Conditions: Leukemia
Keywords: Leukemia Acute Myeloid Leukemia AML High-risk Myelodysplastic Syndrome MDS Chronic Myelomonocytic Leukemia CMM Maximum tolerated dose MTD Vosaroxin Decitabine Dacogen
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 66
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if the combination of vosaroxin and decitabine can help to control AML or MDS. The safety of these drugs will also be studied.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Up to 4 groups of up to 6 participants will be enrolled in the Phase I portion of the study, and up to 60 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of vosaroxin you receive will depend on when you joined this study. The first group of participants will receive the highest dose level of vosaroxin. If no intolerable side effects are seen, the study will move on to Phase II. If intolerable side effects are seen, each new group will receive a lower dose of vosaroxin than the group before it until the most tolerable dose is found.

If you are enrolled in the Phase II portion, you will receive vosaroxin at the highest dose that was tolerated in the Phase I portion.

All participants will receive the same dose level of decitabine.

Study Drug Administration:

You will receive the study drugs in cycles. The study cycles will be 4-12 weeks long, depending on if/how the disease responds to the treatment, how your bone marrow reacts to treatment, and what the doctor thinks is in your best interest.

On Days 1-5 of each study cycle, you will receive decitabine by vein over about 1 hour. On Days 1 and 4 of each cycle, you will also receive vosaroxin by vein over 8-10 minutes, before you receive decitabine. Depending on how the disease responds to the study drugs, the number of days you receive the study drug may change. Your doctor will discuss this with you.

The first 2 cycles are called Induction Cycles. All cycles after that are called Consolidation Cycles. All participants will receive Induction Cycle 1. If the study doctor thinks it is needed, you will also receive Induction Cycle 2. If after that the study doctor thinks it is in your best interest, you will receive up to 5 Consolidation Cycles of treatment.

Study Visits:

On Day 1 of each cycle, you will have a physical exam.

Every week, blood (about 1 tablespoon) will be drawn for routine tests. If at any point you appear to have a response to the study drugs, this blood will then be drawn every 1-2 weeks while you are still receiving the study drugs. If your doctor thinks it is needed, more blood may need to be drawn.

On Day 21 of Cycle 1 (+/- 7 days), then every 4 weeks after that, you will have a bone marrow aspiration and/or biopsy to check the status of the disease. If the doctor thinks it is needed, these may be done more or less often, depending on your response to the study drugs.

Length of Study:

You may receive the study drugs for up to 7 cycles. You will be taken off study if the disease gets worse, intolerable side effects occur, or if the study doctor thinks it is in your best interest.

Your participation in the study will be over after the follow-up period.

End-of-Study Visit:

If you are taken off study or if you leave the study early, you will have an end-of-study visit. At this visit:

Blood (about 2-3 teaspoons) will be drawn for routine tests. If the study doctor thinks it is needed, you will have a bone marrow aspiration.

You will then be contacted during a study visit or called and asked about any side effects you may be having 30 days after the end-of-study visit. This call will last about 5 minutes.

Follow-up:

If you do not leave the study early, you will have follow-up visits and calls for up to 5 years after you stop receiving the study drugs.

Every 4-8 weeks, blood (about 1 tablespoon) will be drawn for routine tests. If you cannot return to the clinic, you may have blood drawn at a clinic close to your home.

Every 3-6 months, you will be contacted during a clinic visit and asked how you are doing. If you cannot make it to the clinic for this visit, you will be called. The phone call should last about 5 minutes.

This is an investigational study. Vosaroxin is not FDA approved or commercially available. It is currently being used for research purposes only. Decitabine has been approved by the FDA for the treatment of MDS, which is a precursor of AML, but has not been approved for the treatment of AML. The use of these drugs in combination is investigational. The study doctor can explain how the drugs are designed to work.

Up to 84 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: The first 6 patients on study (first cohort) receive 1 or 2 induction cycles of therapy according to the following starting schedule: Vosaroxin administered intravenously on days 1 and 4 at a dose of 90 mg/m2 in the first cycle (induction 1) for a total dose of 180 mg/m2/cycle in combination with Decitabine at a dose of 20 mg/m2 intravenously daily for 5 consecutive days (Days 1 to 5).

Following the phase I portion, patients in phase II receive the following induction:

1. Vosaroxin intravenously on days 1 and 4 at a dose of 70 mg/m2 for a total dose of 140 mg/m2/cycle (days 1 and 4), or the final induction dose (MTD) determined in phase I.
2. Decitabine intravenously at a dose of 20 mg/m2 for 5 consecutive days (days 1 to 5), or the final induction dose (MTD) determined in phase I.

Interventions: intervention 1: Vosaroxin intervention 2: Decitabine
Intervention descriptions: intervention 1: Phase I Starting Dose: 90 mg/m2 by vein on Days 1 and 4 of each cycle.

Phase II Starting Dose: 70 mg/m2 by vein on Days 1 and 4 of each cycle, or maximum tolerated dose from Phase I. intervention 2: Phase I and II: 20 mg/m2 by vein daily for 5 consecutive days (Days 1 to 5).

Protocol document:
Prot_SAP_000.pdf: 
Protocol Page
A Phase I/II Study of Vosaroxin and Decitabine in Older Patients with Acute 
Myeloid Leukemia and High-risk Myelodysplastic Syndrome 
2013-0099
Core Protocol Information
Short Title 
Study of Vosaroxin and Decitabine in Older Patients with 
Acute Myeloid Leukemia and High-risk Myelodysplastic 
Syndrome
Study Chair: 
Naval Daver
Additional Contact:
Dana E. Brown
Vicky H. Zoeller
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-7305
Unit:
425
Study Manager:
N
Full Title: 
A Phase I/II Study of Vosaroxin and Decitabine in Older 
Patients with Acute Myeloid Leukemia and High-risk 
Myelodysplastic Syndrome 
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated -- Closed to new patient entry as of 10/02/2019
Version:
14
Document Status:
Saved as "Final"
Submitted by:
Dana E. Brown--9/23/2019 9:57:48 AM
OPR Action:
Accepted by:  Otisia M. Holiday -- 10/2/2019 2:45:21 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


Vosaroxin and decitabine in AM L 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase 1/11 Study of Vosaroxin and Decitabine in Older 
Patients with Acute Myeloid Leukemia and High-risk 
Myelodysplastic  Syndrome 
 
 
 
 
 
 
 
 
 
Principal Investigator: Naval Daver, M.D. and Co-Principal Investigator: Farhad Ravandi , M.D. 
Sponsor: University ofTexas, MD Anderson Cancer Center 
IND number : 118,699 
 
University of Texas 
 
MD Anderson Cancer Center 
Leukemia Department , Unit 428 
Telephone:  713-794-4392 
Email : ndaver@mdanderson.org 


Vosaroxin and decitabine in AM L 
2 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
1.1 HYPOTHESIS  AND  OBJECTIVES 
1.2 Hypothesis 
1.3 Objectives 
 
2.1 BACKGROUND AND RATIONALE 
2.2 AML and High-risk MDS in Older Patients 
2.3 Vosaroxin (formerly voreloxin) 
2.3.1 Rationale and Mechanism of Action 
2.3.2 Pharmacodynamics, Pharmacokinetics and Preclinical Experience 
2.3.3 Clinical Experience 
2.3.4 Dosing and Schedule 
2.4 Decitabine (DAC) 
2.4.1 Rationale and Mechanism of Action 
2.4.2 Pharmacodynamics, Pharmacokinetics and Preclinical Experience 
2.4.3 Clinical Experience 
2.4.4 Dosing and Schedule 
2.5 Rationale for Combined Treatment with Vosaroxin and Decitabine 
 
3.1 STUDY DESIGN AND ELIGIBILTIY 
3.2 Study Design 
3.3 Patient Eligibility 
3.3.1 Inclusion Criteria 
3.3.2 Exclusion Criteria 
 
4.1 TREATMENT  PLAN 
4.2 Treatment Plan in Phase I and II 
4.3 General Study Treatment Plan 
4.4 Induction Therapy in Phase I 
4.5 Definition of Dose Limiting Toxicities and Criteria in Phase I 
4.6 Induction Therapy in Phase II 
4.7 Post-remission Therapy in Phase II 
4.8 Management of Toxicities and Dose Modifications 
4.8.1 Induction, Re-Induction, and Consolidation Cycles 
4.8.2 Hematologic (Blood/Bone marrow) Toxicity 
4.8.3 Non-hematologic Toxicity 
4.8.4 Supportive Care 
4.8.5 Concomitant Medications 
 
5.0  PRETREATMENT  EVALUATION 
 
6.1 EVALUATIONS 


Vosaroxin and decitabine in AM L 
3 
 
 
 
 
 
 
 
6.2 Evaluations During Study 
6.3 Follow-up Evaluations 
 
7.1 DISCONTINUATION  OF TREATMENT 
7.2 Discontinuation Criteria for Individual Patients 
7.2.1 Patient Withdrawal 
7.2.2 Investigator  Discontinuation  of Patient 
7.2.3 Criteria for Protocol-Deimed Required Discontinuation of Treatment 
7.2.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
7.3 Study Stopping Rules 
7.4 Protocol Violations and Deviations 
 
8.1 CRITERIA FOR RESPONSE 
8.2 Complete response (CR) 
8.3 Complete response without platelet recovery (CRp) 
8.4 CR with insufficient hematological recovery (platelets or neutrophils) (CRi) 
8.5 Overall Response rate (ORR) = CR + CRp + CRi 
8.6 Disease-free survival (DFS) 
8.7 Overall survival (OS) 
 
9.1 REGULATORY AND REPORTING  REQUIREMENTS 
9.2 Expedited Adverse Event Reportin g 
9.3 Serious Adverse Event Reporting 
9.4 Reporting to FDA 
9.5 Reporting to Sunesis 
 
10.1 
STATISTICS 
10.2 
Sample size 
10.3 Statistical Design 
10.4 Statistical Analysis Plan 
 
11.0 
DATA CONFIDENTIALITY  PROCEDURES 
 
12.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
1.1 HYPOTHESIS  AND OBJECTIVES: 
 
1.2 Hypothesis: 


4 
 
 
Vosaroxin and decitabine in AML 
 
 
 
 
Vosaroxin (formerly voreloxin) , a DNA topoisomerase II inhibitor, and decitabine (Dacogen®; 
DAC) an analogue of the natural nucleoside 2'-deoxycytidine with hypomethylating activity, are 
effective and overall tolerable treatments for older patients with acute myeloid leukemia (AML) 
and high-risk myelodysplastic syndromes (MDS). Combination of these agents in older patients 
with AML and high-risk MDS may improve the overall clinical response to therapy without 
causing excessive toxicity. We propose an open label, phase IIII trial using vosaroxin in 
combination with decitabine in older patients with AML and high-risk MDS. 
 
 
 
1.2 Objectives: 
 
1.2.1 Primary: 
 
Phase I: 
 
• To detennine the safety ofvosaroxin in combination with decitabine in patients with 
high-risk MDS or AML who are elderly (age 60) and/or unable to tolerate standard 
therapy and to determine phase II schedule. 
 
• To detennine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of 
vosaroxin in combination with decitabine in patients with high-risk MDS or AML who 
are elderly (age    60) and/or unable to tolerate standard therapy. 
 
 
Phase II: 
 
• To determine the overall response rate (ORR) of vosaroxin in combination with 
decitabine in patient s with high-risk MDS or AML who are elderly (age 
60) and/or 
unable to tolerate standard therapy. Overall response rate = Complete response (CR) + 
CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). 
 
 
 
 
 
1.2.2 Secondary : 
 
 
Phase II: 
 
• To detennine the safety ofvosaroxin in combination with decitabine in patients with 
high-risk  Myelodysp lastic Syndrome or  Acute Myeloid Leukemia who are elderly (age 
60) and/or unable to tolerate standard therapy. 
• To determine the duration of response of patients with AML and high-risk MDS treated 
with this combination. 
• To determine the disease-free survival (DFS) of patients with AML and high-risk MDS 
treated with this combination 


5 
 
 
Vosaroxin and decitabine in AML 
 
 
 
 
• To determine the induction mortality (mortality within first 8 weeks of initiation of 
therapy) for patients with AML and high-ri sk MDS treated with this combination. 
• To detennine the toxicity of the regimen for patients with AML and high-risk MDS 
treated with this combination. 
• To determine the overall survival of patients with AML and high-risk MDS treated with 
this combination. 
 
 
 
 
2.1 BACKGROUND AND RATIONALE 
 
2.2 AML and High-risk MDS in Older Patients: 
 
AML is primarily a disease of older people with a median age of diagnosis of 68 years. There are 
approximately 13,000 new cases of AML per year in the United States and 55% of these occur in 
individuals who are age 65 years and older]. AMLin older patients is phenotypically different 
from AML in younger patients. As compared to their younger counterparts, older patients with 
AML more frequently have an antecedent hematological disorder or unfavorable cytogenetics, 
and respond less well to chemotherapy 
 
Elderly patients with AML or high-risk MDS have a poor prognosis , which is attributed to 
having disease that is inherently more resistant to current standard cytotoxic agents and/or 
relatively poor tolerance of these agents because of comorbidity and reduced tolerance of 
adverse effects. As a result , despite steady progress in the therapy of AML in younger patients , 
treatment for elderly patients with AML has not improved for decades. Among patients 70 years 
or older and those with adverse karyotypes the 4-8 week mortality with intensive chemotherapy 
is 30%-50%, and the median survival is 4-7 months. Therefore such patients derive little benefit 
from intensive chemotherapy, and some may in fact be hanned with intensive chemotherapy. 
Such high induction mortality rates and poor tolerance to chemotherapy have resulted in a 
reluctance to treat AML in older patients. A  Surveillance Epidemiology and End Results 
database analysis has indicated that 64% of AML patients over age 65 receive no therapy for 
AML, other than supportive care. This untreated group has a dismal median survival of 1.7 
months. 
 
These results emphasize the need to explore alternate strategies to intensive chemotherapy for 
AML and high-risk MDS in older patients and/or those unable to tolerate intensive 
chemotherapy (based on predicted high eight-week mortality rates of 30% or more). The 
development of novel and effective anti-AML agents and/or combinations is crucial to 
improving the outcome of older patients (age >/= 60) with AML. Therefore , we would like to 
evaluate the efficacy and tolerability of a novel combination ofvosaroxin in combination with 
decitabine in older patients with AML and high-risk MOS. 
 
 
 
2.3 Vosaroxin (formerly voreloxin) 


6 
 
 
Vosaroxin and decitabine in AML 
 
 
 
 
2.3.1 Rationale and Mechanism of Action: 
 
Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative with a unique 
mechanism of action that appears to parallel the activity of the quinolone antibiotics in 
prokaryotes. Vosaroxin intercalates DNA and inhibits topoisomerase II activity through both 
enzymatic inhibition and direct poisoning [8, 9]. Vosaroxin preferentially targets actively 
replicating cells, and the extent of DNA damage is cell-cycle dependent with maximum activity 
in the G2/M phase. The DNA damage results in arrest at G2/M phase and cell death by 
apoptosis. 
 
Vosaroxin is mechanistically similar to the anthracyclines such as idarubicin and daunorubicin, 
and the anthracenedione, mitoxantrone. However, in contrast to idarubicin and daunorubicin 
which are rapidly metabolized to the less active idarubicinol and daunorubicinol[ 10, 11], 
respectively; vosaroxin is minimally metabolized and does not require metabolism for cytotoxic 
activity. When administered on days 1 and 4 at 90 mg/m2, concentrations ofvosaroxin are 
sustained above IC5o for more than 7 days, with IC90 concentrations achieved for approximately 
5 days. 
 
Vosaroxin demonstrated potent anti-proliferati ve effects on human leukemic cell lines in vitro. 
Vosaroxin also demonstrated anti-proliferative activity in a phase I study in advanced 
hematologic malignancies (SP0-0004, completed in 2008)[12]. Two studies in AML have been 
completed , including a phase II study evaluating vosaroxin as a single agent in patient s at least 
60 years of age with previously untreated AML (SP0-0014)[13] and a pha se Ib/II study 
evaluating the combination of vosaroxin with cytarabine in patients with relapsed or refractory 
AML (SP0-0012)[14]. The current Phase III, Randomi zed, Conhꞏolled , Double-Blind  , 
Multinational Clinical Study of the Efficacy and Safety ofVosaroxin and Cytarabine Versus 
Placebo and Cytarabine in Patients With First Relapsed or Refractory Acute Myeloid Leukemia 
(VALOR) is ongoing. In this study vosaroxin is administered at a dose of90 mg/m2 on days 1 
and 4 for a total dose of 180 mg/m2/cycle in combination with cytarabine 2-hour IV infusion of 1 
g/m2/day for 5 days. Vosaroxin was well tolerated at this dose. This dosing schema forms the 
basis for the vosaroxin dosing schedule we plan to use in our current protocol. 
 
 
 
2.3.2 Pharmacodynamics, Pharmacokinetics and Preclinical Experience: 
 
Vosaroxin demonstrated potent activity as a single agent on human leukemic cell lines 
in vitro, in AML patient bone marrow biopsies ex vivo, in hematologic xenograft model s[8], 
and in a mou se model of marrow ablation[ 15]. 
 
The cytotoxic activity ofvosaroxin was evaluated  in the human acute leukemia cell lines 
MV4-11 , HL-60, and CCRF-CEM. The average half-maximal inhibitory concentration 
(IC5o) values for vosarox in in the myeloid leukemia cell lines, MV4-11 and HL-60, were 
95±8 nM and 884± 114 nM, respectively. The acute lymphoblastic leukemia (ALL) cell line, 
CCRF-CEM, was also sensitive to vosarox in, with an average IC50 of 166±0.4 nM. 


7 
 
 
Vosaroxin and decitabine in AML 
 
 
 
 
 
Vosaroxin was highly active in two hematologic xenograft models, with 98% tumor growth 
inhibition of established tumors (Table 3). At maximum-tolerated  dose (MTD), vosaroxin as 
a single agent ablated normal mouse bone marrow by 80% relative to vehicle control. This 
effect was reversible, with recovery of both marrow and peripheral blood counts. 
 
Tablel: Vosaroxin  Tumor Growth Inhibition  in Human Xenograft  Cancer Models 
 
 
Human 
Vosaroxin 
Vosaroxin 
Percent 
Complete 
Tumor 
Dose 
Schedule 
CeU Line 
Inhib (1] 
 
Response  (3] 
ALL 
25 mglkg 
IV. q7d>c: 3 
CCRF-CEM 
98.1 
6/6 
016 
Acute 
Lymphoma 
(75 mg/m2 ) 
IV.q 7dx 5 
LM-3 Jck 
99 
616 
416 
Source:  Hoell 2009. 
Abbreviations: Inhib. inhibition :ALL. acme lymphoblastic leukemia :IV. imravenous: q7d, every 
7 day. 
[1] Values represem (1-average mmor weight treated I average rumor weight comrol) x 100%. 
[2] (number surviving animal at end of study I number animals at beginning of study). 
[3]  (number of CR at end of smdy I mllllber animals at beginning of smdy). 
 
 
 
The combination of an anthracycline with cytarabine is a standard of care treatment for 
AML. Therefore, studies were also undertaken to evaluate the effects of vosaroxin in 
combination with cytarabine in vitro and in vivo. The combination index method was used 
to assess the activity ofvosaroxin combined with cytarabine in acute leukemia cell lines in 
vitro (Figure 1). The combination resulted in synergi stic activity in the myeloid leukemia 
cell lines, MV4-11 and HL-60, and additive activity in the ALL cell line, CCRF-CEM[15]. 


8 
 
 
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Vosaroxin and decitabine in AML 
 
 
 
 
Figure 1. Vosaaꞏoxin Combined \\'ith Cytarabine Has Additive or Synergistic Activity 
in Acute Leukemia Cell Lines 
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Assnys were perfonued with lnunan Acut e leukemia cell lin es nꞏeated with vo!.llroxin alone (•). or vosarox in 
combined wit h cytnrabine ( "'). Cells were exposed for 72 botuꞏs to senally diluted vosaroxin or vosaroxin and 
cytarabine . Viabili ty is displayed as percent of vehicle control.  A. MV4- l l :B. HL-60: an d C. CCRF-CEM . 
D . The combin:nion mdex (CI) calculnted from the cwves inA-Cis displnyed   CI < 0.85 indicates synergy.  
Cl 0.85-I .2 indicat es ndclit ivity. and Cl > 1.2 indicates antagoni sm . Each dat n point represent s an independent 
experiment. O. l\1V4- l l : D. HL-60: .t:;.. CCRF-CEJ\-1. Vosaroxin comrol is vosnroxin alone. 
 
 
Vosaroxin and cytarabine were active as single agents and had supra-additive activity in 
combination in a normal mouse bone marrow ablation and recovery mod el that mimics the AML 
treatment paradigm[ IS]. Animal s received vosaroxin IV once daily or cytarabine IV 3 times 
daily, or both , on days 0 and 4. Bone marrow cellularity was reduced 80% in animals receivin g 
vosaroxin at MTD and 26% in animals receiving cytarabine at MTD (Figure 2). The MTD of 
vosaroxin and cytarabine combined was 10 mg/kg vosaroxin (50% single-agent MTD) 
coadministered  with 20 mg/kg cytarabin e (33% single-agent MTD). At those doses, bone  
marrow cellularity was reduced 89% for the agents combined. Peripheral neutrophils and 
lymphocyte s decreased following vosaroxin or cytarabine treatment alone or in combination; the 
effect on platelets was less profound. Both bone marrow cellularity and peripheral blood cell 
counts recovered to normal levels within 1 week, reflecting the recovery of hematopoiesis. 


 
 
Vosaroxin and decitabine in AML 
 
 
 
 
Figure 2. Vosaroxin and Cytarabine, Alone or in Combination, Ablate Norm 1l Bone 
farrꞏow 
 
Sotuce: Scatena 2010.44 
CD- I mice (n = 2-3) received vehicle.vosaroxin .cytarabine.or vosa roxin and cytarabine in combination on 
days 0 and 4 . On day 6. femw-s were isolated and cellularity wa s assessed in H&E-stained bone man-ow 
sections (shown at 01iginal magnification x I 00). Ablation for vehicle-trea ted animals was subtracted from 
ablation of drug-treated animal!.. A. vehicle. 5% ablation: B. cytarabine at maximum-tolera ted dose (MTD). 
26'l-o ablation :C. vosaroxin at MTD. 80% ablation:D. cytarabine at 33% MTD.0% ablation:  E. vosaroxin at 
50% MTD.36% ablation: F. combination ofcytarabine at 33% MTD and vosarox in at 50% MTD.89°'0 
ablation. 
 
 
 
The ex vivo evaluation of patient resistance to cytarabine and vosaroxin suggests a key role for 
vosaroxin in clinical activity and supports combination therapy . Patient bone marrow aspirates 
from both the single-agent study in newly diagnosed AML (SP0-0014) and the study of 
vosaroxin in combination with cytarabine in relapsed or refractory AML (SP0-0012) were 
evaluated for extreme drug resistance (EDR) ex vivo to vosaroxin and doxorubicin. Patient 
samples from SP0-0012 were also tested for EDR to cytarabine. Resistance to vosarox in was 
profiled to evaluate whether clinical outcome correlated with ex vivo response. Doxorubicin was 
included as a comparator for both studies, as anthracyclines are commonly used to treat patients 
with AML. However , P-glycoprotein (P-gp) expression may affect response to anthracyclines as 
they are substrates for this efflux transporter. Vosaroxin is not a P-gp substrate[16] , yet it acts 
through a similar but differentiable mechanism of action as anthracycline drugs. 
 
Concentrations of 1  M and 3  M were used to characterize EDR for both vosaroxin and 
cytarabine, as these concentrations are observed in human plasma at the doses tested in 
SP0-0012. The concentrations tested for the anthracyclines were 0.1 f.!M doxorubicin and 
0.05  M daunorubicin, levels that were sustained for 24 hours at clinically relevant doses[17, 
18]. Daunomycin was also incorporated into the analysis, and 1 of 4 available samples from SP0-
0012 had EDR to daunomycin . 
 
Bone marrow aspirates were collected and assayed from 86 patients at baseline prior to dosing. 
Vosaroxin antiproliferative activity compared favorably with both cytarabine and doxorubicin , as 
shown in Table 2. 
 
 
 
 
 
 
 
9 


Vosarox in and decitabine in AM L 
10 
 
 
 
Extreme Drug Resistance  
SP0-0014 
Pre\iously 
SP0-0012 
Rtlapstd or 
 
Cone. 
OwraiJ 
rntrtated 
Rtfractoi' 
Drug 
( 1) 
::'\=86 
=37 
=49 
Vosaroxin 
 
27% 
35% 
20% 
 
3 
2% 
0% 
4% 
Cytarabine 
 
ne 
ne 
73% 
 
... 
.) 
ne 
ne 
40% [I] 
Doxorubicin 
0.1 
55% [2] 
57% 
53% [1] 
 
 
 
 
 
 
Table 2: Percentage of Bone Marrow Aspirate Samples With Extreme Drug Resistance to 
Vosaroxin and Other Common Chemotherapeutic Agents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TI1e Exiqon extreme dmg resistance (EDR®) assay was adapted to analyze proliferation ill hematologic 
samples using the luminescem Cell Titer Glo® proliferation assay (Promega Corporation). Assa ys were 
petfmmed at Exiqon Diagnostic:. (Tustin. CA). Exiqon defines EDR as < 50% inhibition of proliferation 
based on validation smdies in solid mmors. 
Abbreviation s: Cone., concentration: ne.not evaluated. 
[1]  For SP0-00 12. 40 of 49 samples were analy7ed for EDR to 3  1M cytarabine.and 45 of 49 samples 
were evaluated for EDR to doxombici.J1. 
[2]  Overall. 82 of 86 samples were evaluated for EDR ro doxombicin . 
 
 
The assay is not validated to predict resistance for hematologic malignancie s, but it does provide 
evidence that vosaroxin is a key contributor to response, and that the combination ofvosaroxin 
with cytarabine can potentiate the activity of each drug as a single agent. Patients from the 
single-agent study (SP0-0014) whose bone marrow aspirates were inhibited less than 46% by 1 
j.tM vosaroxin had a greater chance of treatment failure (p = 0.036) than those whose aspirates 
were inhibited at least 46% (Figure 3A). The threshold value of 46% identified a significant 
difference in chance of treatment failure; 50% inhibition did not meet this criterion. Of the 8 
patient s with inhibition less than 46%, 7 (88%) experienced treatment failure. In contrast, of the 
29 patients whose aspirates were inhibited at least 46%, 14 (48%) experienced treatment failure. 
 
A similar analysis for the combination treatment study (SP0-0012) showed that most patients 
who responded met or exceeded the 46% threshold for vosaroxin, in contrast to cytarabine 
(Figure 3B). Eleven patients who had post-treatment CRs had bone marrow aspirates at baseline 
(predose) for evaluation ofEDR, defined here as less than 46% inhibition of proliferation. As 
shown in Figure 3C, 2 of the 11 patient samples had EDR to 1 j.tM vosaroxin, 6 had EDR to I 
j.tM cytarabine, and 1 was resistant to both . Taken together, these data suggest that vosaroxin is a 
major contributor to the observed clinical CRs, given the limited ex vivo resistance to vosaroxin 
in the presence of ex vivo resistance to cytarabine in patients subsequently treated with the 
combination. Furthermore, these data suggest enhanced activity of the combination treatment , as 
7 of 11 patients in remission had EDR ex vivo to cytarabine, vosaroxin , or both . In agreement 


Vosarox in and decitabine in AM L 
11 
 
 
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with these data, vosaroxin combined with cytarabine had synergistic activity in 22 of25 samples 
from patients with primary AML treated ex vivo with the drugs[l9]. 
 
 
 
Figure 3. Patients in Complete Remission May Have Extreme Drug Resistance to 
Cytarabine, Vosaroxin, or Both, Suggesting Enhanced Activity in 
Combination 
A 
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Vosaroxm 
Vosarolcin    Cytarabwe 
VosaroXlll   Cytarabine 
 
Bone manow aspirates were collected at ba seline and analyzed at Exiqon Diagnostics in the luminescent Cell 
Titer-Glo® proliferation assay (Promega Co1poration) . Hatched line indicates 46% inhibition of prolifera tion . 
The threshold value of 46% identified a significant difference in chance of treatment failure: 50% inhibition did 
not meet this c1iterion. 
A. Assay of a<>pirates fi:om SP0-0014 pa tients (single-agent vosaroxin) showing percent growth inhibition by 
1 t•M vosaroxin. 0 Treatment faihu:e: + complere remission (C'R). 
B. Assay of aspirare s from SP0-0012 patiems (vosaroxin in combination wirb cytarabine) showing: percent 
growth inhibition by 1 
vosaroxin and 1 11M cytarabine. 0 Treatment faihuꞏe:+ C'R 
C'. Assay of aspirates from SP0-0012 patienrs in C'R showing percent growth inhibition by 1 tM vosaroxin and 
1 p.M cytarabine using the same symbol for each individual patient . Cytarabine C'IV is a continuous 
intravenous (IV) infi.lsion for 24 homꞏs ar 400 mg/m2/day for 5 days:2-h IV is a 2-hour IV infusion at 
1 g/m2/day for 5 days. 
 
 


Vosarox in and decitabine in AM L 
12 
 
 
Details of additional nonclinical studies of vosaroxin are presented in the vosaroxin investigator 
brochure (IB). 
 
2.2.3 Clinical Experience: 
 
No clinical studies combining vosaroxin with decitabine have been conducted as of yet. Ours 
will be the first clinical trial to evaluate the efficacy and tolerability of this novel combination . 
However , clinical data and toxicity profiles from the SP0-0012; a phase lblll dose-escalation 
study of two dose regimens (schedules) ofvosaroxin in combination with cytarabine in patient s 


Vosaroxin and decitabine in AML 
 
 
 
 
 
with relapsed or refractory AML are available and will be briefly discussed. These may serve as 
a possible guide to efficacy and toxicity profiles we may anticipate in our study. 
 
The enrollment for study SP0-0012; a phase Ib/ll dose-escalation study of two dose 
regimens (schedules) ofvosaroxin in combination with cytarabine in patients with relapsed 
or refractory AML is complete (110 patients) and patients are in follow-up[20]. Data from this 
study provide the preliminary safety and clinical activity information for combination treatment , 
and formed the basis for the pivotal phase III VALOR study of vosaroxin in combination with 
cytarabine . SP0-0012 had two phases: dose escalation (phase Ib) and dose expansion at the 
MTD (phase II). In phase II, patient s either had first relapsed AML (relapse following an initial 
CR 
3 month s and S 24 months) or primary refractory AML (failed to achieve a CR or CRp 
[CR with incomplete platelet recovery] following 1 or more cycles of induction, or an initial 
CR < 3 months). Treatment was with 80 or 90 mg/m2 vosaroxin on days 1 and 4 in combination 
with cytarabine either as a continuous intravenou s (CIV) infusion (400 mg/m2/day) on days 1-5 
or a 2-hour intravenous (IV) infusion (1 g/m2/day) on days 1-5. Characteristics ofthe 69 patients 
treated in phase 2 are shown in Table 3. Clinical activity endpoints are shown in Table 4. A 
summary of grade 3 or greater treatment-emergent adverse events (TEAEs) with more than 10% 
incidence by regimen is shown in Table 5. 
 
Table 3: Study Population Characteristics in Phase 2 of SP0-0012 (N = 69) 
 
 
 
First Relapse 
(I\= 36) 
Primary Refractor y 
(I\ = 33) 
0\'eraU Population 
= 69 (1]) 
Initial C'R < 12 months (N = 23) 
52% 
33% 
48% 
na 
Initial C'R  12-24 months (N = 13) 
I9% 
na 
Median duration of initial CR months (range) 
7.3 (3.3-23.7) 
na 
Median prior induction cycles (range) 
na 
2 (1-6) 
Median age. years (range) 
61 (35-73) 
57.5 (18.5-71) 
z 60 years 
64% 
34% 
ECOG 0-1 
89% 
85% 
Cytogenetics per NCCN Practice Guidelines 2010 
 
 
Favorable 
3% 
3% 
Intermediate 
64% 
58% 
Unfavorable 
28% 
2 1% 
Data source: ASCO/EHA 20 I 0 poster presenta tions.49ꞏS6 
Abbrevia tions: CR.complete remission:na, not applicable: ECOG . Eastem Cooperative Oncology 
Group:NCCN .National Compr ehensive Cancer Network. 
[I] Patients ;vere treated \vith vosaroxin at 80 or 90 mg/m2 on days I , 4 and cyrarabine 400 mg/m2 CIV 
or 1 glm- IV on days 1-5. 
 
 
 
 
 
 
 
 
12 


Vosaroxin and decitabine in AML 
 
 
 
Advtrst Evtnt 
CIV 
(:\" = 30) 
2-Hour IV 
(N = 38) 
OvtraU 
(N= 68) 
Upper GI mucositis [I ] 
20% 
11% 
15% 
Febrile neutropenia 
53% 
34% 
43% 
Sepsis I Bacteremia [1] 
30% 
24% 
27% 
Infections [1] 
10% 
13% 
12% 
Pneumonia [1] 
17% 
8% 
12% 
Hypoka lemia 
27% 
13% 
19% 
Hypophospha temia 
13% 
0% 
6% 
 
 
 
 
Table 4: Clinical Activity ofVosaroxin (80 to 90 mg/m2} and Cytarabine Combination 
Treatment in Phase 2 of SP0-0012 
 
Endpoint 
Outrome 
CR rate 
Combined CR rare  (CR+CRp+CRi) 
Primaty refractoty 
First relapse 
Initial CR < 12 months 
Initial CR 12-24 months 
Leukemia-free mviva l. days (95% CI) [I] 
Overall 
Primaty refi:act01y 
First relapse 
Median overall s\uvival. days (95% CI) 
17 of69 (25%) 
20 of69 (29%) 
6 CR. 1 CRp 
 
 
4CR 
7 CR. 1 CRp. 1 CRi 
 
329 (222. nr) 
nr (260. nr) 
329 (175. m) 
•.\11 
2 16  (140.307) 
First relapse 
2 18 (131. 377) 
Ptimaty refractory 
209  (124.307) 
Data source: ASCO/EHA 20 10 poster presentations_4Y.SU At the time of data cutoff (May 2010). 
20 patients were in follow-up. 
Abbreviations: CR. complete remission: CRp.CR with incomplete platelet recovety:CRi.CR with 
incomplete recovery of platelets or neutrophils: CI. confidence intetval:nr. not reached. 
[1] Time from complete remission (CR. CRp. CRi) to relapse or death. 
Patients were treated with vosaroxin at 80 or 90 mg/m2 on days 1.4 and cytarabine 400 mg/m2 CIV or 
1    m2 IV on days 1-5. 
 
 
 
 
Table 5: All Treatment-Emergent Adverse Events Grade 3 by Regimen for Patients 
Treated With Vosaroxin at 80 to 90 mg/m2 in Combination With Cytarabine in 
Phase 2 of SP0-_0012 (N = 69) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: ASCO/EHA 2010 poster presentations.4b0 
Abbreviation : CIV.continuous intravenou s: IV, inn-aveuou s: GI. gastrointestinal. 
[1]Aggregates of multiple prefelTed tenus. 
Patients were treated with vosaroxin at 80 or 90 mg/m2 on days 1. 4 and cytarabine 400 mg/m2 CIV or 
1g/m2 IV on days 1-5. 
 
13 


 
 
Vosaroxin and decitabine in AML 
 
 
 
 
2.2.4 Dosing and Schedule: 
 
How supplied: 
Vosaroxin is a clear, colorless to pale- yellow liquid formulated for IV administration 
manufactured in accordance with current Good Manufacturing Practices (GMP). Vosaroxin vials 
may contain either 100 mg or 230 mg vosaroxin at a concentration of 10 mg/mL. Each milliliter 
also contains 45 mg ofD-sorbitol to maintain isotonicity. Methanesulfonic acid is added to assist 
in the solubilization ofvosaroxin. The sterile nonpyrogenic solution is formulated without 
preservatives. 
 
Packaging and Labeling: 
Vosaroxin injection is supplied in single use vials, either 10 mL or 25 mL Type 1 glass vials 
labeled as vosaroxin. The product is packaged in boxes (kits) that contain vosaroxin and 
appropriate number of sterile 0.22 11m filters. 
 
At minimum , the label of each vial and other packaging will include the following 
information , consistent with country-specific regulations as appropriate: 
 
 
 
Vosaroxin 
Protocol number 
Product code and lot number 
Content: 1vial of either 10 mL or25 mL s lution ofVosaroxin (10 mg/mL) for 
intravenous administration only 
Sterile single use vial only 
Administer as directed in the protocol 
Protect from light 
Store in an upright position 
Do not store above 25°C 
Manufacture date, expiration date, or use-by date (as applicable) 
Caution statement 
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., Suite 400 
South San Francisco, CA 94080 USA Tel: (650) 266-3500 
 
 
Disposal of unused/ expired drug: 
Unused/ expired vosaroxin will be disposed per MD Anderson policy. 
 
Storage: 
Vosaroxin vials must be stored as packaged in an upright position at room temperature. 
Thermostatically  controlled storage conditions consistent with United States Pharmacopeia (USP)-
defined  "Controlled Room Temperature " are recommended. 
 
Vosaroxin must not be frozen or stored in a refrigerator. When vosaroxin is drawn 
 
14 


Vosaroxin and decitabine in AML 
 
 
 
 
 
 
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 (eg, amber bag, brown paper bag), this 2-hour stability 
maximum can be extended up to 24 hours. The pharmacy manual has more information on 
storage conditions. 
 
Preparation and Administration of Vosaroxin 
Undiluted vosaroxin should be administered before the infusion of decitabine 
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, flush the line thoroughly with 
5% dextrose in water (D5W) before and after administration. 
 
 
 
Suggested Procedure for Preparation: 
 
1. Calculate the dose according to protocol or pharmacy manual instructions. 
 
2. Attach the provided 0.22 fliD sterile filter unit to the tip of the sterile plastic syringe that will 
be used to administer vosaroxin. 
 
3. Attach an appropriate gauge needle to the filter unit. 
 
4. Withdraw the proper dose from the vosaroxin vial into the syringe. 
 
5. Discard the used filter unit and needle and cap the syringe. 
 
6. Protect the filled, capped syringe from light until ready to administer . 
 
 
 
Suggested Procedure for Administration : 
 
1. A bilurnenal or trilurnenal catheter is recommended. Start an IV infusion through 
one of the lumens using D5W or analogous solution available locally such as Glucose 
Intravenous Infusion BP 5% at a slow rate sufficient to keep the vein open ("keep 
 
15 


Vosaroxin and decitabine in AML 
 
 
 
 
 
vein open"rate). 
 
2. Before administering vosaroxin, increase the D5W infusion rate to approximately 100 
mL/hour, and continue this rate during the vosaroxin infusion. 
 
3. Administer vosaroxin via syringe by accessing an available hub or stopcock. 
 
4.   Administer vosaroxin as a short infusion over approximately 8 to 10 minutes, either 
manually or using a syringe pump with a + 20-25 minute window to allow for flushing 
time as reflected in documentation. 
5. At the end of the infusion, flush the IV line with D5W per institutional standard. 
 
6. If a central catheter or heparin Jock is in place, it may be capped according to the 
study site's usual procedure s. 
 
Vosaroxin is not known to be a vesicant or irritant. If extravasation is observed or suspected, 
treat according to standard institutional procedures 
 
 
2.3 Decitabine (DAC) 
 
2.3.1 Rationale and Mechanism of Action: 
 
Decitabine (Dacogen®, 5-aza-2'-deoxycytidine) is an analogue of the natural nucleoside 2'- 
deoxycytidine. It exerts its antineoplastic effects after phosphoryla tion and direct 
incorporation into DNA and inhibition of DNA methyltransferase, causing hypometh ylation 
of DNA and cellular differentiation or apoptosis . Decitabine inhibits DNA methylation in 
vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. 
In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the 
formation of covalent adducts between DNA methyltransferase and decitabine incorporated 
into DNA. Non-proliferating cells are relatively insensitive to decitabine[21-23]. 
 
 
 
2.3.2 Pharmacodynamics, Pharmacokinetics and Preclinical Experience: 
 
Decitabine has been extensively studied in humans. After IV injection pharmacokinetic s of 
decitabine, using bioassay to measure drug concentration, has been characteri zed by a two 
compartmental body model , with a t112 of the distribution phase of 7 minutes[24, 25]. The 
terminal phase t 112 was between 10 and 35 minutes and a mean volume of distribution of 4.6 
L/kg. Decitabine is rapidly metabolized by deamination by liver cytidine deaminase. Mean total 
plasma clearance was 126 mL/minlkg. Renal excretion ofunmetabolized decitabine was quite 
low, less than 1% of the total dose. 
 
 
 
 
16 


Vosaroxin and decitabine in AML 
 
 
 
 
 
Decitabine does not block the progression of G 1-phase cells into S-phase or the progression of S- 
phase cells to mitosis, as measured by the incorporation of radioactive thymidine into DNA and 
by autoradiography, which suggests that the cytotoxic action of decitabine is not self- 
limiting[24]. Exposure time appears to be an important factor relative to the cytotoxicity 
produced by decitabine. Greater cytotoxicity was produced at longer rather than shorter exposure 
times for both experimental leukemic cell lines and tumor cells[26, 27]. Exposure of cells to 
decitabine during the first cell cycle produced minimal growth inhibition, whereas increasing the 
exposure time to two or more cell cycles resulted in an increased inhibition of cell growth[27, 
28]. Further, there is an optimal concentration at which analogs of 5-azacytosine induce cellular 
differentiation; higher concentrations produce less differentiation and more cytotoxicity. 
 
Decitabine's mechanism of action, hypomethylation of DNA followed by stimulation of gene 
expression and cell differentiation , is a relatively new approach to cancer treatment. Decitabine 
has shown considerable activity against various types of experimenta lleukemias[29-31]. In in 
vivo comparative studies, decitabine showed greater activity than cytarabine. In addition, 
decitabine has considerable antitumor activity in vitro and in in vivo animal tumor systems, 
exceeding that of structurally analogous compound s, such as cytarabine. Clinical experience wi th 
decitabine confinned that it produces an antineoplastic effect in acute leukemia , chronic 
leukemia, and myelodysplastic syndrome and its differentiation-inducin g properti es have been 
confirmed in vivo in humans. 
 
 
 
2.3.3 Clinical Experience : 
 
Multiple phase I and II studies using decitabine as a therapy for leukemia have been reported. 
The first studies were in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) . 
Rivard et al.[32] conducted the first study with decitabine as a single agent for remission 
induction in pediatric patients with refractory or relapsed leukemia. Dose-dependent activity was 
noted in this first small study, which was followed by another small study[33]. A response rate of 
37%, based on 22% complete response (CR) and 15% partial response (PR) was noted in this 
second study, along with 48% hematological improvement (HI). Several subsequent studies of 
decitabine as a single agent have also demonstrated efficacy in the treatment of AML and 
ALL[34]. Combination studies included decitabine with amsacrine[35], idarubicin[35], and 
daunorubicin[36]. Response rates were generally higher in relapsed than in refractory disease[34] 
and lower in heavily pretreated patients[37]. 
 
Decitabine has been approved by the Food and Drug Administration (FDA) in the United 
States for treatment of patient s with MDS including previously treated and untreated , de novo 
and secondar y MDS[38]. Decitabine has been reported to have anti-leukemic activity in AML. In 
a phase II study in elderly patients (2: 60 years) with previously untreated AML, decitabine 
resulted in a complete remission rate of24% with a median overall survival of7.7 months, and a 
30-day mortality rate of 7%[39]. In this study decitabine was administered at a dose of20 mg/m2 
intravenously for 5 consecutive days of a 4-week cycle. The most common toxicities were 
myelosuppression, febrile neutropenia , and fatigue. 
 
17 


Vosaroxin and decitabine in AML 
 
 
 
 
 
 
 
 
2.3.4 Dosing and Schedule: 
 
How Supplied: 
Decitabine is supplied as a lyophilized white to almost white, finely crystalline, odorless powder 
for injection in 20mL vial glass vials, containing 50 mg of decitabine, monobasic potassium 
phosphate, and sodium hydroxide. 
 
Storage: 
The intact vials should be stored at room temperature (15-30 oc; 59-86°F) 
 
Stability: Shelf life surveillance of the intact vials is on-going. The intact vials are stable for at 
least 1 year at room temperature (22- 25°C), 2 years at 2-8°C or 6 months at 40° C. 
 
Reconstitution and dilution of the powder for injection (with 1OmL of sterile water for injection) 
results in a rapidly decomposing solution. The concentration of decitabine in the reconstituted  
and diluted solution decreases about 10% after 4 hours at 25°C or about 10% after 24 hours at 
4°C. Since 10% is the maximum allowable decomposition, and the solution will also decompose 
during administration (infusion), the solution should be prepared just prior to administration. 
Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold 
(2-8°C) infusion fluids and stored at 2-8°C for a maximum of up to 7 hours until administration. 
This solution can be infused over a maximum period of 3 hours. 
 
Preparation and administration: 
When reconstituted with 10 mL of sterile water for injection each mL will contain 5 mg of 
decitabine, 6.8 mg ofKH2P04, and approximately 1.1 mg NaOH. The pH of the resulting 
solution is 6.5- 7.5. The reconstituted solution can be further diluted to a concentration of 1 
mglmL or 0.1 mglmL in cold infusion fluids (0.9% Sodium Chloride Injection USP, 5% 
Dextrose in Water Injection , USP, or Lactated Ringer's Injection USP). 
 
Decitabine is to be administered as a continuous intravenous infusion over approximately one 
hour. 
 
Drug handling precautions will be strictly followed. Skin contact with the solution should be 
avoided and protective gloves should be worn. Drug spilling can be inactivated by 2 M sodium 
hydroxide solution. The skin should be treated with a borax buffer solution pH 10 and after that 
thoroughly washed with water and soap. 
 
Drug supply and distribution: 
Decitabine is commercially available from EISAI, Inc and will be obtained commercially and 
charged to patient 's account. Detailed instructions for its use may be found in the pharmacy 
manual. 
 
 
18 


Vosaroxin and decitabine in AML 
 
 
 
 
 
Reported Adverse Events and Potential Risks: 
Autoimmune reaction (antiplatelet antibodies, erythema nodosum), decreased hemoglobin, 
decreased leukocyt es (total WBC), decreased neutrophils/granulocytes (ANC/AGC), decreased 
platelets, fatigue (lethargy, malaise, asthenia), alopecia, diarrhea, peritonitis, nausea , vomiting, 
anorexia, stomatitis/pharyngitis (oral/pharyngeal, mucositis), increase bilirubin, increased SGOT 
(AST) (serum glutamic oxaloacetic transaminase), increased SGPT (ALT) (serum glutamic 
pyruvic transaminase), liver damage, depressed level of consciousness, abdominal pain or 
cramping. 
The following adverse events have been reported in decitabine trials:: allergic reaction; allergic 
rhinitis ;GVHD; bone marrow cellularity; atrial fibrillation; cardiac ischemia/infarction; 
cardiopulmonary arrest; hypotension; left ventricular systolic dysfunction; right ventricular 
dysfunction; fever; insomnia; rigors/chills; weight loss; pruritus; rash; anal ulcer; ascites; 
constipation; distension; esophagitis; GI obstruction; ileus; taste alteration; CNS hemorrhage; GI 
hemorrhage; lung hemorrhage ; nose hemorrhage ; petechiae; urinary hemorrhage; cholecystitis ; 
liver dysfunction/failure; infection without neutropenia; opportunistic infection; perianal abscess; 
head/neck edema; alkaline phosphatase; creatinine; hypercalcemia; hyponatremia; fracture; 
agitation; CNS ischemia; confusion; depression; dizziness; extrapyramidaVinvoluntary  
movement; motor neuropathy ; psychosis ; seizure; sensory neuropathy; bone pain; headache; 
muscle pain; urinary pain; ARDS; bronchospasm ; cough; dyspnea; hiccoughs ; 
pneumonitis/pulmonary infiltrates; cystitis; renal failure; urinary frequency; phlebitis; 
thrombosis/thrombus/embolism; veno-occlusive disease. 
 
 
 
2.4 Rationale for Combined Treatment with Vosaroxin and Decitabine: 
 
Standard treatment for patients diagnosed with acute myeloid leukemia (AML) comprises of two 
chemotherapy phases, induction and consolidation[40]. Such an approach is curative for younger 
patients or those with favourable cytogenetics but is rarely curative for older patients (  65 years) 
or those with unfavourable cytogenetics. Older patients have dismal CR rates (24% to 33%), 
increased risk of induction mortality (29%) and high rate ofleukemia relapse[41, 42]. Thus, new 
safe and effective therapies are urgently needed for older patients and/or patients unable to 
tolerate standard therapy. 
 
Vosaroxin and decitabine have non-overlapping primary molecular mechanisms of action. 
Vosaroxin targets the topoisomerase II and results in G2/M phase arrest and apoptosis. In 
contrast to vosaroxin, decitabine inhibits the DNA-methyltransferase  activity resulting in 
hypomethylation and cell cell cycle arrest at the G 1 phase via p21(WAF1) and the G2/M phase 
via the p38 MAP kinase pathway[43]. The non-confluent safety profile ofvosaroxin and 
decitabine (refer to respective toxicity profiles under section 2.2.3 and 2.3.4) and their unique 
and non-overlapping anti-leukemic activities make them well suited for frontline combination 
therapy in elderly patients and/or patients unable to tolerate standard therapy for AML or high- 
risk MDS. 
 
 
 
 
19 


 
 
Vosaroxin  and decitabine in AML 
 
 
 
 
3.1 STUDY DESIGN AND ELIGIBILTIY: 
 
3.2 Study Design: 
 
This will be a single ann, single center, open label study of the combination of vosaroxin with 
decitabine in previously untreated patients with acute myeloid leukemia or high-risk 
myelodysplastic syndrome who are elderly (age 2 60) and/or unable to tolerate standard therapy. 
The study will consist of a lead-in phaseIp01tion to determine the safe dose of vosaroxin in 
combination with decitabine to move into the phase IIportion of the study. A total of up to 84 
evaluable patients (including up to 24 patients in the run-in phase I and up to 60 patients in the 
phase II) will be treated on this protocol. 
 
In the initial portion (Phase I) we will treat 6 patients with vosaroxin administered intravenou sly 
on days 1 and 4 at a dose of 90 mg/m2 in the first cycle (induction 1) for a total dose of 180 
mg/m2/cycle in combination with decitabine at a dose of20 mg/m2 intravenously for 5 
consecutive day (Days 1 to 5). These doses have been given safely in previous studies as follows. 
A vosaroxin dose of 90mg/m2 was identified as the MTD in the dose-esca lation (phase lb) of the 
SP0-0012 study. In the pha se II of this study 69 patients who had either first relapsed AML (relapse 
following an initial CR 3 months and :s; 24 months) or primary refractory AML (failed to achieve a 
CR or CRp [CR with incomplete platelet recovery] following 1or more cycles of induction, or an 
initial CR < 3 months) were treated with 80 or 90 mg/m2 vosaroxin on days 1and 4 in combination 
with cytarabine either as a continuous intravenous (CIV) infusion (400 mg/m2/day) on days 1-5 or a 
2-hour intravenous (IV) infusion (1 g/m2/day) on days 1-5. The combination of vosaroxin at a dose 
of 90mg/m2 and IV cytarabine was well tolerated. Data from the SP0-0012 study provide the 
preliminary safety and clinical activity information for combination treatment, and formed the basis 
for the pivotal phase Ill VALOR study of vosaroxin in combination with cytarabine which is currently 
ongoing. Decitabine has been approved for trea tment of MDS and AML at a dose of 20 mg/m2/day 
for days 1-5. Decitabine is less cytotoxic, less myelosuppressive and has lower incidence of 
mucositis th an IV cytarabine which has safely been administaered in combination with vosaroxin in 
the SP0-0012 and VALOR studie s. Therefore, we anticipate that a starting dose of vosarxoin 
administered intravenously on days 1and 4 at a dose of 90 mg/m2 in the first cycle (induction 1) for 
a total dose of 180 mg/m2/cycle in combination with decitabine at a dose of 20 mg/m 2  
intravenously for 5 consecutive day (Days 1to 5) would be a reasonable optionThese doses have 
been given safely in previous studies. The purpose of the lead-in phase Iportion is to ensure 
safety. If clinically significant, study drug related grade 3-4 toxicity is observed during the first 
cycle in 1 or less of 6 evaluable patients treated, the study will transit to the Phase II portion. If 
clinically significant, study drug related grade 3-4 toxicity is observed during the first cycle in 2 
or more of 6 evaluable patients treated , six additional patients will be treated on the Phase I 
portion at a lower dose level (see section 4.4 and section 10.2) until we define a Phase II safe 
dose schedule at which 1 or less out of 6 evaluable patients on the Phase I experience clinicall y 
significant, study drug related grade 3-4 toxicity during the first cycle. After the Phase I portion 
ensures safety thereby defining the Phase IIdose schedule, all subsequent patients will receive 
the same dose schedule in the Phase IIportion. This Phase IIportion will include up to a total of 
60 evaluable patients. 
 
20 


Vosaroxin and decitabine in AML 
 
 
)
 
 
 
 
 
The primary endpoint of the Phase II portion is overall response rate. Overall response rate = CR 
+ CRp + CRi. Early stopping rules will be implemented for low ORR rates (see section 10.2). 
 
 
 
3.3 Patient Eligibility: 
 
3.3.1 Inclusion Criteria: 
 
1) Previously untreated AML (>/= 20% blasts). Patients with high-risk MDS (defined as 
having >/= 10% blasts in the bone marrow) or patients with  Chronic Myelomonocytic 
Leukemia (having >/= 10% blasts in the bone marrow) may also be eligible after 
discussion with Principal Investigator (PI). Prior therapy with hydroxyurea , biological or 
targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth 
factors is allowed, however prior therapy with chemotherapy agents for the disease under 
study is not allowed. Patients may have received one dose of cytarabine (up to 2 g/m2 
administered  at presentation for control ofhyperleucocytosis. 
For patients with prior MDS or Chronic Myelomonocytic Leukemia who transformed to 
AML, therapy received for MDS is not considered as prior therapy for AML. 
 
 
 
2) Age >/= 60 years and not candidates for conventional cytotoxic chemotherapy or refuse 
it; OR patients below the age of 60 years who are considered unfit and/or unabl e to 
tolerate standard chemotherapy at the discretion of the treating physician or the principal 
investigator. 
 
 
 
3) Eastern Cooperative Oncology Group perfonn ance status </= 2. {Appendix  D) 
 
4) Adequate hepatic (serum total bilirubin </= 1 .5 x upper limit normal (ULN), alanine 
aminotransferase and/or  aspartate transaminase </= 2.5 x ULN) and renal function 
(creatinine </= 2.0 mg/dL). 
 
5) Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition 
(MUGA) scan or echocardiogram (ECHO) 
 
6) Patients must be willing and able to review, understand, and provide written consent 
before starting therapy. 
 
7) Females must be surgically or biologically sterile or postmenopausal  (amenonꞏheic for 
at least 12 months) or if of childbearing potential, must have a negative serum pregnancy 
test within 14 days before the start of the treatment. Women of childbearing potential 
may have a urine pregnancy test, instead of a serum pregnancy test. If either the serum or 
urin e pregnancy test is equivocally negati ve the patient will be eligible for the protocol. 
 
21 


Vosaroxin and decitabine in AML 
 
 
 
 
 
Women of childbearing potential must agree to use an adequate method of contraception 
during the study until 30 days after the last treatment. Males must be surgically or 
biologically sterile or agree to use an adequate method of contraception during the study 
until 30 days after the last treatment. 
 
 
 
3.2.2 Exclusion Criteria : 
 
I) New York  Heart Association class III or IV heart disease, active ischemia or any other 
uncontrolled 
cardiac condition such as active angina pectoris, clinically significant cardiac arrhythmia 
that requires therapy in the opinion of the treating physician or PI, uncontrolled 
hypertension (blood pressure > 160 systolic and > 110 diastolic not responsive to 
antihypertensive medication) , uncontrolled diabetes mellitus in the opinion of the treating 
physician or PI, or uncontrolled congestive heart failure in the opinion of the treating 
physician or PI. 
 
2) Myocardial infarction in the previous 12 weeks (from the start of treatment). 
 
3) Active and uncontrolled disease/infection as judged by the treating physician. 
 
4) Pregnant or breastfeeding 
 
5) Known Human Immunodeficiency Virus seropositivity 
 
6) 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 
 
7) Acute promyelocytic leukemia (APL). 
 
 
 
 
 
 
4.1 TREATMENT PLAN: 
 
4.2 Treatment Plan in Phase I and II: 
 
In Phase I six patients will be treated with vosaroxin administered intravenously on days 1 and 4 
at a dose of 90 mg/m 2 for a total dose of 180 mg/m2/cycle in combination with decitabine at a 
dose of20 mg/m2 intravenously on days 1 through 5. Patients will be assessed for non- 
hematological toxicities during the first 28 days on therapy and for hematological toxicities for 
the first 42 days on therapy. The purpose of the lead-in Phase I portion is to ensure safety. If first 
cycle DLT is observed in 1 or less of 6 patients treated this dose level will be the MTD and the 
study will transit to the Phase II portion. A summary and rationale for continuation of treatment 
22 


Vosaroxin and decitabine in AM L 
 
 
 
 
 
will be submitted to investigational new drug (IND) office for review . Cohort summaries will 
also be submitted when going to a lower dose cohort in phase I.  Once approved, the Phase II 
portion of the study will be opened. Up to 60 patients will be treated on the Phase II portion. The 
primary endpoint of the Phase IIstudy will be efficacy as measured by ORR rate. Early stopping 
rules will be implemented for excessive toxicity or lack of efficacy. Please refer to statistical 
section 10.2 for details. 
 
 
 
4.2 General Study Treatment Plan: 
 
All chemotherapy infusions will be done at MDACC only. The intent of the study design is for 
all patients to receive up to 7 courses, including up to two courses of induction therapy and up to 
five courses of consolidation therapy. Treatment will be continued during the duration of the 
study unless patients exhibit evidence of treatment failure, disease progression , experience an 
unacceptable toxicity, or the investigator determines that discontinuation of treatment is in the 
best interest of the patient. Patients will be treated with study drugs based on a calculation 
determined from the patient's body surface area (BSA). BSA will be calculated before each cycle 
and will be based on the patient's height (measured at baseline) and weight (measured each 
cycle). Dosing of both drugs will be based on actual body weight with no capping of dose based 
on BSA. 
 
 
4.3 Induction Therapy in Phase 1: 
 
The first 6 patient s on study (first cohort) will receive 1 or 2 induction cycles of therapy 
according to the following starting schedule: vosaroxin will be administered intravenously as a 
short infusion over 8 to 10 minute s on days 1 and 4 at a dose of 90 mg/m2 in the first cycle 
(induction 1) for a total dose of 180 mg/m2/cycle in combination with decitabine at a dose of20 
mg/m2 administered as a continuous intravenous infusion over approximately 1 hour given daily 
for 5 consecutive days (Days 1 to 5). These doses have been given safely in previous studies. If a 
dose is missed , the patient may take the missed dose if it has been less than 48 hours. 
 
Patients, who have not achieved remission (CR, CRp, Cri) following the initial induction 
(induction I) course, can receive one additional induction course (induction 2) at the same dose 
as induction 1 to optimize response if indicated. The re-induction must be given within 4-8 
weeks of documented refractory leukemia. Re-induction (Induction 2) may be given beyond the 
stipulated 8 weeks if approved by the study PI. 
 
If the bone marrow aspirate and/or biopsy(s) perfonned  after the induction courses reveal a 
remission marrow (CR/CRp/CRi), then the patient may proceed to consolidation therapy at the 
discretion of the treating investigator. In addition, any clinically significant drug-related, 
nonhematologic toxicity experienced by a patient should return to < grade 2 or the baseline grade 
before the patient continues treatment. 
 
 
 
23 


Vosaroxin and decitabine in AML 
 
 
 
 
 
Should the patient not achieve CR/CRp/CRi after the second induction course, they will be taken 
off study unless clinical benefit is observed and the PI approves continuation of therapy on the 
protocol. 
 
Hydroxyurea 1.5 g orally daily for up to 10 days is allowed in the first induction course for white 
blood count >30.0 x 109/L. 
 
 
 
4.4 Defmition of Dose Limiting Toxicities and Criteria in Phase 1: 
 
Dose limiting toxicities will be according to the NC I CTEP criteria Common Terminology 
Criteria for Adverse Events version 4.0[44]. A non-hematologic dose-limiting toxicity (DLT) is 
defined as a clinically significant (as assessed by treating physician) grade 3 or 4 adverse event 
or abnormal laboratory value (according to CTCAE criteria) assessed by treating physician as 
related to study drug (and unrelated to disease progression, intercurrent illness, or concomitant 
medications) occurring during the first 28 days on study. A hematologic DLT is defined as 
severe myelosuppression with a hypoplastic marrow with less than 5% cellularity and no 
evidence ofleukemia 42 days from start of therapy. This will define severe and delayed 
myelosuppression  not related to persistent leukemia and likely related to treatment. 
 
The purpose of the lead-in Phase I portion is to ensure safety. If first cycle DLT is observed in 1 
or less of 6 evaluable patients treated, this dose level will be considered the MTD and the study 
will transit to the Phase II portion. If first cycle DLT is observed in 2 or more of 6 evaluable 
patients treated , 6 additional patients will be treated on the Phase I portion at a lower dose level 
as detailed below until we define a Phase II dose schedule (MTD) at which 1 or less out of 6 
patients on the Phase I experience first cycle DLT. After the Phase I portion ensures safety 
thereby defining the Phase II dose schedule, all subsequent patients will receive the same dose 
schedule in the Phase II portion. 
 
a. The first 6 patients on study (Phase I portion of study) will receive vosaroxin IV on days 1 and 
4 at a dose of90 mg/m2 in the first cycle (induction 1) for a total dose of 180 mg/m2/cycle in 
combination with decitabine at a dose of 20 mg/m2 intravenously for 5 consecutive days (Days 1 
to 5). IfDLT's are observed in 0-1/6 in phase I, this dose level will be considered to be the MTD 
for this study and the study will open broadly for the Phase II at this dose schedule. 
 
b. IfDLT's are observed in 2/6 or more patients, this dose level would exceed the MTD, and the 
induction chem otherapy dose will be reduced to vosaroxin at a dose of 70 mg/m2 IV on days 1 
and 4 in the first cycle (induction I) for a total dose of 140 mg/m2/cycle in combination with 
decitabine at a dose of 20 mg/m2 intravenously for 5 consecutive days (Days 1 to 5). Six patients 
will be treated to evaluate the safety ofthis schedule, and after consultation with and approva l of 
the Pl. IfDLTs are observed in 0- 116 in phase I, the study will open broadly for the phase II at 
this schedule at this dose schedule . 
 
c. IfDLT's are observed in 2/6 or more patients, this dose level would exceed the MTD, and the 
induction chemotherapy dose will be reduced to vosaroxin at a dose of 50 mg/m2 IV on days 1 
and 4 in the first cycle (induction 1) for a total dose of 100 mg/m2/cycle in combination with 
24 


Vosaroxin and decitabine in AML 
 
 
 
 
 
decitabine at a dose of 20 mg/m2 intravenously for 5 consecutive days (Days 1 to 5). Six patients 
will treated to evaluate the safety of this schedule, and after consultation with and approval of the 
Pl. If DLTs are observed in 0-1/6 in phase I, the study will open broadly for the phase II at this 
schedule at this dose schedule. 
 
d. If DLT's are observed in 2/6 or more patients, this dose level would exceed the MTD, and the 
induction chemotherapy dose will be reduced to vosaroxin at a dose of 50 mg/m2 IV on days 1 
and 4 in the first cycle (induction 1) for a total dose of 100 mg/m2/cycle and the decitabine will 
be reduced to 20 mg/m2 IV for only 4 consecutive days (Days 1 to 4). Six patients will be treated 
to evaluate the safety of this schedule, and after consultation with and approval of the PI. If 
DLTs are observed in 0-1/6 in phase I, the study will open broadly for the phase II at this 
schedule at this dose schedule. 
 
After the first 6 subjects have been treated with vosaroxin and decitabine at the selected MTD 
(either dose-level a, b, cor d), and assessed for toxicity, a summary and rationale to continue 
enrollment will be provided by the study team to the IND Office including a separate cohort 
summary for each dose level tested.  These will be reviewed by the IND Office Medical Monitor. 
The IND Office Medical Monitor will indicate whether the study may continue enrollment. 
 
 
 
4.5 Induction Therapy in Phase II: 
 
Following the phase I portion to ensure safety, all subsequent patients will receive the following 
induction regimen (induction 1): 
 
a. Vosaroxin  intravenously on days 1 and 4 at a dose of70 mg/m 2 for a total dose of 140 
mg/m 2/cycle (days 1 and 4), or the final induction dose (MTD) determined in phase I. 
 
b. Decitabine IV at a dose of20 mg/m2  for 5 consecutive days (days 1 to 5), or the final 
induction dose (MTD) determined in phase I. 
 
The 70mg/m2 day 1 and 4 dosage ofvosaroxin has been implemented in the REVEAL-I  study 
(single agent vosaroxin in elderly AML) and was felt to be as efficacious as the 90 mg/m2 dose 
with a lower incidence of mucositis. Based on our current experience and the data from 
REVEAL 1 we would like to request IND approval to reduce the vosaroxin induction dose from 
90 mg/m2 days 1 and 4 to 70 mg/m2 days 1 and 4 with the intention of decreasing toxicity while 
maintaining equivalent efficacy. 
 
 
 
Treatment may be repeated every 4-7 weeks. If a dose is missed, the patient may take dose the 
missed dose if it has been less than 48 hours. 
 
Patients, who have not achieved any response (CR, CRp, Cri) following the initial induction 
(induction 1) course, can receive one additional induction course (induction 2) at the same dose 
as induction 1 or other dose modifications for re-induction may be made in the best interest 
 
25 


Vosaroxin and decitabine in AML 
 
 
 
 
 
of patient after discussion with the PI  to optimize response if indicated. The re-induction must 
be given within 4-8 weeks of documented refractory leukemia. Re-induction (Induction 2) may 
be given beyond the stipulated 8 weeks if approved by the study Pl. 
 
If the bone marrow aspirate and/or biopsy(s) performed after the induction courses reveal a 
remission marrow (CR/CRp/CRi), then the patient may proceed to consolidation therapy at the 
discretion of the treating investigator. In addition, any clinically significant drug-related, 
nonhematologic toxicity experienced by a patient should return to < grade 2 or the baseline grade 
before the patient continues treatment. 
 
Should the patient not achieve CR/CRp/CRi after the second induction course, they will be taken 
off study unless clinical benefit is observed and the PI approves continuation of therapy on the 
protocol. 
 
Hydroxyurea  1.5 g orally dail for up to 10 days is allowed in the first induction course for 
white blood count >30.0 x 10 /L. 
 
 
 
 
4.6 Post-remission Therapy in PhaseIand Phase II: 
 
Patients achieving a CR/CRp/CRi may receive consolidation/ maintenance therapy as follows: 
 
Consolidation - Up to 5 additional cycles as follows: 
a. Vosaroxin intravenousl y on days 1 and 4 at a dose of70 mg/m2 for a total dose of 
140 mg/m2/cycle (days 1 and 4). Decitabine at a dose of20 mg/m2 intravenou sly 
for 5 consecutive days (days 1-5), or the final induction dose determined in phase 
I. 
 
 
Patients who achieve a CR/CRp/CRi should receive the consolidation cycle no sooner than 28 
days from Day 1 of the previou s induction or re-induction cycle provided their peripheral blood 
counts have recovered (ANC >I= 1.0 x 109/L and platelet count >/= 50 x 109/L). If patient has 
documented CRp they may proceed with consolidation cycles even if the platelet count remains 
</= 50 x 109/L if approved by the PI. If patient has documented CRi they may proceed with 
consolidation cycles even if the platelet count remains </= 50 x 109/L and/or ANC </= 1.0 x 
109/L if approved by the Pl. 
 
If the peripheral count recovery is delayed beyond 42 days from Day 1 of the prior induction or 
re-induction cycle and the delay is presumed to be secondary to the induction therapy, the stud y 
drug doses for the consolidation must be reduced as follows: reduce the dose of vosaroxin to 
50mg/m2 IV on days 1 and 4 for a total dose of 100 mg/m 2/cycle in combination with decitabine 
at a dose of 20 mg/m2 intravenously for 5 consecutive days (Days 1 to 5). 
 
Consolidation cycles to be given every 4-8 weeks upon recovery of counts and toxicities. 
Consolidation cycles may be given beyond the stipulated 8 weeks if approved by the study Pl. 
 
 
26 


 
 
Vosaroxin and decitabine in AML 
 
 
 
 
If the patient experienced a dose modification during induction , the patient may remain at the 
modified dose level or return to the original dosing schedule during consolidation as determined 
to be in the patient' s best interest by the treating physician and Pl. Dose adjustments to the 
subsequent cycles of the consolidation schedule will depend on toxicity with previous courses. 
Dose adjustments felt to be in the best interest of the patient are allowed but must be discussed 
with PI and the discussion documented in the patient's medical record. For clinically significant, 
study regimen related grade 3-4 toxicities, reduce the dose ofvosaroxin to 50 mg/m2 Non days 
1 and 4 for a total dose of 100 mg/m2/cycle in combination with decitabine at a dose of20 mg/m2 
intravenously for 5 consecutive days (Days 1 to 5). If Grade 3 or 4 toxicities recur or persi st at 
this lower dose, reduce the dose of vosaroxin to 50 mg/m2 IV on days 1 and 4 for a total dose of 
100 mg/m2/cycle in combination with decitabine at a dose of 20 mg/m2 intravenously for 4 
consecutive days (Days 1 to 4). If Grade 3 or 4 toxicities recur or per sist at this lower dose, 
reduce the dose of vosaroxin to 50 mg/m2 IV on days 1 and 4 for a total dose of 100 mg/m2/cycle 
and reduce the decitabine to 20 mg/m2 N  for only 3 consecutive days (Days 1 to 3) 
 
Other dose modifications may be petmitted if in the patient's best interest after discussion with 
the Principal Investigator and the discussion documented in the patient 's medical record. 
Vosaroxin may be omitted in consolidation cycles for patients in CR/Cri/CRp based on their toxicity in 
the first cycle, as judged by th e treating phy sician, and only after discussion with the Pl. Up to a total 
of 7 cycles of induction-con solidation wi ll be given (up to 2 induction cycles and up to 5 
consolidation cycles). 
 
 
 
4.7 Management of Toxicities and Dose Modifications: 
 
4.7.1 Induction, Re-Induction, and Consolidation Cycles: 
 
All dose delays, reductions, and modifications for hematologic and non-hematologic toxicities 
will be assessed according to sections 4.7.2 and 4.7.3. 
 
4.7.2 Hematologic (Blood/Bone marrow) Toxicity: 
 
No dose redu ctions, delays, or modifications are required for hematologic toxicities during the 
induction or re-induction cycles. It is assumed that low counts at diagnosis are due to  
involvement by the disease process and require therapy for improvement. Likewise, patients who 
are considered for re-induction have persistent disease and thus no recovery of hematologic 
parameters can be expected. Patients who achieve a CRJCRp/CRi should receive the 
consolidation cycle no sooner than 28 days from Day 1 of the previous induction or re-induction 
cycle, provided their peripheral blood counts have recovered (ANC >/= 1.0 x 109/L and platelet 
count >/= 50 x 109/L). If patient has documented CR   they may proceed with consolidation 
cycles even if the platelet count remains </= 50 x 10 /L if approved by the Pl. If patient has 
documented CRi they may proceed with consolidation cycles even if the platelet count remains 
</= 50 x I 09/L and/or ANC </= 1.0 x 109/L if approved by the Pl. If the peripheral count 
recovery is delayed beyond 42 days from Day 1 of the prior induction or re-indu ction cycle and 
 
27 


 
 
Vosaroxin and decitabine in AML 
 
 
 
 
the delay is presumed to be secondary to the induction therapy, the study drug doses for the 
consolidation must be reduced as follows: reduce the dose of vosaroxin by one dose level as 
described in section 4.7.4in combination with decitabine at a dose of20 mg/m2 intravenously for 
5 consecutive days (Days  1 to 5). 
 
 
 
4.7.3 Non-hematologic Toxicity: 
 
If clinically significant grade 2 toxicity occurs during a course of induction or consolidation 
therapy, and it is unresponsive to optimal treatment and is thought to be possibl y related to 
vosarox in treahnent, vosaroxin treatment may be withheld after the onset of an event until the 
adverse event (AE) has returned to baseline or </= grade 1. If the AE has returned to baseline or 
</= grade 1 within the 5-day induction or 5-day consolidation treatment interval from the start of 
therapy, treahnent may resume at the same dose, but missed doses will not be made up. If the AE 
has returned to </= grade 1 before administration of the next cycle, no dose reduction s will be 
made with subsequent cycles. 
 
If grade 3 or greater toxicity occurs during a course of induction or consolidation therapy, and it 
is unresponsive to optimal treatment and is thought to be possibly related to vosaroxin treatment , 
vosaroxin treatment may be withheld after the onset of an event until the AE has returned to 
baseline or </= grade 1. If the AE has returned to baseline or </= grade 1 within the 5-day 
induction or 5-day consolidation treatment interval from the start of therapy, treatment may 
resume but at a reduced dose.. Reduce the dose ofvosaroxin by one dose level as described in 
section 4.7.4 for the day 4 dosage of that cycle only. Missed doses will not be made up. In 
subsequent cycles of therapy, the dose ofvosaroxin will remain at the reduced dose level for 
each subsequent cycle in combination with decitabine at a dose of 20 mg/m 2 intravenously for 5 
consecutive days (Days 1 to 5). If the toxicity recurs or persists in spite of reducing the vosarox in 
dose to, further dose reduction s as outlined in section 4.7.4 will be allowed. If the toxicity recurs 
or persists after reducing to the lowest dose level, as described in section 4.7.4, then no further 
dose reductions will be pennitted and the patient will be taken off study unless otherwise 
discussed with the Pl. 
 
If persistent grade 2 toxicity occurs after completion of a cycle of therapy (i.e., after day 5 of an 
induction treatment cycle or day 5 of a consolidation treatment cycle), and it is unresponsive to 
optimal treatm ent and is thought to be possibly related to vosaroxin treatment, vosaroxin 
treahnent may be delayed up to 21 days after the onset of an event or until the AE has returned to 
baseline or S grade 1. Then administer 100% of the planned dose. If toxicity persists longer than 
21 days or recurs, the vosaroxin dose may be delayed and the dose of vosaroxin will be reduced 
as specified in section 4.7.4. Additional dose reductions can be performed, as specified in 
section4.7.4, if toxicity recurs or persists during induction or consolidation treatment cycles 
respectively .. If the toxicity recurs or persists after reducing to the lowest level as outlined in 
section 4.7.4, then further dose reductions will not be permitted and the patient will be taken off 
study unless otherwise discussed with the PI. . 
 
 
 
28 


Vosaroxin and decitabine in AML 
 
 
 
 
 
If grade 2:3 toxicity occurs after completion of the vosaroxin treatment (i.e., after day 5 of an 
induction treatment cycle or day 5 of a maintenance treatment cycle), and it i s suspected that 
vosaroxin played a role in toxicity, the next scheduled cycle of vosaroxin therapy should be 
withheld until toxicity returns to grade 0 or 1 or to baseline. The dose of vosaroxi n for each 
subsequent cycle will be reduced as specified in section 4.7.4.  Additional dose reductions can be 
performed, as specified in section 4.7.4, if the toxicity recurs or persists .. If the toxicity recurs or 
persists after reducing to the lowest dose level, then further  dose reductions will not be 
permitted and the patient will be taken off study unless otherwise discussed with the Pl. 
 
For those patients who are receiving consolidation cycles of Decitabine with no Vosaroxin , as discussed 
in section 4.6, dose adjustments will be allowed based on the discretion of the treating physician. The 
Dose adjustments for the Decitabine will follow the same dose adjustments listed in section 4.7.4. 
 
Dose modifications different from those stated in the protocol will be evaluated by the principal 
investigator and the sponsor -MDACC IND office and may only be allowed after approval by 
Pl. 
 
Dose modifications for the patients in CR who are deemed eligible to continue on decitabine 
only after the first induction cycle will be done at the discretion of the treating physician but only 
after discussion with the PI. 
 
Adverse events which are moderate to severe in intensity and which are assessed as possibly or 
probably related to study drug, may result in the termination of study treatment in the affected 
study patient. Such termination should be reviewed with the PI at the earliest possible time. 
Following review with the PI, the study patient may be permanentl y withdrawn from the study 
depending upon the nature and severity of the event. 
 
4.7.4 Dose Modifications 
 
 
 
Dose Modifications 
 
 
 
 
 
 
 
 
 
Dose Level 
Vosaroxin 
Decitabine 
 
Dl &D4 
 
-3 
50 mg/m2 
 
-2 
50 mg/m2 
20 mg/m2 (Days 1 - 3) 
 
20 mg/m2 (Days 1 -4) 
 
 
29 


Vosaroxin and decitabine in AML 
30 
 
 
 
 
 
 
-1 
50 mg/m2 
20 mg/m2 (Days 1 -5) 
 
0 
70mg/m2 
 
 
 
 
 
 
 
 
4.7.5 Supportive Care: 
20 mg/m2 (Days 1 -5) 
 
Supportive care measures including blood products, infection prophylaxis and growth factors 
will be administered according to institution al and Leukemia Department guidelines. 
 
4.7.6 Concomitant Medications: 
 
Concomitant medications are recommended as prophylaxis for nausea , vomiting, and infections, 
and are allowed for managing myelosuppression as shown in Table 6. Myelosuppression is 
expected in patients with AML due to underlying disease, as well as due to chemotherapy (such 
as vosaroxin and decitabine), or both. Most patients 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 recommended. A suggested regimen is ciprofloxacin 
(500 mg po q 12h), fluconazole (200 mg po qd), and acyclovir (800 mg po q 12h). One dose of 
prophylactic intrathecal chemotherapy will be allowed with diagnostic lumbar puncture. 
 
 
 
 
 
 
All ongoing medications and therapies (including herbal products , nutritional supplements, and 
nontraditional medicat ions) at screening will be considered prior medications. Concomitant 
medication data will not be collected or entered into the case report form; however, the subject 's 
medication record will contain a list of concomitant medications. Patients will discontinue study 
treatment if they intentionally receive or require treatment with a medication prohibited by the 
protocol. If however prohibited medication is inadvertently administered/ taken by the patient , 
the patient may remain on study as long as the prohibited medication is discontinued as soon as 
feasible. End-of-treatment procedures will be performed , and follow-up will commence. 
Prohibited medications are shown in Table 6. 


Vosaroxin and decitabine in AML 
31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6: Instructions for the use of concomitant medications and therapies 
 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Proph ylactic antibiotics, 
antifungal agents, and 
antiviral agents 
 
Antiemetic agents 
Strongly encouraged 
 
 
 
According to standard of 
care at MDACC 
None 
 
 
 
None 
Allowed 
Oral allopurinol or 
At  investigators discretion 
None 
rasburi case 
 
 
 
Intrathecal chemotherapy 
At investigators discretion 
One dose of low-dose 
 
 
cytarabin e or methotrexate 
 
 
with diagnostic LP 
Leukapheresis 
Accordin g to standard of 
Before induction 1 day 1 
 
care at MDACC 
only 
 
Red blood cell transfusion 
 
None 
None 
Platelet transfusion 
None 
None 
 
White blood cell 
At investigators discretion 
None 
transfusion 
according to standard of 
 
 
care at MDACC 
 
Myeloid growth factors 
At investigators discretion 
None 
 
according to standard of 
 
 
care at MDACC 
 
Erythropoetin or 
At investigators discretion 
None 
darbepoetin 
 
 
Any other medication for 
At investigators discretion 
 
None 
supportive care 
according to standard of 
care at MDACC 
Prohibited 
Hydroxyurea 
Hydroxyurea at a dose </= 
1.5 g orally daily for up to 
10 days is allowed in the 
first induction course for 
WBC >30.0 x 109/L. 
Hydroxyurea cannot be 
used beyond day 10 of 
induction 1 


Vosaroxin and decitabine in AML 
32 
 
 
 
 
 
 
MDACC = MD Anderson Cancer Center 
 
 
 
 
 
 
5.0 PRETREATMENT EVALUATION: 
 
History and physical exam including measurement of height, weight, and vital signs (blood 
pressure, heart rate, temperature, and breathing rate) and performance status, CBC with 
differential and platelets , chemistry profile (total bilirubin, serum creatinine, SGPT or SOOT, 
uric acid, LDH, potassium , magnesium, glucose), and ECG within 14 days oftherapy initiation. 
 
ECHO or MUGA within 28 days prior to treatment start. 
 
Women of childbearing potential must have a negative serum or urine pregnancy test within 3 
days before receiving the first dose of study drug. 
 
Bone marrow aspirate and/or biopsy within 28 days of therapy start The bone marrow evaluation 
will include immunophenotyping by flow cytometry and cytogenetic studies. 
 
 
 
6.1 EVALUATIONS: 
 
6.2 Evaluations During Study: 
 
Patient will have physical examination prior to each course. CBC with differential and platelet 
counts at least once a week until remission (CR/CRp/CRi), then every 1 to 2 weeks during active 
treatment , and every 4 to 8 weeks thereafter as long as on study. No differential is needed if the 
WBC is < 1.0 x 109/L. The patients in CR who are deemed eligible to continue on decitabine 
only will need to have physical examination after every 2-3 courses of decitabine. 
 
Chemistry profile at least weekly until remission , then every 2 to 4 weeks during active 
treatment. 
 
For those patients who are receiving Decitabine alone without Vosaroxin, as outlined in sect ion 4.6, 
these patients may receive Decitabine with a loca l physician but will be required to return to MDACC 
every two to three cycles for a physical exam. 
 
The patient may have the laboratory work done at a local clinic and the results reported to the 
research nurse for the study. The laboratory work done at the local clinic will be forwarded to the 
patient's attending physician at MDACC or PI of the study, who will sign off on the labs to 
verify that the results have been reviewed. 
 
Outside Physician Participation During Treatment 


Vosaroxin and decitabine in AML 
33 
 
 
 
 
 
 
1. MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician . 
 
This will be documented in the patient record 
 
2. A letter to the local physician outlining the patient' s participation in a clinical trial will request 
local physician agreement to supervise the patient's care (Appendix H) 
3. Protocol required evaluations outside MDACC will be documented by telephone , fax ore- 
mail. Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that they 
have reviewed it. 
4. Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representati ve prior to initiation, and will be documented in the 
patient record. 
5. A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
6. Documentation to be provided by the local physician will includ e drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and documentation 
of any hospitalizations. 
7. The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
 
 
 
 
 
Bone marrow aspirate and/or biopsy starting on day 21 (+/- 7 days) of therapy and then every 4 
weeks(+/- 7 days) as required by leukemia evolution until confirmation of remission 
(CR/CRp/CRi) or nonresponse. Bone marrow evaluations to include immunophenotyping by 
flow cytometry and cytogenetics at the discretion of the treating physician. 
 
 
 
Bone marrow tests can be ordered more frequently if mandated by development of peripheral 
blood counts. No repeat bone marrow is necessary if nonresponse or progressive disease can be 
unequivocally diagnosed from peripheral blood tests or, in patients with a WBC < 0.3 if the bone 
marrow test is considered noncontributory by the investigator at any time point. Patient will be 
followed for survival at MD Anderson Cancer Center (MDACC) every 3 to 6 months for up to 5 
years after compl etion of active treatment and while still on study. If the patient is unable to 
return to MDACC the follow-up visits may be conducted via telephone. 
 
Concomitant medication data will not be collected or entered into the case report form; however, 
the subject's medication record will contain a list of concomitant medications. 


Vosaroxin and decitabine in AML 
34 
 
 
 
 
 
 
Data regarding adverse events will be collected during the study. Please see Appendix E 
regarding data capturing of adverse events and adverse events source documentation. Protocol 
specific data will be entered into PDMS/CORe. PDMS/CORe will be used as the electronic case 
report form for this protocol. Only unexpected AEs will be recorded in the Case Report Form 
(CRF). The Principal Investigator will sign and date the AE log per each patient at the 
completion of each course. Following signature, the AE log will be used as source 
documentation for the adverse events for attribution. 
 
Treatment may be discontinued for a variety of reason s, including patient withdrawal, 
investigator decision, and reasons specified by the protocol. Reasons for discontinuation of 
treatments are described below . 
 
 
 
6.2 Follow-up Evaluations: 
 
After completion of induction and consolidation treatment patients will continue to be followed 
at MDACC for 5 years. 
 
Every 4-8 weeks, blood will be drawn for routine standard of care tests. If the patient cannot 
return to the MDACC clinic for blood draws, the blood draws can be set up at a local clinic 
closer to the patient's residence and the results reported to the research nurse for the study. The 
laboratory work done at the local clinic will be forwarded to the patient's attending physician at 
MDACC or PI of the study, who will sign off on the labs to verify that the results have been 
reviewed 
 
Every 3-6 months, patients will be scheduled for clinic visits for clinical evaluation and physical 
examinations. If the patient cannot make it to the MDACC clinic for these visits, the patient can 
be followed by a local physician. The local physician will perfonn the physical examination and 
the records will be forwarded to MDACC. 
 
7.1 DISCONTINUATION  OF TREATMENT : 
 
7.2 Discontinuation Criteria for Individual Patients 
 
7.2.1 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 jeopardi ze 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. 
 
7.2.2 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. 


Vosaroxin and decitabine in AML 
 
 
 
 
 
 
7.2.3 Criteria for Protocoi-Defmed Required Discontinuation of Treatment 
 
The protocol requires discontinuation of study treatment for the following reasons: 
 
1. Patient requests discontinuation. 
 
2. There is unacceptable toxicity (i.e., NCI CTCAE version 4.0 clinically significant grade 4 
drug-related non hematologic toxicity). 
 
3. Patient experiences an NCI CTCAE version 4.0 >/= grade 3 drug-related non-hematologic 
toxicity or clinically significant infection of any grade that is not recovered by Day 75 from the 
onset of the toxicity. 
 
4. Patient experiences a third occurrence of an NCI CTCAE version 4.0 clinically significant 
grade 3 drug related non-hematologic toxicity. 
 
5. Patient experiences study drug related asymptomatic grade 2 total bilirubin or creatinine 
abnormality that is not recovered by Day 75 from the onset of the toxicity. 
 
6. There is a need for any treatment not allowed by the protocol. 
 
7. Treatment failure or disease relapses. Patients may continue if they are determined to have 
clinical benefit following discussion with the PI and the treating Physician. The discussion 
will be documented in the medical record.  
 
8. Investigator discretion. 
 
 
 
7.2.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
 
Patients who discontinue treatment for any reason will complete end-of-treatment procedures. 
End of treatment procedures will include a CBC with differential and platelets and a limited 
chemistry profile (total bilirubin , serum creatinine, SGPT or SGOT, potassium, magnesium , 
glucose). A bone marrow aspiration may be recommended only if non-response or progressive 
disease cannot be unequivocally diagnosed from peripheral blood. Although treatment will be 
discontinued at that time, all patients who do not withdraw consent for follow-up, die, or become 
lost to follow-up, will remain on study for follow-up evaluations. Subject will be followed for 
toxicity for at least 30 days after the last protocol treatment. The 30 day follow-up visit will be 
scheduled as a clinic visits for clinical evaluation and physical examinations. If the patient 
cannot make it to the MDACC clinic for this visit,the required follow up treatment procedure s 
may be done with a local physician and the records forwarded to MDACC. The research nurse 
will contact the patient by telephone and get a verbal assessment of the patient' s condition. The 
phone conversation will then be documented in the patients charts. 
 
 
35 


Vosaroxin and decitabine in AML 
 
 
 
 
 
 
 
 
7.2 Study Stopping Rules 
 
The principal investigator and MDACC IND office have the right to tenninate this clinical study 
at any time. The principal investigator and MDACC IND office, as appropriate, will be involved 
in any decisions regarding tenninating the study, temporarily suspending enrollment , or stopping 
ongoing treatment with study treatment. 
 
Reasons for te1minating the clinical study or a study site's participation include, but are not 
limited to, the following: 
 
• The incidence or severity of an adverse reaction related to treatment in this study or 
 
other studies indicates a potential health hazard to patient s 
 
• Patient enrollment is unsatisfactory 
 
• Data recording is inaccurate or incomplete 
• Study site personnel are noncompliant with study procedures 
 
 
 
 
7.3 Protocol Violations and Deviations 
 
Protocol violations are defined as significant departures from protocol-required processes or 
procedure s 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, 
interruption, reduction, or delay; or discontinuation criteria 
 
• Investigational product handling, including storage and accountability 
 
• Informed consent and ethical issues 
 
 
 
8.0 CRITERIA FOR RESPONSE 
36 


Vosaroxin and decitabine in AML 
37 
 
 
 
 
 
 
8.1 Complete response (CR) 
 
• Peripheral blood counts: 
 
Neutrophil count 2: 1.0 x 109/L 
 
Platelet count 2: 100 x 109/L 
 
• Bone marrow aspirate and biopsy 
 
:S5% blasts 
 
• No extramedullary leukemia 
 
8.2 Complete response without platelet recovery (CRp) 
 
• Response as in CR but platelets < 100 x 109/L 
 
8.3 CR with insufficient hematological recovery (platelets or neutrophils) (CRi) 
 
• Response as in CR but platelets <100 x 109/L or neutrophils < 1 x  109 
 
8.4 Overall Response rate (ORR) = CR + CRp + CRi 
 
8.5 Disease-free survival (DFS) 
 
Time from CR, CRp or CRi until the date of first objective documentation of disease-relapse or 
death. 
 
8.6 Overall survival (OS) 
 
• Time from date of treatment start until date of death due to any cause 
 
 
 
9.1 REGULATORY AND REPORTIN G REQUIREMENTS 
 
Adverse event reporting will be as per the NCI criteria and the MDACC Leukemia Specific 
Adverse Event Recording and Reporting Guidelines. 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) most current version will be utilized for adverse event reporting. 
(http://ctep.cancer.gov /reporting/ctc.html)[ 44). (Appendix F) 


Vosaroxin and decitabine in AML 
38 
 
 
 
 
 
 
9.2 Expedited Adverse Event Reporting: 
 
Refer to Appendix E for Leukemia-Specific Adverse Event Recording and Reporting 
Guidelines. Protocol specific data will be entered into PDMS/CORe. PDMS/CORe will be used 
as the electronic case report form for this protocol. Only unexpected AEs will be recorded in the 
Case Report Fonn (CRF). The Principal Investigator will sign and date the AE log per each 
pati ent at the completion of each course. Following signature, the AE log will be used as source 
documentation for the adverse events for attribution . 
 
These guidelines serve to bring the Department of Leukemia in compliance with the institutional 
policy on Reporting of Serious Adverse Events-definition of expected AE-  "All clinical 
protocols should include a list of the expected and anticipated events or hospitalizations relating 
to the study treatment"and Guideline for Good Clinical Practice 4.11.1 "All serious adverse 
events (SAEs) should be reported immediately to the sponsor except for those SAEs that the 
protocol or other document (e.g., Investigator 's Brochure) identifies as not needing immediate 
reporting". 
 
Adverse event is any untoward medical occurrence that may present during treatment with a 
phannaceutical product but which does not necessarily have a causal relationship with this 
treatment. 
 
Adverse drug reaction is a response to a drug which is noxious and unintended and which occurs 
at doses normall y used in man for prophylaxis, diagnosis, or therapy of disease or for the 
modification of physiologic function. 
 
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general , a drug may be considered a contributory cause of an adverse 
event if, had the drug not been administered, 1) the event would not have happened at all, 2) the 
event would have occurred later than it actually did, or 3) the event would have been less severe. 
 
Adverse Events (AEs) will be evaluated according to current CTCAE version in each protocol. 
Only unexpected AEs will be recorded in the Case Report Form (CRF). 
 
 
 
 
Adverse events which are moderate to severe in intensity and which are assessed as possibly or 
probab ly related to study drug, may result in the tennination of study treatment in the affected 
study patient. Such termination should be reviewed with the principal investigator at the earliest 
possible time. Following review with the principa l investigator, the study patient may be 
permanently withdrawn from the study depending upon the nature and severity of the event. 


Vosaroxin and decitabine in AML 
 
 
 
 
 
Expected events during leukemia therapy are: 
 
1. Myelosuppression related events (due to disease or leukemia therapy): 
a.febrile or infection episodes not requiring management in the intensive 
care unit 
b. epistaxis or bleeding except for  catastrophic CNS or pulmonary 
 
hemorrhage 
 
c. anemia, neutropenia, lymphopenia, thrombocytopenia, leukopenia, 
 
leukocytosis 
 
2. Disease related events: 
 
a. symptoms associated with anemia 
i.fatigue 
ii. weakness 
 
iii. shortness of breath 
 
b. electrolyte abnormalities  (sodium, potassium , bicarbonate, C02, 
 
magnesium) 
 
c. chemistry abnormalities (LDH, phosphorus , calcium, BUN, prot ein, 
 
albumin, uric acid, alkaline pho sphatas e, glucose) 
 
d. coagulation abnormalities 
 
e. disease specific therapy (induction, maintenan ce, salvage, or stem cell 
 
therapy) 
 
f alopecia 
 
g. bone,joint, or muscle pain 
 
h. liverfun ction test abnormalities associated with infection or disease 
progr ession 
39 


Vosaroxin and decitabine in AML 
 
 
 
 
 
 
i. disease progr ession 
 
3. General therapy related events: 
 
a. catheter related events 
 
b. renal failure related to tumor lysis syndrome or antibiotic/antifungal 
 
therapy 
 
c. rash related to antibiotic use 
 
4. Hospitalization for the management ofany of the above expected events 
 
Abnonnal hematologic values will not be recorded on the CRF. For abnormal chemical values 
grade 3 or 4, the apogee will be reported per course in the CRF. 
 
 
 
9.3 Serious Adverse Event Reporting: 
 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience- any adverse experience that places the patient , 
in the view of the initial reporter , at immediate risk of death from the adverse experience as 
it occurred . It does not include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
• 
Inpatient hospitali zation or prolongation of existing hospitali zation 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be  life-threat ening,  or  require 
hospitali zation may be considered a serious adverse drug experience 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. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsion s that do not  result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
 
 
 
40 


Vosaroxin and decitabine in AML 
 
 
 
 
 
 
• Important medical events as defmed above may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedure s outlined in 
"University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices". Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected , must be reported to the IND Office, regardless 
of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the 
IND Office and MDACC IRB. 
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of  the  event  has  stabilized,  or 
there has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
(Please see Appendix E regarding data capturing of adverse events and adverse events source 
documentation.) 
 
 
9.4 Serious Adverse Event Reporting to FDA : 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices , the 
protocol guidelines, the sponsor's guidelines, and Institutional Review Board policy. 
 
 
 
 
41 


Vosaroxin and decitabine in AML 
42 
 
 
 
 
 
9.4 Serious Adverse event Reporting to Sunesis Inc. 
 
The assigned research staff will send via fax a courtesy copy of the MD Anderson electronic 
SAE form within the timeframe specified in the protocol but will not answer sponsor queries 
associated with these SAEs. 
 
 
 
 
10.1 
STATISTICS 
 
10.2 
Sample size 
 
 
This will be a single arm, single center, open label study of the combination ofvosaroxin with 
decitabine as an induction therapy in previousl y untreated patients with acute myeloid leukemia 
(AML) or high risk myelodysplastic syndrome (MDS) who are elderly (age 2: 60) and/or unable 
to tolerate standard therapy.  A total of up to 84 patient s will be enrolled in the study. 
 
Phase I 
 
A total of up to 24 patients will be accrued into the Phase I part. 
 
Phase II 
 
A total of up to 60 patients (including 6 patients treated at the MTD from the Phase I part) will be 
recruited for the Phase II part. 
 
The primary efficacy endpoint is overall response rate (ORR). ORR = CR + CRp + CRi. 
Responses will be evaluated at the end of the first induction cycle and second induction cycle (if 
a second induction cycle is needed). With a null hypothesis of 40% historical response rate, a 
sample size of 60 patients would be required to demonstrate a response rate of 60% for the 
combination ofvosaroxin and decitabine using a one-sample exact binomial test and with a two- 
sided alpha of 0.05 and a power of 82%. 
 
 
10.3 
Statistical Design 
 
Phase I 
 
. In phase I portion of the study the MTD is defined as the highest daily oral dose evaluated at 
which <33% of patients experience a DLT. Six patients will be treated. If clinically significant 
drug related Grade 3-4 toxicity is observed during the first cycle in 0-1 patient out of 6 patients , 
this will define a safe schedule and the study will open broadly for the Phase II portion. If drug 
related Grade 3-4 toxicity is observed in 2 or more of 6 patients , this dose will exceed DLT, and 
a lower dose schedule will be investigated in an additional 6 patients. Please refer to Section 4.4. 
The dosing algorithm is presented in Table?. 


Vosaroxin and decitabine in AML 
43 
 
 
 
 
 
 
 
 
Table7.Dosing algorithm 
 
 
Dose
V
Level 
osaroxin 
Decitabine 
 
Dl&D4 
 
50mg/mL 
20 mg/m2 (Days 1-4) 
 
50 mg/m 2 
20 mg/m2 (Days 1 - 5) 
 
70 mg/m-
') 
20 mg/m 2 (Days I - 5) 
 
90mg/m2 
20 mg/m2 (Days 1 - 5) 
-3 
 
-2 
 
-1 
 
0 
 
 
 
 
Phase II 
 
Efficacy 
 
The historical data suggested an ORR of 40% and with the assumption that the improved ORR is 
60% the study will be stopped early if the observed patients' data suggest that: 
 
 
 
Pr (n> 0.6J data) < 0.025 
 
 
Here n is the overall response rate (ORR). That is, if at any time during the study we determine 
that there is a less than 2.5% chance that the average ORR is greater than 60%, we will terminate 
the study. The ORR is assumed to follow a non-informative prior of Beta (1.2, 0.8). The stopping 
boundaries for ORR, based on these assumptions and monitoring conditions are found in table 8. 
We will apply these stopping boundaries starting from the fifth patient and in cohorts of 5. For 
example, accrual will cease if only 2 or less than 2 patients experience overall response among 
the first 10 patients treated. The operating characteristics are summarized in table8. 
 
 
 
 
 
Table 8.Stopping boundaries for ORR 
 
Number of 
 
patients evaluated 
 
5 
 
10 
 
15 
 
20 
 
25 
 
30 
 
35 
 
40 
 
45 
 
50 
 
55 
 
60 


Vosaroxin and decitabine in AML 
44 
 
 
 
 
 
 
for response 
 
 
 
 
 
 
 
 
 
 
 
 
Number of 
patients with 
response 
(i.e., CR, CRp 
 
or CRi) 
 
 
 
 
 
0 
 
 
 
 
 
0-2 
 
 
 
 
 
3-5 
 
 
 
 
 
6-7 
 
 
 
 
 
8-9 
 
 
 
 
 
10-12 
 
 
 
 
 
13-15 
 
 
 
 
 
13-17 
 
 
 
 
 
18-20 
 
 
 
 
 
21-22 
 
 
 
 
 
23-25 
 
 
 
 
 
26-28 
 
Table 9. Operating characteristics for monitoring of overall response rate 
Tr ue overall 
 
 
Sample size  
 
 
Early Stopping Probability  
 
 
Res ponse Rate 
 
 
25%, 50%, 75% 
 
0.35 
0.974 
10 
15 
30 
0.40 
0.888 
15 
20 
35 
0.45 
0.702 
15 
35 
60 
0.50 
0.442 
30 
60 
60 
0.55 
0.209 
60 
60 
60 
0.60 
0.079 
60 
60 
60 
0.65 
0.027 
60 
60 
60 
 
 
Toxicity Monitoring 
 
Following are the rules for the monitoring of toxicities in the Phase II portion of the study. Toxicity 
will be defined as clinically significant non-hematologic drug related grade 3 or higher adverse 
events. The probability of toxicity is denoted by PE. We assume PE - beta (0.6, 1.4). Our 
stopping  rule  is  given  by  the  following  probability  statement:  Probability  (PE  >  0.30  I 
data)>0.975. That is, we will stop the study if, at any time during the study, we determine that 
there is more than 97.5% chance that the toxicity is more than 30%. This stopping rule will be 
applied in each cohort. The stopping boundaries for clinically significant toxicities 
observed during the first cycle, based on these assumptions and monitoring conditions found in 
table  10  . We will apply these stopping boundaries starting from the fifth patient and in cohorts of 
5. For example, accrual will cease if 4 patients experience clinically significant toxicities during 
the first cycle among the first 5 patients treated. The operating characteristics are summarized in 
table 11. 


Vosaroxin and decitabine in AML 
45 
 
 
 
 
 
Table 10. Stopping boundaries for Phase II toxicities  
 
The number 
of patients 
evaluated 
for toxicities 
 
 
 
 
5 
 
 
 
 
10 
 
 
 
 
15 
 
 
 
 
20 
 
 
 
 
25 
 
 
 
 
30 
 
 
 
 
35 
 
 
 
 
40 
 
 
 
 
45 
 
 
 
 
50 
 
 
 
 
55 
 
 
 
 
60 
The number 
 
of patients 
with DLTs 
 
 
 
4 
 
 
 
5-6 
 
 
 
7-8 
 
 
 
9-10 
 
 
 
11-12 
 
 
 
13-14 
 
 
 
15-16 
 
 
 
17-18 
 
 
 
19 
 
 
 
20-21 
 
 
 
22-23 
 
 
 
24-25 
 
 
 
 
 
Table 11. Operating characteristics 
 
Sample Size 
True Toxicity Rate 
Early Stopping Probability     
 
25111 percentil e 
Median 
75t11 percentile 
 
 
0.10 
0.008 
60 
60 
60 
0.20 
0.010 
60 
60 
 
60 
0.30 
0.082 
60 
60 
60 
0.40 
0.474 
30 
60 
60 
 
0.50 
0.906 
15 
25 
40 
 
 
 
 
10.4 
Statistical Analysis Plan 
 
All patient s who received at least 1 dose of the combination therapy will be included in the 
intent-to-treat analysis for efficacy and safety. Demographic/clinical characteristics and safety 
data of the patients will be summarized using descriptive statistics such as mean, standard 
deviation, median and range. Response rates will be presented with 95% confidence interval s. 
The association between response and patient and clinical characteristics will be examined by 
Wilcoxon 's rank sum test or Fisher's exact test. Overall survival time will be estimated using the 


Vosaroxin and decitabine in AML 
46 
 
 
 
 
 
 
Kaplan-Meier method. Patients who drop out of the study will be included in the time to event 
data as "censored data".  The two-sided log-rank test will be used to assess the differences of 
time to events between groups. 
 
 
 
 
11.0 DATA CONFIDENTIALITY PROCEDURES: 
 
Samples are identified by patients' unique identification number, which allows patient 
identification and linkage to the clinical database. Because many of these studies require clinical 
correlation, the medical record number (MRN) is maintained in the Oracle database. Only 
designated users may view data associated with patient identifiers. Other users see only a unique 
patient identifier. Dates ofbirth are not available to general users, this information is only 
available to central personnel and it is used to calculate age, as part of data that may be important 
to correlate with research assay results. This database is password-protected. 
 
 
 
 
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