 
(SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally 
pretreated (MP) based on therapeutic history. 
In the SPO-0001 study (N=41; 24 HP/17 MP), patients were treated in eight dose cohorts 
using 3-75 mg/m2.  At the 60 mg/m2 dose, four HP patients experienced DLTs of grade 4 
neutropenia (N= 3; one with fever) and grade 3 febrile neutropenia/pneumonia (N=1). At the 


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75 
mg/m2 
dose, 
two 
MP 
patients 
experienced 
DLTs 
of 
grade 
4 
neutropenia/thrombocytopenia (N=1) or grade 2 oral thrush for >29 days (N=1). The MTD 
was established at 48 mg/m2 (HP patients) and 60 mg/m2 (MP patients). 
In the SPO-0002 study (N=21), patients were treated in six dose cohorts using 3-24 
mg/m2. At the 18 mg/m2 dose, two patients experienced DLTs of grade 3 neutropenia (one 
with pleural effusion, each >14 days). The MTD was established at 15 mg/m2. Vosaroxin 
exhibited low clearance (2 L/h/m2), a long terminal half-life (22 hours), and dose- 
proportional exposure. Overall, 31 of 62 patients achieved stable disease and one patient 
(ovarian cancer) achieved a partial response per Rustin criteria. 
Phase 1b SPO-0004 Trial: Relapsed/Refractory Leukemia 
The purpose of this study was to evaluate the DLT, MTD, pharmacokinetics (PK), 
clinical activity and pharmacodynamics of vosaroxin in patients with in relapsed/refractory 
leukemia (N=73). 12  Vosaroxin was administered weekly on days 1, 8 and 15 or twice 
weekly on days 1, 4, 8 and 11. The treated patients had a median age of 65 years, 85% had 
acute myeloid leukemia and 78% had refractory disease. Patients treated on the weekly 
schedule (N=42) received 18-90 mg/m2 and the MTD was found to be 72 mg/m2. Patients 
treated on the twice-weekly schedule (N=31) received 9-50 mg/m2 and the MTD was 40 
mg/m2. The DLT was stomatitis and the primary non-hematologic toxicity was reversible 
gastrointestinal symptoms and febrile neutropenia. The 30-day all-cause mortality was 11%. 
Five patients had complete or incomplete remissions with a median duration of 3.1 months. 
A morphologic leukemia-free state (bone marrow blast reduced to <5%) occurred in 11 
additional patients. Antileukemic activity was associated with total dose or weekly time 
above 1 μmol/L plasma vosaroxin concentration (p<0.05). Vosaroxin exposure was dose 
proportional over 9-90 mg/m2 dose range The average terminal half- life was ~25 h and 
clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. 
Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. 
Phase 1/2 SPO-0012 Trial: Relapsed/Refractory AML 
This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients 
with relapsed/refractory (AML). 13,22 Escalating vosaroxin doses (10-90 mg/m2; Days 
1 and 4) were given in combination with cytarabine using one of two schedules: 
Schedule A (24-hour continuous IV infusion, 400 mg/m2/day, Days 1-5) or Schedule B 
(2-hour IV infusion, 1 g/m2/day, Days 1 and 5). Following dose escalation, enrollment 
was expanded at the MTD. Among the 110 patients enrolled, 108 received treatment. 
The MTD for schedule A was vosaroxin 80 mg/m2 (dose-limiting toxicities: grade 3 
bowel obstruction and stomatitis); the MTD was not reached for schedule B 
(recommended phase 2 dose: 90 mg/m2). In the efficacy population (all first relapsed or 
primary refractory patients treated with vosaroxin 80-90 mg/m2; N=69), the complete 


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remission (CR) and combined CR (CR or CR with incomplete blood count recovery) rates 
were 25% and 28%, respectively. The 30-day all-cause mortality was 2.5% among all 
patients treated at 80-90 mg/m2. 
Phase 2 SPO-0014 Trial: Previously Untreated AML  
This study evaluated single-agent vosaroxin in patients ≥60 years of age with previously 
untreated AML with an unfavorable prognosis (N=113). 23,24   Dose regimen optimization 
was explored in sequential cohorts (A: 72 mg/m2 days 1, 8, 15; B: 72 mg/m2 days 1, 8; C: 
72 mg/m2 or 90 mg/m2 days 1, 4). The primary endpoint was combined complete remission 
(CCR) rate (complete remission [CR] plus CR with incomplete platelet recovery). Common 
(>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anemia, 
neutropenia, sepsis, pneumonia, stomatitis, and hypokalemia. Overall CR and CCR rates 
were 29% and 32%; median overall survival (OS) was 7.0 months; 1-year OS was 34%. 
Schedule C (72 mg/m2) had the most favorable safety and efficacy profile, with faster 
hematologic recovery (median 27 days) and lowest incidence of aggregate sepsis (24%) and 
30-day (7%) and 60-day (17%) all-cause mortality. At this dose and schedule, CR and CCR 
rates were 31% and 35%, median OS was 7.7 months, and 1-year OS was 38%. Overall, 
vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 
mg/m2 days 1, 4 is recommended for further study in this population. 
Phase 1/2 MD Anderson Cancer Center Trial: Older patients with Newly Diagnosed AML 
and High Risk MDS  
Patients eligible for enrollment in this study had AML or high-risk MDS (defined as 
having ≥ 10% blasts in the bone marrow), were ≥60 years old and had adequate performance 
status (ECOG ≤ 2) and organ function. 25  Patients <60 who were unsuitable for standard 
chemotherapy were also eligible. During phase 1 of the study, the first six patients received 
vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This 
dose was well-tolerated and used for phase 2 of the study; however, the induction dose was 
reduced to 70 mg /m2 starting with patient 25 due to mucositis. The vosaroxin dose could be 
maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were 
repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles of vosaroxin and 
decitabine. Dose adjustments and dose delays of one or both agents, were allowed based on 
toxicity. 
The primary endpoint was the overall response rate including complete response (CR) + 
CR without platelet recovery (CRp) + CR with insufficient hematological recovery (Cri). 
Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and 
early mortality. At the time of this report, 34 patients with AML (N=31) and high-risk MDS 
(N=3) with a median age of 70 years (range, 41-78) had been enrolled and 33 (97%) were 
>60 years old. These included 14 (41%) with diploid cytogenetics, 12 (35%) with complex 


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cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and eight (24%) 
with other miscellaneous abnormalities. Twelve patients with AML (36%) had antecedent 
hematological disorders (AHD) including MDS (N=7; 21%), myeloproliferative neoplasm 
(N=3; 9%) and MDS/MPN (N=2; 6%). Three patients with AHD had received prior therapy 
including 5-azacytidine (N=1), ruxolitinib + 5- azacytidine (N=1) and lenalidomide (N=1). 
Additionally, five patients (15%) had therapy- related disease with prior exposure to 
chemotherapy or radiation therapy. Median bone marrow blast%, median white blood cell, 
hemoglobin, and platelet counts were 38% (range, 9-97), 4.1 x 109/L (range, 0.4-57.0), 9.4 
g/dL (range, 6.8-11.5), and 41 x 109/L (range, 7-333), respectively. The patients evaluable 
for response (N=30) achieved CR (N=13; 43%), CRp (N=6; 20%), and CRi (N=3; 10%) for 
an overall response rate of 73%.. Patients had received a median of 2 (range, 1-6) treatment 
cycles with the median number of cycles to response being 1 (range, 1-4). The median 
duration of CR/CRp/CRi had not been reached. Four patients had proceeded to allogeneic 
stem cell transplant. The 4- and 8-week mortality rates were 0% and 17%, respectively. The 
regimen was well tolerated with the main grade ≥ 3 toxicity being mucositis (N=8; 24%). 
Phase 3, randomized, double-blind, placebo-controlled, pivotal clinical trial of vosaroxin in 
combination with cytarabine to evaluate overall survival in patients with first relapsed or 
refractory AML 
Patients eligible for this trial were > 18 years of age with either refractory AML 
(persistent disease after induction, or first complete remission [CR1] < 90 d) or AML in first 
relapse (early relapse: CR1 of 90 d to 12 mo; late relapse: CR1 of 12 mo to 24 mo). Patients 
were allowed to have received 1-2 cycles of prior induction chemotherapy including at least 
1 cycle of prior anthracycline (or anthracenedione) and cytarabine. Randomization was 
stratified by disease status (refractory, early relapse, late relapse), age (< 60, ≥ 60 years), and 
geographic location (US, non-US). Primary efficacy and safety endpoints were overall 
survival (OS) and 30- and 60-day mortality; secondary endpoints were complete remission 
(CR) rate and incidence of adverse events (AEs). 
Enrollment occurred between December 2010 and September 2013 with 711patients 
randomized to receive either vosaroxin+cytarabine  (n = 356) or placebo+cytarabine (n = 
355) at 124 sites.  Per the adaptive design, a prespecified 1-time sample size increase of 225 
patients was implemented after the interim analysis.  At the final analysis, median OS was 
7.5 mo (95% CI: 6.4-8.5) with vosaroxin+cytarabine vs. 6.1 mo (95% CI: 5.2-7.1) with 
pla/cyt (HR = 0.866 [95% CI: 0.73-1.02]; 2-sided unstratified log-rank P = 0.06). The OS 
difference was statistically significant in a preplanned analysis accounting for the 
stratification factors at randomization (2-sided stratified log-rank P = 0.02). 
Overall, 29.5% of patients underwent allogeneic stem cell transplant, including 45.8% 
of patients < 60 years and 20.2% of patients ≥ 60 years. Transplant rates were comparable 
between the 2 treatment arms (30.1% with vosaroxin+cytarabine and 29.0% with 


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placebo/cytarabine). In a predefined analysis censoring for subsequent ASCT, median OS 
was improved with vosaroxin+cytarabine (6.7 mo vs 5.3 mo with placebo+cytarabine; HR = 
0.81 [95% CI: 0.67-0.97]; P = 0.02; stratified P = 0.03). In predefined subgroup analyses, 
OS benefit was greatest in patients aged ≥ 60 years (7.1 mo with vosaroxin+cytarabine vs 
5.0 mo with placebo+cytarabine; HR = 0.75; P = 0.003) and those with early relapse (6.7 
mo vs 5.2 mo; HR = 0.77; P = 0.04). OS with vosaroxin+cytarabine vs. placebo+cytarabine 
was 9.1 mo vs 7.9 mo in patients < 60 years (HR = 1.08; P = 0.60); 6.7 mo vs 5.0 mo in 
patients with refractory disease (HR = 0.87; P = 0.23); and 14.1 mo vs 12.3 mo in patients 
with late relapse (HR = 0.98; P = 0.96), respectively. A CR was achieved in 30.1% of 
patients treated with vosaroxin+cytarabine vs. 16.3% treated with placebo+cytarabine (P = 
0.00001). 
Thirty-day and 60-day all-cause mortality was similar in the 2 arms (30-day: 7.9% vs 
6.6%; 60-day: 19.7% vs 19.4% with vosaroxin+cytarabine vs. placebo+cytarabine, 
respectively).  Most common serious AEs were febrile neutropenia (11.3% with 
vosaroxin+cytarabine vs. 7.4% with placebo/cytarabine), sepsis (8.7% vs 4.3%), pneumonia 
(7.6% vs 4.9%), bacteremia (8.5% vs 2.9%), and stomatitis (3.4% vs 1.4%). Serious and 
non-serious cardiac, renal, neurologic, and hepatic AEs were comparable between treatment 
groups. 
2. OBJECTIVES 
2.1. Primary Objectives 
• To assess the rate of complete remission (CR) after induction therapy with the 
combination of “7+V” [vosaroxin and standard dose infusional cytarabine] for 
patients with newly diagnosed, previously untreated acute myelogenous leukemia 
(AML) 
 
2.2. Secondary  Objectives 
• 
To further evaluate and the safety and tolerability of “7+V”  
• 
To evaluate for the presence of minimal residual disease (MRD) remaining after 
“7+V” induction and/or re-induction 
• 
To determine CR/ CRi rate after one and / or 2 cycles of “7+V” induction 
• 
To determine time to neutrophil and platelet recovery following “7+V” induction 
• 
To assess disease free survival (DFS) at 1yr of patients achieving CR / CRi after 
“7+V” induction  
• 
To assess overall survival (OS) at 1yr of all patients receiving protocol defined 
therapy  
• 
To determine correlation of pretreatment HSCT comorbidity index,  AML-Score,  
and Wheatley Index scores with disease response, DFS and OS 
 
 


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2.3. Exploratory Objectives 
• 
To describe the mutational burden of this cohort of AML patients 
• 
To correlate genomic aberration with response rate, DFS, and OS 
• 
To determine the number of patients treated with vosaroxin who eventually go to 
allogeneic HSCT 
 
3. STUDY DESIGN 
3.1. Overall Design and Plan 
• Single-arm, open-label, phase II study of vosaroxin in combination with cytarabine 
in patients with newly diagnosed AML.   
• Vosaroxin will be administered intravenously at 90 mg/m2 on days 1 and 4.  
Cytarabine will be administered in standard fashion as a continuous infusion of 100 
mg/m2 daily on days 1-7.  
 Patients with evidence of residual leukemia on “Day 14 biopsy” following initial 
induction will be offered re-induction with intravenous vosaroxin at 70 mg/m2 
on days 1 and 4 in combination with continuous infusion cytarabine at 100 
mg/m2 daily on days 1-7. 
• Two-stage design.  Forty-one (41) patients will provide 80% power to detect a 
20% increase in complete remission rates (from 40% to 60%) with a Type I Error 
rate of 5%. The design permits one interim look to examine evidence of futility 
after the first 17 patients are evaluable for response.  If ≤ 7 patients achieve CR 
then the likelihood of reaching the goal endpoint of ≥ 60% remission would be 
diminished.  In this case, the DSMB (consisting of a representative from the 
funding organization, the study chairs, a biostatistician, and participating 
investigator to be selected by the study chairs) will review the clinical data to 
determine the merits of continued enrollment.  If > 7 CRs are observed then the 
second stage will open automatically and increase enrollment to 41 patients.   
• Stage 1: First 17 patients who are evaluable for response prior to futility 
analysis 
• Stage 2: Patients 18-41 enrolled after futility analysis   
 
• Likelihood-based assessment of the statistical evidence be used to determine the 
reliability of the data generated and will provide the option of adding one or two  
extension cohorts of 10 participants each if the initial trial results are 
inconclusive.   
 
 
 
 
 
 
 


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3.2. Duration of Study 
• First potential date of Study Activation: Feb 01, 2016  
 
 
 
• Accrual duration: 12 months 
• First patient enrolled/treated: Mar 2016 
• Last patient enrolled/treated: Feb 2017 
 Completion of 12-month follow-up post enrollment: Feb 2018 
 
4. SELECTION OF STUDY POPULATION 
4.1. Inclusion Criteria 
Patients meeting the following criteria will be eligible: 
• Age ≥ 18 years of age 
• Ability to provide informed consent 
• Ability to tolerate intensive therapy with vosaroxin 90mg/m2 and standard dose of 
cytarabine as per investigator discretion 
• ECOG performance status 0-2 at time of study entry (Appendix A) 
• Morphologically confirmed new diagnosis of AML in accordance with WHO 
diagnostic criteria (Appendix B) 
• Patients who have received hydroxyurea alone or have previously received “non-
cytotoxic” therapies for MDS or MPN (e.g., thalidomide or lenalidomide, 5-
azacytidine or decitabine, histone deacetylase inhibitors, low-dose cytoxan, tyrosine 
kinase or dual TK/src inhibitors) will be allowed  
• Renal function: Serum creatinine ≤ 2.0 mg/dL 
• Hepatic enzymes (ALT, AST) ≤ 2.5 x upper limit of normal  
• Total bilirubin ≤ 1.5 x upper limit of normal unless clearly related to Gilbert’s 
Disease, hemolysis or leukemic infiltrate 
 
• For patients in stage 1 (patients #1-#17).  
 ≥ 55 years of age with AML of any risk classification, OR 
 18-54 years of age with high-risk AML disease based on one of the following: 
o Antecedent hematologic disorder including myelodysplasia (MDS)-related 
AML (MDS/AML) and prior myeloproliferative disorder (MPD)  
o Treatment-related myeloid neoplasms (t-AML/t-MDS) 
o AML with FLT3-ITD  
o Myeloid sarcoma  
o AML with multilineage dysplasia (AML-MLD)  
o Adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 
21q or 17p; t(6;9); t(9;22); trisomy 8; trisomy 13; trisomy 21; complex 
karyotypes (≥ 3 clonal abnormalities); monosomal karyotypes 
 
 
 
 


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• For patients in stage 2 (enrolled patient #18 and beyond).   
• ≥ 55 years of age with AML of any risk classification, OR 
• 
18-54 years of age with intermediate or high risk AML as defined by NCCN risk 
assignment   (Appendix C) 
 
4.2 EXCLUSION CRITERIA: 
Stage I: 
• Patients 18-54 years of age with “good risk” AML defined as the presence of t(8;21) , 
inv(16), or t(16;16) as diagnosed by morphologic criteria, flow cytometric 
characteristics, and rapid cytogenetics or FISH (Patients with t(8;21), inv(16), 
t(16;16) who are unable to receive anthracycline based induction will be allowed to 
enroll provided the medical reason they are unable to receive anthracyclines is 
clearly documented and provided they fulfill all other eligibility and criteria).     
 
Stage I and Stage II: 
• Patients with Acute Promyelocytic Leukemia (APL) as diagnosed by morphologic 
criteria, flow cytometric characteristics, and rapid cytogenetics or FISH or molecular 
testing 
• Any previous treatment with vosaroxin  
• Concomitant chemotherapy, radiation therapy 
 For patients with hyperleukocytosis with > 50,000 blasts/uL; leukopheresis or 
hydroxyurea may be used prior to study drug administration for cytoreduction at 
the discretion of the treating physician. Hydroxyurea must be stopped 24 hours 
prior to initiation of protocol defined therapy. 
• Active CNS leukemia  
• Active, uncontrolled infection. Patients with infection under active treatment and 
controlled with antibiotics are eligible.  
• Active, uncontrolled graft vs. host disease (GVHD) following allogeneic transplant 
for non-AML condition (e.g. MDS, lymphoid malignancy, aplastic anemia). Patients 
with GVHD controlled on stable doses of immunosuppressants are eligible.  
• Known HIV seropositivity 
• Any other medical, psychological, or social condition that may interfere with study 
participation or compliance, or compromise patient safety in the opinion of the 
investigator or medical monitor 
• LVEF < 40% as measured by echocardiogram or MUGA 
• Women who are pregnant or breastfeeding 
• Renal insufficiency requiring hemodialysis or peritoneal dialysis 
 
 
 
 


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5. STUDY PROCEDURES  
(see Table 1: Study Calendar) 
5.1. Screening 
Eligibility requirements and signed informed consent should be obtained within 
15 days prior to Induction 1, Day 1. 
 
5.1.1 TRIAL REGISTRATION 
The Vanderbilt-Ingram Cancer Center (VICC) Multi-Institutional Coordinating 
Center (hereafter referred to the as “the Coordinating Center”) will coordinate enrollment 
onto the study. Once the Coordinating Center confirms eligibility and approves 
enrollment onto the study, it will provide the sites with confirmation and assigned patient 
ID numbers.   
 
5.1.2 TRIAL REGISTRATION PROCESS 
To enroll a patient onto the study, participating sites should submit the enrollment 
packet to the Coordinating Center for eligibility confirmation and enrollment prior to the 
initiation of protocol therapy.  
 
The enrollment packet includes:  
• Enrollment Form 
• Eligibility Screening Worksheet  
• Signed patient consent form  
• Eligibility supporting documents such as pathology reports, laboratory tests, etc. 
The enrollment packet should be submitted via secure email transfer or fax using the 
contact information listed below: 
Attn: VICC Multi-Institutional Coordinating Center 
Fax:  615-875-0040 
or  
Coordinating.Center@vanderbilt.edu 
 
The enrollment packet should be submitted to the Coordinating Center as early as 
possible to ensure timely patient registration. Same-day enrollments cannot be 
guaranteed. 
 
Vanderbilt typically does not grant exceptions to eligibility criteria. 
 


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Once the Coordinating Center has confirmed eligibility, the site will be notified 
via email with assigned patient sequence number. 
 
5.2. Treatment / Hematologic Recovery 
The treatment period will include up to two cycles of treatment (Induction 1, 
Induction 2).  In each cycle, the first day of study treatment will be considered day 1. 
Each cycle will include vosaroxin treatment on Days 1 and 4 and cytarabine on Days 1-7 
followed by a variable interval required to achieve hematologic recovery defined as 
absolute neutrophil count (ANC) > 1000 cells/µL and platelets > 100,000 cells/µL. 
Hematologic recovery is expected to occur approximately 5 to 6 weeks after the first 
treatment day  of each cycle. Each cycle will be a minimum of 14 days and a maximum 
of 8 weeks.  
 
5.2.1. Induction 1 
An early assessment of antileukemic activity (bone marrow biopsy or aspirate) 
will be performed at approximately Day 14 for the sole purpose of guiding treatment 
decisions. If the early treatment assessment indicates an ablated bone marrow with < 5% 
blasts, CBC will be examined as noted in the schedule of events thereafter to monitor for 
hematologic recovery. 
If the early treatment assessment indicates residual leukemia (≥ 5% blasts) and a 
second cycle is indicated in the judgment of the investigator, the investigator may initiate 
Induction 2 any date prior to Induction 1 day 57 (no later than 8 weeks after Induction 1, 
Day 1) if eligibility criteria are met. Bone marrow assessments may be repeated as 
necessary per standard of care (investigator discretion) to clarify or confirm a finding of 
residual leukemia.  In the event that blasts are ≥ 5% blasts, but ≤ 10%, the investigator 
may choose to pursue an additional bone marrow biopsy at a future date prior to making 
decision on whether Induction 2 is warranted. 
5.2.2 Induction 2 
Induction 2 will not be necessary for all patients, but may be appropriate if the 
Induction 1 early treatment or hematologic recovery assessment indicates residual 
leukemia is present, and if a second cycle is indicated in the judgment of the investigator. 
Eligibility for Induction 2 requires that non-hematologic toxicity and abnormal laboratory 
values be resolved to grade ≤ 1, if assessed by the investigator as related to treatment and 
clinically significant. Recovery of ANC, hemoglobin/hematocrit, and/or platelet counts is 
not required prior to Induction 2. 
 
 
 
 


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5.2.3 Consolidation 
Consolidation therapy is not defined by the protocol.  Patients achieving CR/CRi 
will proceed with consolidation therapy and/or hematopoietic stem cell transplantation at 
the discretion of the treating physician in accordance with institutional practice.     
 
5.3. End of Treatment 
End of treatment procedures will be performed for all patients when study 
treatment is discontinued for any reason or another AML therapy is started, including 
conditioning regimens for transplantation. Every reasonable effort will be made to 
complete the procedures to prevent loss to follow up.  A separate visit may not be 
required, and the procedures performed at the last visit may satisfy the required end of 
treatment procedures. Ongoing serious adverse events (SAEs) assessed by investigators 
as related to study treatment will be followed with reasonable effort until the event 
resolves, stabilizes, is considered irreversible, or the patient receives a new AML therapy 
or dies. 
 
5.4. Follow-Up 
At the end of treatment, the purpose of follow-up will be to document survival 
status for all patients and to document disease status for patients in continuing CR or CRi. 
Every reasonable effort must be made to obtain information about patient status. In the 
event of death, additional information will be obtained, such as the date of death, cause of 
death, date of last contact, and laboratory and bone marrow results to document disease 
status at the time of death, such as continuing remission, relapse, persistent or recurrent 
leukemia. Follow-up for all patients will be based on chart review and/or phone call 
every 3 months after completion of protocol defined therapy for one year.   
 
 


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TABLE 1. 
Study Calendar 
 
Procedures 
Screening 
C1: 
induction 
C1: response 
assessment 
C2: induction 
C2: response 
assessment 
EoT p 
 
Within 15 
days of 
C1D1 
D1 
D4 
Weekly until 
recovery or D57 
(+/- 3d) j,k,l,m 
Within 
3 days 
of C2D1 
D1 
D4 
Weekly until 
recovery or D57 
(+/-3d) j,k,l,m 
 
TESTS & OBSERVATIONS 
Informed consent a 
X 
 
 
 
 
 
 
 
 
Vital signs b 
X 
X 
X 
X 
 
X 
X 
X 
 
H&P b 
X 
X 
 
 
 
X 
 
 
 
ECOG PS b 
X 
X 
 
X 
 
X 
 
X 
 
Directed physical exam b 
 
 
X 
X 
X 
 
X 
X 
 
Adverse event evaluation c 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant med review 
X 
X 
X 
X 
 
X 
X 
X 
 
Vosaroxin d 
 
X 
X 
 
 
X 
X 
 
 
Cytarabined 
 
X 
 
 
 
X 
 
 
 
LABS 
Echocardiogram e 
X 
 
 
 
X 
 
 
 
 
EKG f 
X 
 
X 
 
X 
 
X 
 
 
CBC with differential g 
X 
X 
X 
X 
 
X 
X 
X 
X 
Blood chemistry h 
X 
X 
X 
X 
 
X 
X 
X 
 
PT, PTT, INR, fibrinogen 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test i 
X 
 
 
 
 
 
 
 
 
DISEASE ASSESSMENT 
Bone marrow aspirate and core j 
X 
 
 
X o 
 
 
 
X 
X 
Molecular, cytogenetics, FISH k 
X 
 
 
X 
 
 
 
X 
X 
Correlative laboratory studies l 
X 
 
 
X 
 
 
 
X 
X 
Disease status/survival m 
 
 
 
X 
 
 
 
X 
X 
Comorbidities n 
X 
 
 
 
 
 
 
 
 
 
 
Long Term 
Observations 
Follow-up  
via telephone and/or chart review 
6mo after diagnosis 
12mo after diagnosis 
Disease Status/Survivalm 
X 
X 
Allogeneic HSCT status 
X 
X 
 
Schedule of Assessments for VITAL STUDY 
a 
Informed consent must be obtained within 15 days prior to initiation of trial treatment 
b 
The screening physical examination, ECOG performance status, hematology, chemistry, PT/INR 
and serum pregnancy test must  be conducted within  7 days from C1D1. If the initial 
examinations are obtained within 72 hours of C1D1, they do not need be repeated.  At the 
baseline visit only, height will also be recorded.  PEs and laboratory assessments will be 


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completed until count recovery as directed on calendar. Directed physical exams as per 
investigator discretion.  Vital signs to include weight. 
c 
Adverse event reporting will be required on days  as noted in schedule of assessments.  In the 
event that AEs occur between these visits, they will be captured if they meet criteria as defined in 
section 10. 
d 
Vosaroxin is administered on D1 and D4 as per section 3.1.  Oral cryotherapy will be utilized in 
association with Vosaroxin administration (see appendix E). Cytarabine will be administered via 
continuous infusion D1-D7. 
e 
Echocardiogram will be conducted to assess cardiac function prior to administration of 
chemotherapy.  In the event that there are abnormalities on the initial echocardiogram, or if the 
investigator has concern for cardiac complications during the first induction, a second 
echocardiogram may be conducted as per standard of practice. 
f 
EKGs will be obtained during screening and again after vosaroxin administration on D4 visit. 
g 
CBC with differential will include RBC, Hgb, hematocrit, total WBC, ANC, platelet count, and ≥ 
5 part differential 
h 
Chemistry panel includes the following:  urea or BUN, creatinine, sodium, potassium, calcium, 
magnesium, phosphorus, glucose albumin, total protein, ALT, AST, total bilirubin, uric acid, and 
LDH 
i 
A serum pregnancy will be performed only at baseline when appropriate as per protocol. 
j 
Bone marrow biopsy and aspirate are required prior to enrollment.  In the event that a diagnostic 
bone marrow aspirate/biopsy was performed prior to study-specific informed consent being 
obtained, diagnostics from this marrowing may be reported (and specimen collection at screening 
will be limited to biospecimens for lab correlates, see footnote L below).  Bone marrow aspirate 
and biopsy also are required at the following time points: 
• 
C1D14 (+/- 2 days): for assessment of residual leukemia. Patients with residual leukemia 
at this assessment are eligible for a second round of induction (C2). 
• 
During response assessment period (C1 and/or C2): upon peripheral count recovery (as 
determined per weekly assessments); OR per investigator discretion, even in absence of 
count recovery; OR at EoT occurring no later than D57 (e.g., in absence of peripheral 
count recovery, or patient still being followed for inconclusive prior marrow). Note that 
marrow biopsy/aspirate is NOT required to be repeated as an EoT activity if already 
performed at recovery. 
k 
Molecular (mutation testing) and cytogenetic (classic karyotyping testing ± FISH) will be 
performed as per standard of care. These analyses should be reported at study enrollment and in 
setting of response assessment at recovery or EoT, per standard of care.  
l 
Peripheral blood and aspirate from bone marrow will be required as per the laboratory manual at 
study enrollment and in setting of response assessment at recovery or EoT. 
m 
Disease assessment and survival will be noted during therapy and at 6 and 12mo follow up, as per 
section 3.1. During therapy, disease assessment should be reported in setting of response 
assessment at recovery or EoT. 
n 
Co-morbidities and risk stratification will be assessed prior to therapy via HCT-Comorbidity 
index 26, Wheatley index 27, AML-SCORE 28 (see Appendix F), and then correlated with response 
to induction and rates of allogeneic hematopoietic stem cell transplant as per exploratory 
endpoints. 
o 
At C1D14 (+/- 2 days), bone marrow required for assessment of residual leukemia. Otherwise, 
disease assessment procedures during response assessment period should be performed per 
footnotes J, K, L, and M. 
p 
EoT activities required ONLY if disease assessment procedures not already performed in setting 
of count recovery during response assessment period (C1 and/or C2). See also footnote J, bullet 
point 2.  


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Coordinating Center Protocol Number:  VICCHEM1553 
 
 
6. STUDY DRUG ADMINISTRATION 
6.1. Vosaroxin Formulation 
Each vial contains 2,300 mg vosaroxin at a concentration of 10 mg/mL. Each milliliter 
also contains 45 mg of D-sorbitol to maintain isotonicity.  Methanesulfonic acid is added 
as an aid to solubilize vosaroxin. The sterile nonpyrogenic solution is formulated without 
preservatives. 
 
6.2. Vosaroxin Storage 
Vosaroxin vials must be stored as packaged at controlled room temperature, 
thermostatically maintained from 20°C to 25°C (68°F to 77°F). Do not store above 25°C.  
Stability data supports variations in prevailing temperature between 15°C and 30°C.  
Vosaroxin must not be frozen or stored in a refrigerator. When vosaroxin is drawn into a 
syringe, stability data support a maximum of 2 hours exposure to continuous ambient 
light. If the syringe containing the product is completely wrapped in foil or other 
protective covering from ultraviolet and visible light (e.g., amber bag, brown paper bag), 
this 2-hour stability maximum can be extended up to 24 hours.  
 
6.3. Dose Calculation, Preparation, and Administration 
6.3.1. 
Dose Calculation 
The administration of study drugs (vosaroxin and cytarabine) requires calculation 
of body surface area (BSA) using the patient’s actual, measured body weight and 
height. For patients with a BSA > 2.4 m2, dosing should be calculated using a 
maximum BSA of 2.4 m2. The Mosteller formula29  is recommended to calculate 
BSA in m2; however, pharmacy personnel may calculate BSA according to 
institutional method. 
Mosteller formula: BSA (m2) =   ටℎ𝑒𝑒𝑒ℎ𝑡 (𝑐𝑐) 𝑥 𝑤𝑤𝑤𝑤ℎ𝑡 (𝑘𝑘)
3600 
 
 
6.3.2 Preparation and Administration of Vosaroxin 
Undiluted vosaroxin should be administered according to these general guidelines: 
• Wear gloves and adhere to strict aseptic technique. 
• Inspect the vial and confirm it is not cracked or damaged in any way. 
• Inspect the solution and confirm it is not discolored and contains no visible 
particulates. 
• Do not infuse vosaroxin in the same IV line (tubing) with sodium chloride 
solutions or other medications. The product may precipitate in sodium chloride 
solutions.  If no alternative line is available, flushed saline thoroughly with 5% 
dextrose in water (D5W) before and after administration. 


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Suggested Procedure for Preparation 
• Calculate the dose according to physician instructions. 
• Attach an appropriate gauge needle to the tip of the sterile plastic syringe that will 
be used to administer vosaroxin. 
• Withdraw the product from the vosaroxin vial into the syringe.  Note:  a vacuum 
may result as the product is withdrawn.  Avoid or release the vacuum per 
institutional practice. 
Please note that if using a vent needle to aid in drawing investigational product 
from the vial, the vial should remain upright, and the vent needle should only be 
inserted into the head space containing air.  The needle used to withdraw product 
should be inserted as far as possible to the bottom of the vial to withdraw the required 
volume of drug. 
If pressurizing a vial, do not use a vent needle. Add the equivalent dose volume of 
air to the vial headspace in the upright position, invert the vial, insert the syringe 
needle into the solution, and withdraw the required volume of drug. 
• When the syringe contains the entire dose to be administered, cap the syringe and 
discard the needle. 
• Protect the filled, capped syringe from light and whilst in transit to the patient 
until ready to administer the product.  
Suggested Procedure for Administration 
• A biluminal or triluminal catheter is recommended.  Start an IV infusion through 
one of the lumens using D5W for analogous solution at a slow rate sufficient to 
keep the vein open. 
• Before administration of vosaroxin, increase the D5W infusion rate to 
approximately 100 mL per hour and continue this rate during the vosaroxin 
infusion. 
• Administer vosaroxin via syringe by assessing and available hub or stopcock. 
• Administer vosaroxin as a short infusion within 10 minutes, either manually or 
using a syringe pump. 
• At the end of the infusion, flushed the IV line with D5W per institutional 
standard. 
• If a central catheter or heparin lock is in place, it may be capped according to the 
sites usual procedures. 
Vosaroxin is not known to be a thoracic and/or irritant.  If extravasation is 
observed or suspected, treat according to standard institutional procedures. 
 


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7. CONCOMITANT MEDICATIONS 
Concomitant medications are recommended as prophylaxis for nausea, vomiting, and 
infections, and Darvon for managing myelosuppression as shown in table 2. 
 
Myelosuppression is expected in patients with AML due to underlying disease, as well as 
due to chemotherapy (such as vosaroxin and cytarabine), or both. Most patients will have 
neutropenia, thrombocytopenia, or both at study entry. Myelosuppression may be managed 
with growth factor support and blood transfusion according to institutional standard of care, 
American Society of Clinical Oncology (ASCO) Practice Guidelines, and NCCN Practice 
Guidelines.  
 
Infections secondary to myelosuppression are common in patients with AML, and may 
be related to underlying disease, chemotherapy, or both. Therefore, the use of prophylactic 
antibiotics, antifungal agents, and antiviral agents is required. A regimen of levofloxacin 
(500 mg po daily), fluconazole (400 mg po daily), and valacyclovir (500 mg po q12h) is 
suggested with substitutions permitted as per institutional formulary. (See Appendix E) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2. 
Instructions for the use of concomitant medications and therapies 
Category of use 
Medication 
Comment on use 
Restriction on use 
Recommended 
Prophylactic antibiotics, 
antifungal agents, and 
antiviral agents 
Required 
(see Appendix E) 
None 
Prophylactic antiemetic 
medications 
According to standard of 
care at individual study 
site 
None 
Mouth Care 
Suggested regimen 
See Appendix E 
See Appendix E 
Allowed 
Oral allopurinol or 
rasburicase 
At investigator’s discretion 
according to standard of 
care at individual study 
site 
None 
Leukapheresis 
Before induction 1 day 1 
only 
Transfusion of red blood 
cells 
None 
Transfusion of platelets 
None 
Transfusion of granulocytes 
None 
Erythropoietin or darbepoetin 
None 
Any other medications for 
supportive care 
Must be necessary for the 
patient’s welfare and 
expected not to interfere 
with evaluation of study 
treatment 
Prohibited/Restricted 
Hydroxyurea or medications 
to reduce to blast count 
May use transiently for 
reduction of cells if WBC 
>/= 50,000 
Allowed  only >24hours 
prior to initiation of 
protocol defined therapy  
Myeloid growth factors (e.g., 
sargramostim, filgrastim, 
pegfilgrastim) 
May only use if patient’s 
clinical status declines, 
and investigator uses as 
rescue sepsis, etc. 
Restricted to neutropenic 
sepsis, bacteremia or other 
severe infection 
Investigational products 
(those not approved for any 
indication by the FDA or 
other regulatory authorities 
None 
Prohibited until end of 
protocol defined therapy 
Nonprotocol treatment for 
acute myeloid leukemia 
None 
Prohibited until end of 
protocol defined therapy 
 
 
 
 
 
 
 
 


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8. DISCONTINUATION OF TREATMENT 
Treatment may be discontinued for a variety of reasons, including patient withdrawal, 
investigator decision, and reasons specified by the protocol. 
8.1. Discontinuation Criteria for Individual Patients 
 
8.1.1. Patient  Withdrawal 
Patients may voluntarily withdraw consent to participate in the clinical 
study at any time and without giving any reason. Their withdrawal will not 
jeopardize their relationship with their healthcare providers or affect their future 
care. Patients may also choose to withdraw from study treatment, but agree to 
remain in the study for follow up procedures. 
 
8.1.2. Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study treatment 
if clinically significant changes in clinical status or laboratory values are noted. 
 
8.1.3. Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following 
reasons: 
• Maximum allowed treatment completed  
• Failure to achieve a CR or CRi after 2 attempts (Induction 1 / 2) 
• Disease relapse after a CR or CRi 
• Clinically significant neutropenia or thrombocytopenia in the absence of 
residual leukemia that does not recover to grade ≤ 2 within 57 days  after the 
first dose of vosaroxin in any cycle 
• Clinically significant treatment related non-hematologic AE in the absence 
of residual leukemia that does not recover to grade ≤ 2 within 8 weeks after 
the first dose of vosaroxin in any cycle  
• Any AE that is unacceptable or intolerable  
• Intercurrent illness that prevents the next cycle of treatment 
• Pregnancy 
• Other non-protocol systemic AML therapy or prohibited medication 
initiated 
• General or specific changes, including protocol violations, rendering the 
patient unsuitable for further study treatment 
 
 
 


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8.1.4. 
Protocol violations and deviations 
Protocol violations are defined as significant departures from protocol 
required processes or procedures that affect patient safety or benefit potential, or 
confound assessments of safety or clinical activity. A protocol deviation is a 
departure from the protocol that does not meet the above criteria. Protocol 
violations or deviations may be grouped into the following classes: 
• Enrollment criteria 
• Study activities (missed evaluations or visits) 
• Noncompliance with dose or schedule, including dose calculation, 
administration or discontinuation criteria 
• Investigational product handling, including storage and accountability 
• Informed consent and ethical issues 
The Sponsor is responsible for implementing and maintaining quality 
assurance and quality control to ensure that studies are conducted according to the 
protocol, GCP, and all applicable regulatory requirements. A protocol deviation is 
any noncompliance with the protocol. Noncompliance can be on the part of the 
study participant, the Investigator, or the study site staff. All protocol deviations 
are required to be reported to the Sponsor and submitted to the IRB per 
institutional guidelines. Deviations to the protocol are not permitted except when 
necessary 
to 
eliminate 
an 
immediate 
hazard 
to 
study 
subjects. 
 
9. EFFICACY ASSESSMENTS 
9.1. Determination of Overall Survival 
Survival information will be collected for all patients in the study. 
 
9.2. Determination of Response 
The investigator will determine response based on local laboratory findings to guide 
treatment decisions. Response will be determined based on IWG response criteria as 
summarized in Table 3. 
 
9.3. Time-to-Event Endpoints 
In addition to OS, time to event endpoints include EFS and LFS. 


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TABLE 3. 
Vosaroxin Response Criteria Based on International Working Group 
Criteria30 
Category 
Neutrophils 
(cells/µl) 
Platelets 
(plt/µl) 
Bone 
marrow 
blasts (%) 
Other requirements 
Complete remission 
(CR) 
>1000 
≥ 100,000 
<5 
• No Leukemic blasts in peripheral 
blood. 
• Transfusion independence, except 
for infection, bleeding, or 
medical/surgical conditions 
predisposing to bleeding. 
• No extra medullary disease 
CR with incomplete 
count recovery (CRi) 
≤1000 
≥ 100,000 
<5 
• Meets criteria for CR except for 
neutrophils  
                                    OR 
>1000 
< 100,000 
<5 
• Meets criteria for CR except for 
platelets 
Partial Remission 
(PR) 
>1000 
≥ 100,000 
Decrease of ≥ 
50% to value 
between 5% 
and 25% 
 
Treatment Failure 
(TF)  
Persistent acute myeloid leukemia in blood or bone marrow, or therapy fails to 
achieve a remission of any category, or death prior to response assessment 
 
 
10. SAFETY ASSESSMENTS 
10.1. 
Safety Monitoring 
10.1.1. Common Adverse Events Attributed to Vosaroxin 
The safety profile of vosaroxin is consistent with the common 
pharmacologic effects of cytotoxic chemotherapeutic agents.  Myelosupression 
(including associated fatal infections) and gastrointestinal (GI) toxicity (including 
nausea, diarrhea, and upper GI mucositis) are known risks associated with 
vosaroxin treatment.  Oral mucositis (stomatitis) was the DLT in patients with 
hematologic malignancies treated with higher doses of vosaroxin:  up to 40 mg/m2 
once weekly for 4 weeks (28-day cycle) or up to 90 mg/m2 once weekly for 3 
weeks (28 day cycle; up to 270 mg/m2/cycle). In patients treated with  vosaroxin, 
oral mucositis is dose limiting and grade 3 or 4 oral mucositis usually appears 
within 2 weeks after the first dose. 
 
Per the most recent reference safety information (IB, Version 12), 
infections and febrile neutropenia were reported at a higher frequencies in patients 
with hematologic malignancies (39.7% and 36.9 of 648 patients respectively) than 
in patients with solid tumors (12.3% and 9.2% of 284 respectively). The GI 
toxicities of stomatitis and diarrhea were also reported at higher frequencies in 
patients with hematologic malignancies (46.8% and 47.7% respectively) than in 


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patients with solid tumors (11.3% and 17.3% respectively). For patients with 
hematologic malignancies who received vosaroxin (N = 648), the most common 
treatment-related AEs (with at least 20% incidence) include nausea (53.2%), 
diarrhea (47.7%), stomatitis (46.8%), febrile neutropenia (36.9%), decreased 
appetite (31.3%), vomiting (30.1%), anemia (29.0%), thrombocytopenia (28.5%), 
neutropenia (20.1%), and fatigue (21.0%). The only two grade 3 and 4 treatment-
related AEs reported in at least 20% of all vosaroxin treated patients (N = 932) are 
febrile neutropenia (26.4%) and neutropenia (21.5).  
 
For patients with AML treated with higher doses of vosaroxin, oral mucositis is 
dose limiting and grade 3 or 4 oral mucositis usually appears within 2 weeks after 
the first dose. Oral mucositis can be managed with standard supportive care 
(Appendix E). The incidence of combined grade 3 and 4 nausea and vomiting in 
vosaroxin studies is low (2.7% and 1.4% respectively). 
In general, adverse reactions are manageable with standard and diligent 
supportive care. Myelosuppression and GI toxicities should be managed 
according to Appendix E within the protocol. 
 
10.2. 
Overdose     
An overdose is defined as administering at least 25% more than the 
protocol-specified dose (i.e., ≥125% of the protocol-specified dose). Overdoses 
should be reported to the Coordinating Center regardless if occurrence of adverse 
event within 24 business hours of discovery as instructed per section 11.6. The 
clinical manifestation (if any) of an overdose should be reported as an AE or 
SAE, as appropriate. 
 
10.2.1. Pregnancy   
During the course of the trial, all female patients of childbearing potential 
(the definition of “women of childbearing potential” is listed in Appendix D), 
must contact the treating investigator immediately if they suspect that they may be 
pregnant (a missed or late menstrual period should be reported to the treating 
investigator) after the first dose of study treatment until end-of-treatment 
procedures are performed.   
Male patients that suspect they may have impregnated a partner must also 
notify the treating investigator immediately. If an investigator suspects that a 
patient may be pregnant prior to administration of trial drug(s), the trial drug(s) 
must be withheld until the result of the pregnancy test is confirmed.   
If a pregnancy is confirmed, the patient must not receive any trial drug(s), 
and must be discontinued from the trial, and the investigator must notify the 
Coordinating Center as soon as possible. The Coordinating Center will report the 
pregnancy to a Sunesis representative.    


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Subjects and their partners with reproductive potential must agree to use 
effective contraceptive measures during the study and for 2 months after the last 
dose of study treatment.  
See Appendix D for information regarding effective contraception 
measures. 
 
11. ADVERSE EVENT DEFINITIONS AND REPORTING 
 
11.1. 
Adverse Event Definitions According to ICH Guidelines and FDA Final Rule
 
on Safety Reporting Requirements 
 
Updated definitions according to both ICH and the FDA final rule are provided 
within Table 4. 
Table 4. 
Adverse Event Definitions 
Term 
Definitions per FDA Final Rule 
Adverse Event 
Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related 
Suspected adverse reaction  
Any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the adverse 
event. 
 
Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse 
event caused by a drug. 
Unexpected adverse event or 
unexpected suspected adverse 
reaction  
An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed. 
Includes adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.  


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Term 
Definitions per FDA Final Rule 
Serious adverse event or 
serious suspected adverse 
reaction 
Any untoward medical occurrence that at any dose, in the opinion 
of the investigator or sponsor: 
• Results in death, Is life-threatening, 
NOTE: The term “life-threatening” in the definition of 
“serious” refers to an event in which the patient was at risk 
of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it 
were more severe. 
• Results in a persistent or significant incapacity or a 
substantial disruption of the ability to conduct normal life 
functions, 
• Is a congenital anomaly/birth defect. 
• Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
 
11.2. 
Eliciting Adverse Event Reports 
Simple, unbiased questions should be asked to elicit reports of AEs during the 
clinical study. For example: 
• How have you felt since your last visit? 
• Have you had any health problems since you were last here? 
 
11.3. 
Assessment and Recording  of Adverse Events 
All AEs grade 3 or higher occurring during the reporting period must be 
assessed and recorded as follows: 
• Name of the event (diagnosis preferred, otherwise state signs and 
symptoms) 
• Date of onset and stop date (if available) 
• Course (i.e., intermittent, ongoing) 
• Maximum intensity or severity (grade) based on the NCI CTCAE version 
4.03 
• Relationship to study treatment 
• Seriousness 
• Outcome 
• Use of concomitant medication to treat a patient for an AE 


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Adverse events of special interest that occur at grade 1 or higher will be 
recorded. Adverse events of special interest are: mucositis, infection, 
neutropenia, diarrhea, and thrombocytopenia. 
11.4. 
Guidelines for Recording Adverse Events 
Each reportable AE should be documented as a single medical diagnosis. If 
this is not possible, the signs or symptoms should be documented until a medical 
diagnosis is identified. If an AE resolves and reoccurs at a later date, a new AE 
must be documented and reported as appropriate. The following guidelines should 
be followed to improve the quality and precision of AE data: 
• Recognized medical terms (not colloquialisms, abbreviations, or jargon) 
should be used when recording AEs 
• The diagnosis (i.e., disease or syndrome) should be recorded instead of 
signs and symptoms (e.g., pneumonia instead of shortness of breath, 
coughing, and fever) 
• Any sign or symptom considered as unrelated to an encountered disease or 
syndrome should be recorded as an individual AE (e.g., if nausea and 
severe headache are observed at the same time, each event should be 
recorded as a separate AE) 
• Adverse events occurring within 30 days after EOT should be reported. 
 
11.5. 
Intensity of the Adverse Event 
The investigator will grade each reportable AE based on its maximum 
intensity (or severity) using the NCI CTCAE V4.03 (available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 31  If no grading criteria are 
provided for the AE, it should be graded using the scale presented in Table 5, 
noting that not all grades are appropriate for all AEs. 
 
11.6. 
Adverse Event Attribution 
The investigator will determine the attribution of toxicity relative to the 
vosaroxin, cytarabine, other concomitant medication, or other medical causes in 
accordance with the ICH E2A guidelines. 
 
 
 
 


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Table 5. Definition of Adverse Event  Attribution 
Attribution Description 
Unrelated 
The AE is clearly NOT related to the intervention. 
Unlikely: 
The AE is doubtfully related to the intervention. 
Possible: 
The AE may be related to the intervention. 
Probable: 
The AE is likely related to the intervention. 
Definite: 
The AE is clearly related to the intervention. 
 
11.7. 
Serious Adverse Event Reporting Requirements 
Study site personnel must report all SAEs by fax as soon as possible to the 
Coordinating Center, but within 1 business day of first becoming aware of the 
SAE. The following minimum information is required by the sponsor: 
• Patient identification (i.e., study number, sex, age) 
• Description of the SAE (diagnosis preferred, symptoms, etc.) 
• Investigator name 
• Study drug and causal relationship of the SAE to the study drug(s)  
The SAE report should be submitted via secure email transfer or via fax using the 
contact information listed below: 
Attn: VICC Multi-Institutional Coordinating Center 
Fax:  615-875-0040 
or  
Coordinating.Center@vanderbilt.edu  
Transmission of the SAE report should be confirmed by the site personnel 
submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become 
serious should also be reported to the Coordinating Center as soon as it is 
available; these reports should be submitted using the SAE Report Form.  
Investigators must submit written safety reports as required by their Institutional 
Review Board (IRB) or Institutional Ethics Committee (IEC) within timelines set 
by regional regulations (European Union common technical document or US 
FDA). The study site should retain documentation of the submission of expedited 
safety reports to the IRB/IEC, and their receipt. 
 
 
 


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Persistent or recurrent AML (or “disease progression”), including AML 
leading to death, should not be recorded as an SAE. Persistent or recurrent AML 
is an outcome of treatment and will be documented as treatment failure. 
Associated events resulting from persistent or recurrent AML (or “disease 
progression”) should be recorded as AE or SAEs, and SAEs resulting in death 
should be documented.  
 
11.8. 
General Instructions for Reporting Serious Adverse Events to the FDA and
 
Sunesis Pharmaceuticals 
 
Food and Drug Administration (FDA) 
FDA regulations and statutory provisions establish adverse event reporting 
requirements for human drugs. These requirements apply to the manufacturer of 
the product in question. In general, manufacturers of prescription drugs marketed 
for human use are required to submit postmarketing safety reports of adverse drug 
experiences to FDA.a A report of each adverse drug experience that is both 
serious and unexpected must be made to FDA as soon as possible, but no later 
than 7 days for a life-threatening or fatal event, and 15 days for all others after 
receiving information about the event.b Persons required to file such 15-day Alert 
reports are also required to investigate and submit any new information to FDA.c 
The Sponsor is responsible for reporting SAEs to the FDA. 
SAE supporting documents, such as a discharge summary or pertinent 
laboratory data may be provided; however, the study personnel should not wait to 
receive complete information before notifying the Coordinating Center of an 
SAE. The study site is responsible for requesting pertinent follow-up information 
missing from initial reports and forwarding the information within 24 hours of 
receipt. The Coordinating Center may request additional information if necessary. 
a 21 C.F.R. §§ 310.305(c); 314.80(c); 314.98 (human drugs), 600.80(c) (biologics). To avoid duplication of 
reports, non-applicant manufacturers, packers, and distributors of drug and biological products having an 
approved application may submit all reports of serious adverse drug experiences to the applicant within 5 
calendar days of receipt of information about the event, rather than submitting reports to FDA. See 21 C.F.R.  
 
§§ 314.80(c)(1)(iii), 600.80(c)(1)(iii). Similarly, packers and distributors of prescription drug products 
marketed for human use without an approved application may meet their post-marketing 15-day safety 
reporting obligations under 21 C.F.R. § 310.305 by submitting all reports of serious adverse drug experiences 
to the manufacturer within 5 calendar days of the receipt of information instead of reporting to FDA. 
Applicants/manufacturers receiving such data must then, in turn, submit a 15-day Alert report to FDA.  
b 21 C.F.R. §§ 310.305(c)(1); 314.80(c)(1)(i); 314.98(a) (human drugs), 600.80(c)(1)(i) (biologics). There are 
also certain specific reporting requirements concerning fatalities related to blood and blood products. 21 CFR 
§§ 606.170(b), 640.73. 


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c 21 C.F.R. §§ 310.305(c)(2), 314.80(c)(1)(ii), 314.98(a) (human drugs), 600.80(c)(1)(ii) (biologics). 
 
Sunesis Pharmaceuticals 
 
The Sponsor will report all SAEs regardless of causal relationship to study 
treatment to Sunesis. 
12. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
12.1. Statistical Considerations 
The primary objective of this single-arm, phase II clinical trial is to determine if 
Vosaroxin, in combination with standard dose cytarabine as induction chemotherapy, 
can significantly improve the rate of complete remission (CR) in patients with 
untreated acute myelocytic leukemia.  Forty-one (41) patients will be enrolled in a 
two-stage design that permits one interim look to examine evidence of futility. As per 
convention, the study will not be stopped early on the basis of preliminary evidence 
of efficacy observed at the end of the first stage (i.e., at the interim look). 
 
12.2. Sample Size Considerations 
In accordance with our desire to maintain a uniform study design, we set a total 
sample size of 41 participants.  An interim futility analysis will be conducted 
following enrollment of 17 evaluable patients.  If ≤ 7 patients achieve CR then the 
likelihood ratio in support of reaching the goal endpoint of  ≥ 60% remission would 
be diminished and  the data would then be reviewed by a DSMB to determine if 
further enrollment is warranted.  If > 7 CRs are experienced by the first 17 evaluable 
patients, enrollment will automatically proceed to enroll a total of 41 patients.  Under 
this two-stage design, a 60% complete remission rate by the “7+V” combination is at 
least 3.375 times more likely than a 40% CR rate if 22 or more patients experience 
CR. 
In the context of the planned likelihood assessment the option will be provided to 
add an extension cohort of up to 20 participants if the initial trial results are 
inconclusive. The use of a likelihood based extension cohort results in false positive 
and false discovery rates of 3.7% and 3.9%, respectively. 
 
12.3. Study Design 
Overview: Two-stage single-arm phase II designs with a single interim look for 
futility are common in this setting. Simon’s optimal two-stage design32 is a classic 
design and remains a popular choice. Herein we propose, in the context of a standard 
two-stage design, that a likelihood-based assessment of the statistical evidence be 
used  The unique and informative assessment of the observed evidence provided by 
likelihood ratios is reason enough to employ the approach. 


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We will employ the likelihood ratio (LR), not a tail area probability (p-value), 
to represent the strength of statistical evidence with respect to either a 40% or 60% 
true CR rate. Likelihood ratios are positive and a LR of 1 indicates completely neutral 
evidence. Small likelihood ratios (LR≪1) indicate evidence for the null hypothesis 
and large likelihood ratios (LR≫1) indicate evidence for the alternative. The scale of 
evidence is truly continuous, mapping a gradual shift from weak to moderate to 
strong evidence. 
 
An important advantage is that, unlike p-values, likelihood ratios have three 
evidential zones: evidence favoring the null hypothesis, evidence favoring the 
alternative hypothesis, and weak or inconclusive evidence (i.e., favoring neither 
hypothesis). Of course, p-values have only two zones: evidence against the null 
hypothesis (p<0.05) and inconclusive evidence (p>0.05; large p-values do not 
constitute stronger evidence in favor of the null hypothesis). Moreover, the likelihood 
false discovery rate is easily quantifiable as 1/(LR+1). Thus, an observed likelihood 
ratio of 4 (supporting the alternative) has a false discovery rate of 20%. Lastly, 
likelihood designs have excellent operating characteristics. 
 
Parameters and assumptions: For planning purposes, we assume the complete 
remission rate of standard induction chemotherapy is 40% in the targeted population 
of this trial and that the use of Vosaroxin in combination with cytarabine may 
increase this rate to 60%. We plan to enroll a total of 41 patients, but provide the 
option of adding an extension cohort of 10 to 20 participants if the initial trial results 
are inconclusive. 
 
Two-stage single-arm phase II designs: There are many two-stage designs that 
meet nominal Type I and II Error criteria.  We choose a two-stage design with a 
slightly increased expected sample size (EN) of 25.6 but keeps the two-stage sample 
size below that of a single-stage study (n=42) as follows: In stage I, 17 patients are 
accrued and the study is stopped only if 7 or fewer patients experience a complete 
remission (CR). Stopping in this fashion is interpreted as evidence of futility. If 8 or 
more patients experience a CR, the study continues to accrue an additional 24 
participants (for a total of 41). At the end, the study is said to generate evidence in 
support of the hypothesis that incorporating Vosaroxin into frontline AML induction 
chemotherapy is worthy of future study if 22 or more patients experience CR (i.e. if 
the observed response rate is greater than 53%). If frontline induction therapy with 
Vosaroxin plus standard dose continuous infusion cytarabine fails to improve upon 
the historical CR rate of 40% with conventional 7+3 induction therapy, the study has 
a 64% probability of early termination (PET). 


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A standard (frequentist) two-stage design is unable to handle deviations from 
its planned design (i.e., when the sample size is anything other than 17 or 41). This 
occasionally happens in multi-center clinical trials for practical reasons relating to the 
speed of communication and clinical expediency. Green and Dahlberg33 introduced 
flexible designs to that are able to accommodate such deviations from planed designs 
with minimal impact to their nominal operating characteristics. However, in this case, 
the Green and Dahlberg criteria result in a 25% PET, which poorly protects patients 
from ineffective therapy. This is one motivating factor in our choice of employing a 
likelihood-based assessment of the evidence.  The likelihood ratio reveals alternative 
interim stopping criteria that maintain nominal Type I and Type II Error rates, adding 
significant logistic flexibility (Table 6). Within the context of standard two-stage 
design, we believe our proposed design best balances the probability of early 
termination and expected sample size under the stated constraints. 
 
Table 6.  Interim stopping rules that are constrained to lie between 30% and 60% of total accrual and 
have a probability of early termination that exceeds 50%. Type I & II Error rates are below designed 
nominal levels (5% & 20%). 
Observed CRs 
in stage I 
Stage I sample 
size 
Probability of 
early 
termination 
Expected sample 
size 
Likelihood ratio favoring null 
that corresponds to Simon’s 
futility stopping rule 
7 
17 
64% 
25.6 
1/3.375 
8 
19 
67% 
26.3 
1/3.375 
9 
21 
69% 
27.2 
1/3.375 
10 
23 
71% 
28.2 
1/3.375 
6 
16 
53% 
27.8 
1/5.062 
7 
18 
56% 
28.2 
1/5.062 
8 
20 
60% 
28.5 
1/5.062 
 
Likelihood assessment of evidence: In accordance with our desire to maintain a 
uniform study design, we set a total sample size of 41 participants, a 17 patient first 
stage, and an interim futility criterion of 7 or fewer CRs with the added flexibility at 
the interim analysis indicated in table 1. The interim futility criterion translates to 
stopping the study at the end of the first stage if the observed likelihood ratio is less 
than 1/3.375 (i.e., if the evidence better supports the null hypothesis by a factor of at 
least 3.375). The likelihood ratio is defined as 𝐿𝐿= 𝜃1
𝑟(1 −𝜃1)𝑛−𝑟/𝜃0
𝑟(1 −𝜃0)𝑛−𝑟 
where r is the number of CR’s among n patients treated and 𝐻0: 𝜃= 𝜃0 = 0.4, 
𝐻1: 𝜃= 𝜃1 = 0.6. The translated stopping LRs for the competing designs are listed in 
the last column of table 1. 
 


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An important aspect of the likelihood assessment is that it can quantify the 
reliability of an observed outcome. For example, while the study would stop early with 
either an observed LR of 1/3.375 or 1/15 (evidence favoring the null hypothesis), the 
associated false discovery rates of 0.23 (=1/4.375) and 0.063 (=1/16), respectively, 
distinguish between those results and provide critical information for investigators when 
interpreting this evidence at the end of the study. 
 
With a likelihood design, it can happen that the trial yields weak or inconclusive 
evidence. Technically this can happen in all standard (i.e., frequentist) two-stage designs 
as well, but when it does the standard design forces a ‘call’ of either ‘Reject the null’ or 
‘Fail to reject the null’ (the assignment depends on how the Type I Error is spent 
throughout the study and can lead to some uncomfortable circumstances, such as calling 
evidence supporting the alternative as ‘Fail to reject’ and vice versa). Hence, in 
likelihood designs, it is desirable to minimize the chance of observing weak evidence. 
Our proposed two-stage design accomplished this sufficiently, as we next describe, but 
the important thing to remember is that if the trial does result in weak evidence there is 
no penalty for accruing additional subjects and reporting the combined evidence 
(assuming that resources will allow such action). In a likelihood design, the probability of 
weak evidence is driven to zero by the sample size, so it is always possible to refine 
inconclusive results, often within limited resource constraints. 
 
Table 7 displays a simulation of the proposed trial, potential outcomes, and their 
probability of occurrence. Analytic expressions for these probabilities exist, but 
simulating is simpler and essentially as accurate. Table 2 shows what we expect to 
happen, on average, for our proposed design and what happens if the sponsor chooses to 
add patients at the end of the trial to refine weak evidence (if observed). In particular, it 
shows that the chance of observing weak evidence at the end of the study is ~8%, which 
can be reduce to ~3% (or ~1%) by adding 10 (or 20) more participants. Importantly, only 
an additional 54 false positives were observed, which represents a very modest inflation 
in the Type I Error rate from 4.9% (=247/5000) to 6%, and 286 trials under the 
alternative achieved sufficient evidence to declare efficacy for an increase in power from 
80% (=4026/5000) to 86%.  At the end of stage II, the false discovery rate for any type of 
rejection (i.e., any likelihood ratio greater than or equal to 3.375) is 5.8% (=247/ 
(247+4026)).  Clearly, cohort expansion can proceed with minimal rates of unwanted 
consequences. 
 
 
 


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Table 7.  Simulation results for extending the likelihood two stage trial for the purpose of refining weak 
evidence. Cells contain the number (proportion of 5000) trials in each evidentiary class. 
Results Under True Ho: 
LR Class 
Trials at end 
of two-stage 
design 
Weak 
evidence 
Add 10 
patients 
Weak 
evidence 
Add 10 
patients 
Weak 
evidence 
LR ≤ 1/3.375 
1145 
 
207 
 
105 
 
1/3.375<LR<1 
260 
424 (8.5%) 
113 
179 (3.6%) 
35 
58 (1.2%) 
1<LR<3.375 
164 
66 
23 
LR ≥ 3.375 
247 
 
38 
 
16 
 
Results under true Ha: 
LR ≤ 1/3.375 
143 
 
39 
 
16 
 
1/3.375<LR<1 
148 
397 (7.9%) 
48 
135 (2.7%) 
30 
134 (1.1%) 
1<LR<3.375 
249 
87 
26 
LR ≥ 3.375 
4026 
 
223 
 
63 
 
a 64% (3184) and 8.7% (434) trials stopped early for futility under the true null and true alternative 
hypotheses, respectively. 
 
Under the likelihood evidentiary paradigm observed results are reported as 
follows (let K>1 be the pre-specified LR that maintains a certain false discovery rate): 1) 
sufficiently strong evidence for the null (LR ≤ 1/K) ; 2) actionable weak evidence for the 
null (1/K<LR<1) ; 3) actionable weak evidence for the alternative (1<LR<K) ; 4) 
sufficiently strong evidence for the alternative (LR ≥ 1/K). We will also report the FDR 
for the result at hand, i.e. 1/(LR+1).  As detailed below, this trial may recruit additional 
participants if the observed LR is weak (i.e., 1/K<LR<K ) with a maximum of 61 
participants. 
A significant number (~8%) of discoveries under the null and alternate 
hypotheses for our two-stage design had LR of exactly 3.375. Though such results would 
allow the conclusion of sufficient activity to warrant further investigation in more 
definitive trials because it passes nominal Type I and II Error rate criteria, we propose to 
further evaluate these results in the extension cohorts by setting K=4, treating those trials 
with LR’s of 3.375 as weak evidence. The PET remains unaffected by this slight change. 
However, the design that uses K=4 and a total sample size of 61 patients has a false 
positive rate that decreases to 3.7% and power that increases to 83.7%. This strategy also 
decreases the false discovery rate to 3.9% (table 8). Hence such a design is quite feasible. 
 
 
 


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Table 8.  Simulation results for extending the likelihood two stage trial for the purpose of refining weak 
evidence for K=4. Cells contain the number (proportion of 5000) trials in each evidentiary class. 
Results Under True Ho: 
LR Class 
Trials at end 
of two-stage 
design 
Weak 
evidence 
Add 10 
patients 
Weak 
evidence 
Add 10 
patients 
Weak 
evidence 
LR ≤ 1/4 
878 
 
307 
 
186 
 
1/4<LR<1 
527 
813 (16.3%) 
299 
474 (9.5%) 
175 
273 (5.4%) 
1<LR<4 
286 
175 
98 
LR ≥ 4 
125 
 
32 
 
15 
 
Results under true Ha: 
LR ≤ 1/4 
65 
 
20 
 
21 
 
1/4<LR<1 
226 
833 (16.7%) 
170 
471 (9.4%) 
85 
274 (5.5%) 
1<LR<4 
607 
301 
189 
LR ≥ 4 
3668 
 
342 
 
176 
 
a 64% (3184) and 8.7% (434) trials stopped early for futility under the true null and true alternative 
hypotheses, respectively. 
 
General Statistical Considerations and Analysis Plan 
 
Categorical variables (e.g. gender, response) will be summarized in frequency 
tables using counts and percentage of patients by group. Continuous variables (e.g. age) 
will be summarized using the minimum and maximum values, quartiles, mean and 
standard deviation.  95% confidence intervals will be estimated for all variables.  All 
comparisons will be two-sided and statistical significance is declared for p-values < 0.05.  
All patients receiving at least one dose of therapy will be included in efficacy and safety 
analyses. 
12.4.     Definition of Endpoints Response for Interim Analysis.   
Response for interim analysis will be defined as the best response prior to or on the 
day-84 bone marrow biopsy.  
• Leukemia-free Survival (LFS or DFS) is defined as the time from complete remission 
to disease progression or death for any reason.  Patients who are disease free and alive 
as of last follow-up will be censored at their last follow-up date. 
• Event-free survival is defined as the time from start of therapy to progression or death 
for any reason.  Patient progression-free and alive at last follow-up will be censored 
at their last follow-up date. 
• Overall survival is defined at the time from start of therapy to death for any reason.  
Patients alive as of last follow-up will be censored at their last follow-up date. 
 


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12.5.     Statistical Comparisons 
Categorical variables will be compared among important patient subgroups using 
the chi-square test or Fisher’s exact test, as appropriate.  Continuous variables will be 
compared using rank based non-parametric tests.  Survival distributions will be estimated 
using the method of Kaplan and Meier and comparing these distributions among patient 
subgroups will be made using the logrank test.  Multivariable models of response and 
survival estimates will be constructed using logistic and Cox (proportional hazards) 
regression.  Time to response will be implemented as a time-dependent covariate in 
models assessing LFS. 
 
12.6.     Safety Analysis 
Adverse events and laboratory data will be graded according to the NCI CTCAE 
version 4.03.  As described above frequency and percentage of patients will be 
summarized for any adverse event by grade, attribution, organ class, and preferred term 
overall and by patient.  Change in continuous laboratory data from just prior to therapy 
and by visit will be summarized by frequency of abnormal values.  Linear and non-linear 
regression will be used to model changes over time, accounting for intra-patient 
correlation using mixed models or GEE, as appropriate. 
 
13. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
13.1. Compliance  With Laws and Regulations 
The investigator will conduct this clinical study in compliance with the protocol; 
Title 21 of the Code of Federal Regulations (CFR),34 current Good Clinical Practice 
(GCP); ICH guidelines, including E6-GCP Consolidated Guidance;35  the Declaration 
of Helsinki;36  the requirements of other regulatory agencies as necessary; and local 
ethical and legal requirements. 
To the extent applicable, the investigator will interpret all references to the FDA; 
Federal Food, Drug, and Cosmetic Act; CFR; ICH; GCP; and the like; as also 
referring to any corresponding requirements of local regulatory agencies, regulations, 
and laws. If there is any discrepancy between local, FDA, and ICH requirements, the 
most stringent standard will apply. 
Vanderbilt is the Sponsor of this study. All aspects of the study will be carefully 
monitored by the Sponsor for compliance with applicable government regulations 
with respect to current GCP and standard operating procedures. 
 
13.1.1. Ethics 
Ethical Conduct of the Study and Independent Ethics Committees 
As required by FDA regulation (21 CFR 56) and ICH guidelines for GCP, the 
Investigator must obtain Institutional Review Board (IRB) or Institutional Ethics 
Committee (IEC) review and approval of the study protocol, Informed Consent Forms 


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(ICFs), patient recruitment materials, and any other pertinent documents before any 
study-related activities involving patients are performed. 
As required in 21 CFR 50, the investigator or designee must comply with the 
informed consent process, and ensure that each patient enrolled in this clinical study 
understands the information presented in the IEC-approved ICF and agrees 
voluntarily to participate in the clinical study. 
The investigator must inform the IEC of the progress of the clinical study and 
report any non-administrative changes made to the protocol; in any case, the 
investigator must provide an update to the IEC at least once yearly or per country-
specific guidelines. 
 
13.1.2. IRB Approval 
The trial protocol, ICF, IB, available safety information, any patient documents, 
patient recruitment procedures (e.g., advertisements), information about payments 
(i.e., PI payments) and compensation available to the patients should be submitted to 
the IRB for ethical review and approval if required by local regulations, prior to the 
trial start.   
Information regarding study conduct and progress will be reported to the 
Institutional Review Board (IRB) per the current institutional standards of each 
participating institution. 
The Study Chair (or his designee) is responsible for the coordination and 
development of all protocol amendments. Once approved by the Chair, Vanderbilt 
will disseminate this information to participating institutions. 
IRB approval for protocol amendments and changes to the informed consent 
document must be obtained per the current institutional standards at each 
participating institution. 
Any change to the protocol and informed consent document must be reviewed and 
approved by the Coordinating Center before being submitted to the Institutional 
Review 
Board/Independent 
Ethics 
Committee 
at 
participating 
institutions. 
Amendments should not be implemented until all necessary approvals have been 
obtained, except when necessary to eliminate an immediate hazard to study subjects. 
Safety updates for will be prepared by the Coordinating Center as required, for 
submission to the relevant IRB. 
 
13.1.3. Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her 
willingness to participate in a particular trial, after having been informed of all 
aspects of the trial that are relevant to the subject's decision to participate.  Informed 
consent is documented by means of a written, signed and dated informed consent 
form. 


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The informed consent form will be submitted for approval to the IRB that is 
responsible for review and approval of the trial.  Each consent form must include all 
of the relevant elements currently required by the FDA, as well as local county 
authority or state regulations and national requirements. 
Before recruitment and enrollment into the trial, each prospective candidate will 
be given a full explanation of the trial.  Once the essential information has been 
provided to the prospective candidate, and the investigator is sure that the individual 
candidate understands the implications of participating in this trial, the candidate will 
be asked to give consent to participate in the trial by signing an informed consent 
form. A notation that written informed consent has been obtained will be made in the 
patient’s medical record. A copy of the informed consent form, to include the 
patient’s signature, will be provided by the investigator to the patient.   
If an amendment to the protocol substantially alters the trial design or the 
potential risks to the patients, the patient’s consent to continue participation in the 
trial must be obtained. 
Any change to the informed consent document must be reviewed and approved by 
the Coordinating Center before being submitted to the Institutional Review 
Board/Independent Ethics Committee at participating institutions. 
 
13.1.4. Data Collection 
The trial CRF is the primary data collection instrument for the trial. CRFs will be 
completed using the English language and should be kept current to enable the 
monitor to review the patients’ status throughout the course of the trial. 
In order to maintain confidentiality, only trial number, patient number, initials and 
date of birth will identify the patient in the CRF.  If the patient’s name appears on any 
other document (e.g. laboratory report), it must be obliterated on the copy of the 
document to be supplied to Coordinating Center and replaced instead with the patient 
number and patient’s initials.  The investigator will maintain a personal patient 
identification list (patient numbers with corresponding patient identifiers) to enable 
records to be identified and verified as authentic.  Patient data/information will be 
kept confidential, and will be managed according to applicable local, state, and 
federal regulations. 
All data requested on the CRF must be supported by and be consistent with the 
patient’s source documentation.  All missing data must be explained.  When a 
required laboratory test, assessment, or evaluation has not been done or an 
“Unknown” box is not an option on the CRF, a note should be created verifying that 
the field was “Not Done” or “Unknown”.  For any entry errors made, the error(s) 
must be corrected, and a note explaining the reason for change should be provided. 


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The investigator will electronically sign and date the patient CRF casebook 
indicating that the data in the CRF has been assessed.  Each completed CRF will be 
signed and dated by the PI, once all data for that patient are final. 
 
13.1.5. Trial Monitoring 
Vital Study Data and Safety Monitoring Board (DSMB) 
The VITAL Study DSMB (consisting of a representative from the funding 
organization, the study chairs, a biostatistician, and participating investigator to be 
selected by the study chairs) will review the clinical data to determine the merits of 
continued enrollment. 
VICC Data and Safety Monitoring Committee (DSMC) 
Quarterly safety and monitoring reports are available to the DSMC as determined 
by the VICC Scientific Review Committee (SRC). The DSMC reviews all adverse 
events reported during the previous month for all clinical trials active at the VICC and 
makes recommendations to address concerns of patient safety. The DSMC of the 
VICC SRC will submit an annual report to the VICC Director on activities of the 
preceding year and will make recommendations to improve data and safety 
monitoring activities as needed. 
A Quality Assurance auditor under the direction of the VICC DSMC will audit 
this clinical trial quarterly for compliance with adverse event reporting, regulatory 
and studies requirements, and data accuracy and completion. Audit reports detailing 
the findings are provided to the DSMC. 
Investigators will allow auditors access to all pertinent medical records, as 
required by federal regulations, in order to allow for the verification of data gathered 
in the data case report forms (CRFs) and for the review of the data collection process. 
At visits, the auditor may review various aspects of the trial including, but not limited 
to: screening and enrollment logs; compliance with the protocol and with the 
principles of Good Clinical Practice; completion of case report forms; source data 
verification; study drug accountability and storage; facilities and staff; and regulatory 
compliance. 
VICC Multi-Institutional Coordinating Center 
The trial additionally will be monitored by the VICC Multi-Institutional 
Coordinating Center. The actual frequency of monitoring will depend on the 
enrollment rate and performance of the site. Monitoring will be conducted through 
onsite and remote monitoring, teleconferences with the Investigator and site staff, and 
appropriate communications by mail, fax, email, or telephone. The purpose of 


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monitoring is to ensure that the study is conducted in compliance with the protocol, 
standard operating procedures (SOPs), and other written instructions, and to ensure 
the quality and integrity of the data. 
During scheduled monitoring visits, investigators and the investigational site staff 
must be available to discuss the progress of the trial, make necessary corrections to 
case report form entries, respond to data clarification requests, provide required 
regulatory documents, and respond to any other trial-related inquiries of the monitor. 
In addition to the above, the FDA may review the conduct or results of the study 
at the investigational site.  
 
13.1.6. Closure of the Study 
The sponsor reserves the right to discontinue a site at any time during the study for 
medical or administrative reasons such as: 
• Unsatisfactory enrollment; 
• GCP noncompliance; 
• Inaccurate or incomplete data collection; 
• Falsification of records; 
• Failure to adhere to the study protocol. 
 
13.1.7. Records Retention 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory records, 
must be retained by each Principal Investigator for two years after marketing application 
approval. If no application is filed, these records must be kept two years after the study is 
discontinued and the U.S. FDA and the applicable national and local health authorities 
are notified. 
Following closure of the study, each participating center will maintain a copy of all 
site study records in a safe and secure location. The Sponsor will inform the Investigator 
at each site at such time that the records may be destroyed. 
 


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References 
 
1. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: a cancer journal for clinicians 
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Bloomfield CD, Goldman A, Hassfeld D, de la Chapelle A. Fourth International Workshop on 
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Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid 
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Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute 
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Rollig C, Bornhauser M, Thiede C, et al. Long-term prognosis of acute myeloid leukemia 
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Farag SS, Archer KJ, Mrozek K, et al. Pretreatment cytogenetics add to other prognostic factors 
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10. 
Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic 
classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into 
the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98(5): 1312-20. 
11. 
Stuart RK CL, Maris MB, et al. Voreloxin single agent treatment of older patients >/= 60 years 
with previously untreated acute myeloid leukemia: results from phase 2 study with 3 schedules. . Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 2010; 28(15s): suppl; 
abstr 6525. 
12. 
Lancet JE, Ravandi F, Ricklis RM, et al. A phase Ib study of vosaroxin, an anticancer quinolone 
derivative, in patients with relapsed or refractory acute leukemia. Leukemia 2011; 25(12): 1808-14. 
13. 
Roboz GJ LJ, Cripe LD et al. Final results of a Phase II pharmacokinetic/pharmacodynamic 
(PK/PD) study of combination voreloxin and cytarabine in patients with relapsed or refractory acute 
myeloid leukemia. Journal of clinical oncology : official journal of the American Society of Clinical 
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Ravandi F, Ritchie E, Sayar H, et al. Improved Survival in Patients with First Relapsed or 
Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin Plus Cytarabine Versus Placebo 
Plus Cytarabine: Results of a Phase 3 Double-Blind Randomized Controlled Multinational Study 
(VALOR); 2014. 
15. 
Elsea SH, Westergaard M, Burden DA, Lomenick JP, Osheroff N. Quinolones share a common 
interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs. 
Biochemistry 1997; 36(10): 2919-24. 


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16. 
Tomita K, Tsuzuki Y, Shibamori K, et al. Synthesis and structure-activity relationships of novel 
7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. 
Part 1. Journal of medicinal chemistry 2002; 45(25): 5564-75. 
17. 
Tsuzuki Y, Tomita K, Shibamori K, Sato Y, Kashimoto S, Chiba K. Synthesis and structure-
activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-
carboxylic acids as antitumor agents. Part 2. Journal of medicinal chemistry 2004; 47(8): 2097-109. 
18. 
Hawtin RE, Stockett DE, Byl JA, et al. Voreloxin is an anticancer quinolone derivative that 
intercalates DNA and poisons topoisomerase II. PloS one 2010; 5(4): e10186. 
19. 
Wong OK, Conroy A, Tan N, et al. 598 POSTER Voreloxin (formerly SNS-595) is a potent DNA 
intercalator and topoisomerase II poison that induces cell cycle dependent DNA damage and rapid 
apoptosis in cancer cell lines. European Journal of Cancer Supplements 2008; 6(12): 187. 
20. 
Walsby EJ, Coles SJ, Knapper S, Burnett AK. The topoisomerase II inhibitor voreloxin causes 
cell cycle arrest and apoptosis in myeloid leukemia cells and acts in synergy with cytarabine. 
Haematologica 2011; 96(3): 393-9. 
21. 
Advani RH, Hurwitz HI, Gordon MS, et al. Voreloxin, a first-in-class anticancer quinolone 
derivative, in relapsed/refractory solid tumors: a report on two dosing schedules. Clinical cancer research 
: an official journal of the American Association for Cancer Research 2010; 16(7): 2167-75. 
22. 
Lancet JE, Roboz GJ, Cripe LD, et al. A phase 1b/2 study of combination vosaroxin and 
cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica 2014. 
23. 
Stuart RK, Cripe LD, Maris MB, et al. REVEAL-1, a phase 2 dose regimen optimization study of 
vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia. British journal 
of haematology 2014. 
24. 
Stuart RK, Ravandi Kashani F, Cripe LD, et al. Voreloxin single-agent treatment of older patients 
(60 years or older) with previously untreated acute myeloid leukemia: Final results from a phase II study 
with three schedules. ASCO Meeting Abstracts 2010; 28(15_suppl): 6525. 
25. 
Daver NG, Kantarjian HM, Pierce S, et al. Phase I/II study of vosaroxin and decitabine in older 
patients (pts) with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). 
ASCO Meeting Abstracts 2014; 32(15_suppl): 7098. 
26. 
Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific 
comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106(8): 2912-9. 
27. 
Wheatley K, Brookes CL, Howman AJ, et al. Prognostic factor analysis of the survival of elderly 
patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol 2009; 145(5): 598-605. 
28. 
Krug U, Rollig C, Koschmieder A, et al. Complete remission and early death after intensive 
chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application 
for prediction of outcomes. Lancet 2010; 376(9757): 2000-8. 
29. 
Mosteller RD. Simplified calculation of body-surface area. The New England journal of medicine 
1987; 317(17): 1098. 
30. 
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. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 2003; 21(24): 4642-9. 
31. 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. National Cancer 
Institute, National Institutes of Health, U.S. Department of Health and Human Services. June 14, 2010. 
32. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials 1989; 
10(1): 1-10. 
33. 
Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Statistics in 
medicine 1992; 11(7): 853-62. 
34. 
Code of Federal Regulations.  Title 21, Parts 170 to 199; Revised April 1, 2012. 
35. 
Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance ed. ICH; April 1996. 


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36. 
World Medical A. World Medical Association Declaration of Helsinki. Ethical principles for 
medical research involving human subjects. Bulletin of the World Health Organization 2001; 79(4): 373-
4. 
37. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American journal of clinical oncology 1982; 5(6): 649-55. 
38. 
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of 
antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society 
of America. Clin Infect Dis 2011; 52(4): 427-31. 
 
 
 


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Appendix A. Eastern Cooperative Oncology Group Performance status37  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
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 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am 
J Clin Oncol. 1982;5:649-655. 
 
 


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Appendix B.   WHO diagnostic criteria for AML 
 
The diagnosis of AML required a marrow or blood blast count of 20% or more, except 
for AML with t(15;17), t(8;21), inv(16) or t(16;16), and some cases of erythroleukemia. 
Myeloblasts, monoblasts, and megakaryoblasts are included in the blast count. 
Monoblasts and promonocytes, but not abnormal monocytes, are counted as blast 
equivalents in AML with monocytic or myelomonocytic differentiation. Erythroblasts are 
not counted as blasts except in the rare instance of pure erythroid leukemia. 
 
Categories: 
 
AML with recurrent cytogenetic abnormalities 
 
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);  
Acute promyelocytic leukemia with t(15;17)(q22;q12);  
AML with t(9 ;11)(p22;q23);  
AML with t(6;9)(p23;q34);  
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) 
AML with mutated NPM1 
AML with mutated CEBPA 
 
AML with myelodysplasia-related changes 
Complex Karyotype (≥3 abnormalities) 
Unbalanced abnormalities 
-7/del(7q) 
-5/del(5q) 
i(17q)/t(17p) 
-13/del(13q) 
del(11q) 
del(12p)/t(12p) 
del(9q) 
idic(X)(q13) 
Balanced abnormalities 
t(11;16)(q23;q13.3) 
t(3;21)(q26.2;q22.1) 
t(1;3)(p36.3;q21.1) 
t(2;11)(p21;q23) 
t(5;12)(q33;p12) 
t(5;7)(q33;q11.2) 
t(5;17)(q33;p13) 


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t(5;10)(q33;q21) 
t(3;5)(q25;q34) 
Therapy-related myeloid neoplasms 
Myeloid Sarcoma 
AML, Not Otherwise Specified 
AML with minimal differentiation 
AML without maturation 
AML with maturation 
Acute myelomonocytic leukemia 
Acute monoblastic and monocytic leukemia 
Acute erythroid leukemia 
Acute megakaryoblastic leukemia 
Acute basophilic leukemia 
Acute panmyelosis with myelofibrosis 
Appendix C. AML Risk prognostication 
 
 
 


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Appendix D: Contraceptive Guidelines and Pregnancy 
Women Not of Childbearing Potential are Defined as Follows: 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical 
bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential. 
Contraceptive Guidelines for Women of Child-Bearing Potential: 
 Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 60 days after stopping 
treatment. The highly effective contraception is defined as either: 
1. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
2. Sterilization:  have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks ago.  In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
3.  Male partner sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner 
should be the sole partner for that patient. 
4.  Use of a combination of two of the following: 
a)   Barrier methods with spermicide: 
• condom (male or female) 
• occlusive cap (diaphragm or cervical/vault caps/shield) 
• use of two barrier methods is acceptable (i.e. male condom + diaphragm or equivalent) 
b)  Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
c)  Hormonal implants or combined oral contraceptives 
• Please note it is unknown if vosaroxin may have the potential to decrease the 
effectiveness of hormonal contraceptives. 


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The following are unacceptable forms of contraception for women of childbearing potential:  
• Natural family planning (rhythm method) or breastfeeding  
• Fertility awareness  
• Withdrawal 
Appendix E.  Prophylactic antimicrobials and mucositis care recommendations 
Prophylactic antimicrobials 
Patients should be on antimicrobial prophylaxis for duration of the immunocompromised 
periods during the trial.  This connotes prophylaxis from diagnosis through count 
recovery (minimum ANC > 500 /µl or institutional practice; whichever is greater).  There 
should be three lines of antimicrobial prophylaxis.  These should include: 
Antibacterial (e.g. Levafloxacin 500mg po daily) 
Antifungal (e.g. Fluconazole 400mg po daily) 
Antiviral (e.g. Valacyclovir 500mg po daily) 
Empiric therapy for neutropenic fevers will be per institutional guidelines and will 
supercede needs for prophylactic antimicrobials. 
Consistent with IDSA recommendations, patients with oral or gastrointestinal mucositis 
that interferes with swallowing or causes severe diarrhea as well as those with 
gastrointestinal symptoms, including abdominal pain, nausea and vomiting, or diarrhea 
should be considered at high-risk for serious complications in the setting of neutropenic 
fever and should receive empiric IV antibiotic therapy in the hospital setting.38   
Additionally, severe mucositis in the setting of neutropenic fever should be considered an 
indication for the addition of antibiotics active against gram-positive organisms, if 
fluoroquinolone prophylaxis and empiric ceftazidime (or cefepime) have been employed. 
38 
Mucositis care recommendations (extrapolated from MAASC Practice Guidelines) 
Oral Mucositis 
1. We recommend the use of oral cryotherapy on days 1 and 4 of vosaroxin infusions for 
mucositis prevention.  Ice cubes / chips should be placed in patient’s mouth starting 5 
minutes prior to vosaroxin infusion and continuing for a total of 30 minutes duration.   
2. We recommend patient controlled analgesia with morphine (or alternative narcotic pain 
medication as deemed appropriate per treating physician) be used to treat pain due to oral 
mucositis in patients receiving protocol defined chemotherapy.  


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a. Alternative options 
i. Transdermal fentanyl, morphine mouthwash (0.2%), and doxepin 
mouthwash (0.5%) may also be effective to treat pain due to oral 
mucositis.  
3. Zinc supplements administered orally may also be considered to prevent oral mucositis.   
4. Oral care with salt and soda rinses or alternatives as per institutional practice are also 
allowed.   
5. We recommend avoidance of prophylactic use of antimicrobial lozenges, antimicrobial 
mouthwash, sucralfate mouthwash, chlorhexidine mouthwash, GM-CSF mouthwash, 
misoprostol mouthwash, intravenous glutamine, systemic pentoxifylline, or systemic 
pilocarpine.   
 
Gastrointestinal Mucositis 
1. We recommend octreotide, at a dose of ≥100 µg subcutaneously twice daily, be used to 
treat diarrhea induced by protocol-defined chemotherapy if loperamide and/or lomotil are 
ineffective.   
2. We recommend avoidance of systemic sucralfate, 5-acetyl salicylic acid (or related 
compounds), or misoprostol suppositories, to prevent or treat gastrointestinal mucositis. 
          
  
 
 
 
 


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Appendix F.   Comorbidity Index and Risk Stratification Scoring Systems 
Wheatley Score 
Cytogenetic Group  
 
WBC Count  
 
 
ECOG Performance Status  
Age 
AML Subtype (De novo vs  Secondary vs Unknown)   
 
HCT-CI (www.hctci.org/Home/Calculator) 
Arrythmia 
Cardiovascular Comorbidity 
Inflammatory Bowel Disease 
Diabetes 
Cerebrovascular Disease 
Psychiatric Disturbance 
Hepatic Comorbidity 
Obestity Score 
Infection 
Rheumatologic Comorbidity 
Peptic Ulcer 
Renal Comorbidity 
Pulmonary Score 
Prior Solid Tumor 
Heart Valve Disease 
Age  
 
AML-SCORE (www.aml-score.org) 
Temperature 
Hemoglobin 
Platelets 
Fibrinogen 
LDH 
Age at diagnosis 
Type of Leukemia (de novo, secondary) 
Cytogenetics