Conditions: Anemia Myelodysplastic Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This phase II trial studies how well deferasirox works in treating patients with very low, low, or intermediate-risk anemia or myelodysplastic syndrome that depends on red blood cell transfusions. Deferasirox may treat too much iron in the blood caused by blood transfusions.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the activity of iron chelation therapy (ICT) with deferasirox, in patients with anemia due to myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

I. Reduction in red blood cell (RBC) transfusion requirements. II. Hematologic improvement. III. Change in serum ferritin levels from baseline to the end of the study as measured on a monthly basis.

IV. Safety and tolerability of deferasirox.

EXPLORATORY OBJECTIVES:

I. Blood and marrow samples will be taken to study erythropoiesis and the impact of iron overload on erythropoiesis.

OUTLINE: Patients receive deferasirox orally (PO) once daily (QD). Treatment continues for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive deferasirox PO QD. Treatment continues for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Deferasirox intervention 2: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
9422 
IRO REGO A uG 3 0 2019  
FRED HUTCHINSON CANCER RESEARCH CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Previous version: 07/05/2018 
Current version: 08/19/2019 
Title of Protocol: 
A Phase II Study of Deferasirox in Patients with Myelodysplastic Syndromes who are Anemic with 
Iron Overload 
Investigators List: 
Investigator 
Professional Title 
Phone 
Number 
Bart L. Scott, MD 
Associate Member, FHCRC, Associate Professor of 
Medicine, UW 
(206) 667-1990 
Karen Schiavo, ARNP 
Nurse Practitioner, Seattle Cancer Care Alliance 
(206) 288-7242 
H. Joachim Deeg, MD 
Member, FHCRC, Professor of Medicine, UW  (206) 667-5985 
Pamela S. Becker, MD, PhD 
Member, FHCRC, Professor of Medicine, UW 
(206) 288-6890 
Michael L. Linenberger, MD 
Member, FHCRC, Professor of Medicine, UW 
(206) 667-5021 
Sioban B. Keel, MD 
Assistant Professor, UW 
(206) 685-2196 
Jason P. Cooper, MD. PhD 
Senior Fellow, UW/FHCRC Hematology-Oncology 
(206) 667-2337 
Janis L. Abkowitz, MD 
Clement A. Finch Professor of Medicine, UW 
Head, Division of Hematology, UW 
(206) 685-7877 
Biostatistician: 
Ted A. Gooley, PhD 
Member, FHCRC 
(206) 667-6533 
Research Staff: 
Sheri Fong 
Study Coordinator, FHCRC 
(206) 667-4963 
Emergency number (24 hours): 
• 
Seattle Cancer Care Alliance: 206-598-6190 
• 
Seattle Urgent Care (206) 326-3000 or 
(206) 326-3341 for paging operator after hours 
FHCRC IRB Approval 
OCT 02 2019 
Document Re!e.ased Date 
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TABLE OF CONTENTS  
Page 
1.0 INTRODUCTION  
3 
2.0  BACKGROUND 
2.1  Study Disease  
3 
2.2  Clinical Data to Date  
3-6 
2.3  Study Agent  
6 
2.4  Risks/Benefits  
6 
3.0  STUDY OBJECTIVES 
3.1  Primary Objectives  
6 
3.2  Secondary Objectives  
6 
4.0  STUDY DESIGN 
4.1  Description of Study  
7 
4.2  Endpoints  
7 
5.0  SUBJECT SLECTION  
/ 
5.1  Inclusion Criteria  
7 
 
5.2  Exclusion Criteria  
8 
6.0  SUBJECT REGISTRATION  
8 
7.0  TREATMENT PLAN 
7.1  Agent Administration  
9 
7.2  Treatment Schema  
9 
7.3  Duration of Therapy  
9 
7.4  Duration of Follow Up  
10 
7.5  Concomitant Medication and Supportive Care Guidelines  
10-11 
7.6  Dosing Delays/Dose Modifications  
11-13 
7.7  Criteria for Removal/Withdrawal from Study  
13 
8.0  GUIDELINES FOR ADVERSE EVENT REPORTING 
8.1  Adverse Event Reporting/Institutional Policy  
13-14 
8.2  Study Specific Adverse Event Capture  
14 
9.0  Serious Adverse Events  
14-15 
10.0 DATA AND SAFETY MONITORING PLAN  
16 
11.0 STUDY AGENT INFORMATION 
11.1 Background  
16 
11.2  Deferasirox Preparation and Administration  
16 
12.0 ASSESSMENT OF EFFICACY 
12.1  Efficacy Parameters  
16 
12.2  Method and Timing  
16-17 
12.3  Other Response Parameters  
17 
13.0 DATA MANAGEMENT/CONFIDENTIALITY  
17 
14.0 ETHNIC and GENDER DISTRIBUTION: TARGETED ENROLLMENT  18 
15.0 STATISTICAL CONSIDERATIONS  
18 
16.0 TERMINATION OF THE STUDY  
18 
REFERENCES  
19-21 
APPENDICES  
22-34 
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1.0 INTRODUCTION 
Patients with Myelodysplastic Syndromes (MDS) who are red blood cell (RBC) transfusion dependent are known 
to have a shorter survival in comparison to other MDS patients who do not require RBC transfusions.(1) In addition, 
there are substantial economic burdens to continued RBC transfusion support(2). While erythroid stimulating 
agents (ESA, eg, exogenous erythropoietin) are effective in some patients with MDS, many patientsdo not respond 
and among responders the duration of response on average is one year (3;4). Lenalidomide is effective in reducing 
RBC transfusion requirements with a 67% transfusion independence rate in patients with deletion of the long arm 
of chromosome 5 [del(5q)] MDS(5); however in non-del 5 q MDS the response rate is only 27%(6). It is clear that 
new therapies are needed in this population. Iron chelation therapy (ICT) has been shown to improve hematologic 
parameters in patients with MDS and in some series there is a demonstrated survival benefit to ICT. Therefore, we 
propose a phase II prospective trial using ICT with oral deferasirox in patients with MDS with anemia. 
2.0 BACKGROUND 
2.1 Study Disease 
MDS represents a group of clonal myeloid stem cell disorders with a heterogeneous spectrum of presentation, 
ranging from an indolent course over several years to rapid progression to acute myeloid leukemia (AML). MDS 
typically occurs without a known preceding insult (de novo MDS)(7), but can also occur after chemotherapy or 
radiotherapy resulting in secondary MDS. The natural history of patients with MDS is varied with a median survival 
ranging from 8.8 years for patients with very low-risk IPSS-R (Revised International Prognostic Scoring System) 
scores, to 0.8 years for those with very high-risk scores(8). 
The cornerstone of therapy, particularly for lower-risk disease, is centered on improving hematologic parameters 
thereby reducing the morbidity and mortality associated with low blood counts. At the time of diagnosis over 80% 
of patients with MDS are anemic, and 50% have a hemoglobin level < 10 g/dL(9). RBC transfusion support is 
currently the primary management option for MDS-related anemia(2). Transfusions are almost universally effective, 
ameliorate the patient's symptoms rapidly, and improve health-related quality of life. However, long-term RBC 
transfusion support can lead to iron overload, which has been associated with an inferior outcome in patients with 
MDS(1). Strategies to reduce transfusion requirements and subsequent iron overload are imperative to reduce 
potential harm and to reduce economic and societal costs associated with increased RBC transfusion burdens in 
MDS patients(2). 
2.2 Clinical Data to Date 
Other strategies are used to treat MDS-related anemia. Erythropoiesis stimulating agents (ESA; such as 
erythropoietin or darbepoetin) are the most commonly used agents to treat MDS(10). However, the benefit of ESA 
are largely restricted to patients with lower erythropoietin levels and minimal RBC transfusion requirements in the 
presence of low or intermediate risk disease(11). In approximately 5% of patients, del(5q) is the sole cytogenetic 
abnormality(12). Lenalidomide has been proven to be an effective agent in this population with 67% of the patients 
achieving transfusion independence in a phase III trial(5). In the absence of the del(5q) abnormality, the rate of 
transfusion independence is approximately 27% (6). There is data to indicate that combined therapy with 
lenalidomide and ESA result in improved erythroid responses(13). Combination therapy with lenalidomide and ESA 
are under current investigation in a multi-center trial phase III randomized trial. Hypomethylating agents (HMA: 
azacitidine and decitabine) target the aberrant DNA methylation seen in MDS and result in a response in 
approximately 50% of patients with low-risk MDS (14;15). Azacitidine is FDA-approved for all stages of MDS. 
Decitabine is not FDA-approved for patients with low risk disease by the original International Prognostic Scoring 
System (IPSS)(16). While these agents have been shown to alter the natural history of advanced MDS; there is 
less data to support their routine use in lower risk MDS patients (17;18). Since the route of administration is either 
IV or SQ and there is significant toxicity, the HMA are generally not the preferred therapeutic choice for patients 
with early stage MDS. 
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Cumulative Proportion Surviving 
 
20 40 60 80 100 120 140 160 180 
Survival time (months) 
Figure 1: Survival among 426 patients with low risk 
MDS according to transfusion dependency. 
0.9 
0.8 
0.7 
0.6 
0.5 
0.4 
0.3 
0.2 
0.1 
0.0 
0 
—0 U PRC/4WK 
•••• 1 U PRC/4WK 
 2 U PRC/4WK 
" "3 U PRC/4WK 
— '4 U PRC/4WK 
1.0 
41  
•. 
•?... 
0 
O 0.6 ' 
 
2 
a.  
. 
> • OA 
Elin  Ds! 
— < 1000 61 6 
- - >134  11 
0.2 
0 
12  
24 
Months from Referral 
Figure 2: Impact of ferritin levels on survival in low 
risk MDS patients. 
pr0.01 
0.00  
9422 
In the absence of widely effective interventions, MDS-
related anemia is often mitigated with RBC 
transfusions. Although it can relieve symptoms, 
overtime alloantibodies and iron overload can result as 
a consequence of multiple transfusions(2). Some 
patients with MDS, in particular RARS, develop iron 
overload in the absence of multiple transfusion. This 
may occur through several mechanisms including 
ineffective erythropoiesis resulting in increased 
gastrointestinal  absorption(19).  Concomitant 
hemochromatosis gene mutations 
(HFE) 
and 
polymorphisms in other regulators of iron metabolism 
may also influence the predisposition for iron overload 
in patients with MDS. Consequently, in certain patients 
with MDS (RARS), iron overload may not correlate well 
with the number of RBC transfusions and may occur 
early in the course of disease. 
Several reports have noted a higher mortality rate in 
multiply RBC transfused, iron-overloaded MDS 
patients treated conventionally or after stem cell transplantation (1;20-25). In a retrospective analysis from 426 
patients with low risk MDS the burden of RBC transfusions was significantly associated with overall survival (Figure 
1). All patients were diagnosed with MDS based upon the WHO criteria between 1992 and 2004. This data set 
included patients with a diagnosis of RA, RCMD, RARS, or Del 5q (all with less than 5% blasts). Thus, indicating 
that even among patients who are traditionally thought to have low risk MDS, RBC transfusion dependence was 
strongly predictive of survival. This finding led to the development of a dynamic prognostic system known as the 
WHO-based prognostic scoring system (WPSS) which incorporated RBC transfusion dependence(26). Separately, 
several investigators found that ferritin serum levels were associated with overall survival in low risk MDS(21). In a 
retrospective analysis, ferritin levels were available in 95 patients with low risk MDS. When stratified by > or 
serum ferritin level of 1,000 ng/mL, MDS patients with 
higher ferritin levels were found to have an inferior 
survival (Figure 2). 
Based on preclinical and clinical data, mechanisms 
underlying the inferior survival in this population point to 
excess in labile plasma iron (LPI) as the putative 
mediator(19). This has prompted the use of ICT to 
modify the negative effect of iron overload in patients 
with MDS. Although several reports suggest a survival 
benefit with ICT (27-31), all of them were non-
randomized comparisons and were susceptible to a 
significant selection bias. We know that patients are 
selected to receive ICT on the basis of an expected 
survival; otherwise, they would not life long enough to 
benefit. Therefore, the improved survival in patients 
treated with ICT could be completely due to a selection 
bias that is not necessarily overcome by a matched pair 
analysis(29). In addition, several trials have confirmed the ability of deferasirox to reduce iron content as measured 
by serum ferritin and in some patients to improve hematologic parameters (32-36). However, all of these studies 
are non-randomized and most are retrospective. Currently, there is a prospective randomized controlled trial 
evaluating the use of iron chelation therapy in red cell transfusion dependent MDS patients (TELESTO). In the 
absence of randomized prospective studies controversy still surrounds the implementation of ICT for patients with 
MDS. 
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1.0- 
Threshold of normal L151 k 0.5 omol/L) 
Baseline 
13 
25 
37 
49 
Time (weeks) 
68 
47 
47 
43 
37 
No. at tisk 
0  . 
Mean  LPI (pmol/L) 
 
0.8- 
0.6- 
0.4- 
0.2- 
Figure 3: Mean LPI over 12 months in MDS patients 
with abnormal LPI at baseline. 
Y.  All patients 
0 
. .300. 
.400' 
.1200. 
co 1600- 
% 26 1800-, 
• 
2100   
C  
BL 
• 
s(n) 
335 
20 
10 
6  9  12 
259  225  192  171 
600 
300 . Mewl Iron ihteke! 042 molicgtday 
—o— Serum ferritIn (ng/mL) 
• 
Deferasirox dose (rrtgfkg/day) 
Figure 4: Mean change in serum ferritin and mean 
deferasirox dose among MDS patients in the EPIC Trial 
......... • 
• 
a I 
• 
Erythroid  Platelet  Neutrophil 
Hematologic response 
Figure 5: Percentage of MDS patients with hematologic 
improvement enrolled into the EPIC trial 
25 - 
Patients with  response (%) 
 
20 
15 - 
10 
9422 
In a multicenter, open-label, single-arm, 3-year 
phase II trial (US03), the safety and tolerability of 
deferasirox was evaluated in lower-risk MDS who 
had received at least 20 units of RBC and had a 
serum ferritin 1,000 pg/L(34). Of the 173 patients 
that underwent ICT with deferasirox, 51 (28%) 
experienced hematologic improvement, only seven 
of which received other MDS related therapy. 
Therefore, ICT appears to improve hematologic 
parameters in some MDS patients with iron 
overload.  Mean labile plasma iron (LPI) was 
measured at baseline in 163 patients, among these 
patients 68 had elevated levels (>0.5 LPI units). 
Concentrations of LPI fell within normal limits in all 
47 patients who were assessed at week 13 and 
remained in the normal range through the duration 
of the trial (Figure 3). Additionally, there was a 
decline in the median serum ferritin by 23.2% at one 
year in the patients who completed at least one year 
of ICT. Therefore, deferasirox was able to reduce the iron burden in iron-overloaded MDS patients. The annual 
discontinuation rates of deferasirox were 45%, 
43%, and 35% during years 1, 2, and 3 
respectively. The safety profile of deferasirox in 
this setting was reasonable with discontinuation in 
43 patients (24.8%) because of adverse events 
(such as gastrointestinal disturbances) or disease 
progression and 23 patients (13.2%) because of 
abnormal laboratory values (such as increased 
serum creatinine). All 28 deaths that occurred 
during the study were considered unrelated to 
deferasirox. 
The EPIC trial was a similar study conducted in 
Europe. There were 341 MDS patients enrolled in 
this phase II prospective trial. Patients were treated 
with 20 mg/kg/day of deferasirox if they received 2-
4 U/month of RBC transfusions or 10-30 mg/kg/day 
if there were less or more RBC transfusion 
dependent, respectively. Overall, 175 patients 
completed one year of therapy with deferasirox. Of 
the 166 patients who discontinued therapy, 78 were 
for adverse events. The most frequently reported 
adverse events were gastrointestinal including 
diarrhea, nausea, vomiting, etc. There were 26 
deaths in the study with most common cause being 
infection. None of the deaths were felt to be drug 
related. Serum ferritin levels significantly decreased 
from baseline after 1 year of deferasirox with a 
median reduction of 606 ng/mL (Figure 4). A post-
hoc analysis demonstrated that erythroid, platelet 
and neutrophil responses were observed in 21.5%, 
13%, and 22% of the patients after a median of 109, 
169 and 226 days, respectively (Figure 5)(33). 
The improvement seen in hematologic parameters 
after the initiation of ICT may be a result of improved 
function of the renal oxygen sensing system for 
erythropoietin production, reducing the inhibitory 
effect of oxidative stress on hematopoiesis, or 
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altering intracellular levels of the nuclear transcription factor NF-kB(19). 
There is little clinical data regarding ICT in patients who have received minimal RBC transfusions or in patients with 
a serum ferritin < 1000 ng/mL. However, these patients may still derive benefit from ICT. As discussed earlier, 
patients with MDS may be more susceptible to iron overload or have iron overload in the absence of multiple RBC 
transfusions. Furthermore, ICT may modify disease risk beyond RBC transfusion-related events. ICT in the setting 
of multiple RBC transfusions for other hematologic conditions such as beta-thalassemia major exerts a survival 
effect largely though reduction in iron-related end organ damage. However, the expected survival in MDS at 
baseline, even in the setting of lower-risk disease, is on the order of a few years. Given this short timeframe in 
contrast to the time required to develop RBC transfusion-related end organ damage, the poorer outcome associated 
with iron overload in MDS may not be entirely accounted for by this mechanism. Iron overload in patients with MDS 
has been linked according to several studies to increased infection risk and accelerated transformation to AML in 
addition to end organ damage (28;37;38). By reducing LPI, ICT may decrease the rates of infection and leukemic 
transformation, and may result in selective toxicity towards MDS hematopoietic progenitors relative to normal 
progenitors(19). There is also the possibility that mild iron deficiency may mitigate the ineffective erythropoiesis of 
MDS since emerging data suggest that ineffective erythropoiesis is due, at least in part, to an excess of heme 
relative to globin as red cells mature and heme toxicities. Reducing iron and thus heme in maturing red cells might 
correct this imbalance. With a manageable side effect profile along with its disease-modifying potential it is 
reasonable to explore the efficacy of aggressive ICT with deferasirox in lower risk MDS patients who do not 
necessarily have excessive iron burden according to ferritin levels. 
2.3 Study Agent 
Patients will receive oral deferasirox which has been approved by the FDA for the treatment of chronic iron overload 
due to blood transfusions in patients 2 years of age or older. Deferasirox will be administered to achieve a ferritin 
< 100 ng/mL and, since it is approved for chelation and used regularly for this purpose as a standard of care, the 
dosing and schedule will be at the discretion of the treating clinician based on overall iron loading (ferritin), renal 
function, hepatic function, blood counts, and clinical condition / performance status. Contraindications include the 
following: Serum creatinine greater than two-times the upper limit of normal (ULN) or glomerular filtration rate (GFR) 
of less than 40 mUmin, poor performance status, high risk MDS, advanced malignancies, platelet count of less than 
50,000, pregnancy, and/or known hypersensitivity to deferasirox. 
2.4 Risks/Benefits 
The most frequently occurring adverse reactions are diarrhea, vomiting, nausea, abdominal pain, skin rashes and 
increases in serum creatinine. Among patients with MDS, the major observed toxicity was an increase in serum 
creatinine (37%). The most frequent adverse reactions that led to drug discontinuation were increase in serum 
creatinine, diarrhea, nausea, rash and vomiting. Death was reported in the first year in 8% of the patients. Auditory 
and ocular disturbances occurred in <1% of participants. Deferasirox is considered pregnancy Category C by the 
FDA as animal studies have demonstrated potential embryonal fetal toxicities with decreased offspring viability with 
renal anomalies. The potential benefits of deferasirox are reduction in total body iron with improvement in organ 
function (liver and heart). Additional benefits include the potential to improve hematopoiesis and bone marrow 
function in general. 
3.0 STUDY OBJECTIVES 
3.1 Primary Objectives 
The primary objective is to assess the activity of ICT with deferasirox in patients with anemia due to MDS. 
3.2 Secondary Objectives 
Secondary objectives include a reduction in RBC transfusion requirements, hematologic improvement, change in 
serum ferritin levels from baseline to the end of the study as measured on a monthly basis and safety and tolerability 
of deferasirox. 
3.3 Exploratory Objectives 
Samples will be taken to study erythropoiesis and the impact of iron overload on erythropoiesis on patient samples 
including blood and marrow. 
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4.0 STUDY DESIGN 
4.1 Description of Study 
This study is a single-center open-label prospective phase II trial evaluating deferasirox in patients with very low, 
low or intermediate risk MDS by the IPSS-R criteria(8). 
4.2 Endpoints 
4.2.1 Primary Endpoint 
The primary endpoint is the proportion of patients that achieve erythroid hematologic improvement as defined by 
the modified IWG response criteria at 6 months(39). 
4.2.2 Secondary Endpoints 
1. Change in RBC transfusion requirements. 
2. The proportion of patients who achieve granulocyte or platelet hematologic improvement as defined by the 
modified IWG response criteria(39). 
3. Change in serum ferritin levels from baseline to the end of the study as measured on a monthly basis. 
4. Safety and tolerability profile as measured by grade 3 and 4 non-hematologic adverse events 
5.0 SUBJECT SELECTION 
5.1 Inclusion Criteria 
1.  Capable of giving written informed consent prior to any study-specific procedures 
2.  Diagnosis of MDS as defined by the WHO diagnostic criteria (40) (Appendix A) 
3.  Have very low, low or intermediate risk disease by the IPSS-R (8) (Appendix B) 
4.  Baseline serum ferritin level 100 ng/mL 
5.  Have an ECOG performance status of 0-2 (41) (Appendix C) 
6. Age 18 
7. 
8.  Anemia defined as hemoglobin 10.0 g/dLHave adequate organ function, including: 
a. 
Hepatic: Bilirubin ‘1.5 times upper limits of normal (ULN), alanine transaminase (ALT), and 
aspartate transaminase (AST) 3.5 times ULN 
b. 
Renal: Serum creatinine 5_ 1.5 X ULN and estimated GFR > 40 mL/min 
9. Males and females with reproductive potential must agree to use medically approved contraceptive 
precautions during the study and for 3 months following the last dose of deferasirox* 
10. Females with childbearing potential* must have had a negative urine or serum pregnancy test 7 days 
before the first dose of deferasirox and must also not be breastfeeding 
11.  Reliable and willing to make themselves available for the duration of the study and are willing to follow study 
procedures 
*Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they 
are using effective methods of contraception during dosing of study treatment. 
Effective contraception methods include: 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
• 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/ vaginal suppository 
• 
Total abstinence or (when this is in line with the preferred and usual lifestyle of the subject). Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal 
ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment 
• 
Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized 
male partner should be the sole partner for that subject 
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Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) 
or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow 
up hormone level assessment is she considered not of child bearing potential. 
Sexually active males must use a condom during intercourse while taking drug and for 28 days after stopping study 
medication and should not father a child in this period. A condom is required to be used also by vasectomized men 
in order to prevent delivery of the drug via seminal fluid. 
Please note that deferasirox may reduce the efficacy of hormonal contraception thus it is recommended to 
use alternative methods of contraception as described above. 
5.2 Exclusion Criteria 
1. If the patient is currently receiving ESA (for example, erythropoietin) with plans to continue during study: 
Less than 2 months duration of ESA therapy prior to starting study drug and no dose escalation within 2 
months of start of study drug. 
2. 
If the patient is being treated with GCSF and/or a TPO-mimetic (for example, Eltrombopag or Romiplostim) 
with plans to continue during the study: Less than 2 months duration of GCSF or the TPO-mimetic treatment 
prior to starting study drug; or GCSF and/or TPO-mimetic has been added to ESA therapy within 2 months 
of start of study drug. 
3. If patient is being treated with Lenalidomide with plans to continue during the study: Stable dose for less 
than 3 months prior to start of study drug. 
4. If patient is being treated with HMA (for example, Azacitidine or Decitabine) with plans to continue during 
the study: Stable dose for less than 6 months prior to start of study drug. 
5. 
Currently enrolled in, or discontinued within the last 14 days from a clinical trial involving an investigational 
product or non-approved use of a drug, or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study. 
6. 
Presence of .10% blast by morphologic examination of bone marrow aspirate or biopsy 
7. Platelets 50,000 
8. 
Microcytosis on screening CBC (MCV < 81 fL) 
9. 
Active GI ulceration or hemorrhage 
10. Have a serious preexisting medical conditions that, in the opinion of the investigator would preclude 
participation in the study (for example a GI disorder causing clinically significant symptoms such as nausea, 
vomiting, and diarrhea, or malabsorption syndrome).or that would result in a life expectancy of less than 1 
year 
11. 
Known hypersensitivity to deferasirox 
12. 
History of non-transfusional hemosiderosis 
13. 
Prior hematopoietic stem cell transplant for the diagnosis of MDS 
14. 
A second primary malignancy that in the judgment of the principal investigator (PI) or designee may affect 
the interpretation of results 
15. 
Have an active fungal, bacterial, and/or known viral infection including human immunodeficiency virus (HIV) 
or viral (A, B, or C) hepatitis 
16. 
Currently using aluminum-containing antacid products 
17. 
History of clinically significant auditory or ocular toxicity with ICT 
6.0 SUBJECT REGISTRATION 
Patients will be recruited to participate in this clinical trial during the regular clinical visits of co-investigators. Patients 
will be given a copy of the consent form for this trial and will have ample time to review the study. The study will be 
reviewed with the patient by an experienced co-investigator in detail. Patients will be provided with a signed copy 
of the consent form. Following the signature of a consent form the FHCRC Research Subject Registration Form 
(Appendix D) will be completed and sent to the FHCRC Research Coordinator along with a copy of the signed 
consent form and protocol specific HIPAA form. The original consent form will remain in the patient's chart. Once 
this form has been received and screening has been completed, the eligibility checklist (Appendix E) will be 
completed by study staff. The eligibility checklist must be signed by the PI or designee prior to the start of treatment 
with deferasirox. Ineligible patient will be considered a screen failure and will not be enrolled; however, they may 
be reconsidered for enrollment at a later date. Patients must be consented prior to any screening procedures and 
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must be re-consented with each subsequent attempt at screening. An eligibility checklist must be completed with 
each screening attempt. 
7.0 TREATMENT PLAN 
7.1 Agent Administration 
Deferasirox is available orally and should be administered per the manufacturer's instructions. 
7.2 Treatment Schema 
Deferasirox will be administered orally per the manufacturer's instructions to achieve a ferritin < 100 ng/mL and, 
since it is approved for chelation and used regularly for this purpose as standard of care, the dosing and schedule 
will be at the discretion of the treating clinician based on overall iron loading (ferritin, serum iron), renal function, 
hepatic function, blood counts, and clinical condition / performance status. 
7.3 Duration of Therapy 
1. Screening phase (up to 4 weeks: Day -29 to Day -1)  
Screening evaluations will be performed at one or more clinic visits to determine eligibility for the study. 
Laboratory Assessments 
• 
CBC with differential 
• 
Creatinine and GFR estimation 
• 
Hepatitis Panel 
Screening evaluations include laboratory evaluations as well as a bone marrow aspirate or biopsy. CBC with 
differential and record of transfusional requirements in the preceding 3 months will be obtained during the baseline 
screening. Testing for hepatotrophic viruses will be performed during the screening phase to include: Hep A 
antibody, Hep B surface antibody, Hep B surface antigen, Hep B core antibody, Hep C antibody, and Hep C PCR. 
Baseline ophthalmologic and audiometric examinations will be performed during the screening phase. It is 
recommended that the screening bone marrow aspirate or biopsy be performed once a patient has been found to 
be otherwise eligible. The results from the screening bone marrow aspirate or biopsy will be used as the baseline 
for analyses. Baseline will be defined as the last assessment or procedure conducted prior to the initiation of 
deferasirox (Day 1). Baseline evaluations must be performed within 30 days of start of deferasirox except the 
baseline bone marrow biopsy which can have occurred within 30 days of the start of deferasirox and for pregnancy 
testing in women of childbearing potential which must be performed within 7 days of the start of deferasirox. 
2. Treatment phase (up to 52 weeks: Day 1 to Week 26)  
Patients will receive deferasirox at a starting dose at the discretion of the treating clinician based on baseline 
serum ferritin levels, renal function, hepatic function, blood counts, and clinical condition / performance status The 
target ferritin level is < 100 ng/mL. The primary endpoint of hematologic improvement in the erythroid lineage will 
be assessed at 6 months. Nonresponders will be offered the option of alternative treatments including clinical trials 
if available. The maximum duration of therapy on this protocol is one year. 
3. Monitoring (From Start of therapy till day 30 following last dose)  
Creatinine and GFI/R will be assessed every 2 weeks during the first month of therapy and monthly thereafter; more 
frequent monitoring may be required if clinically indicated. Serum transaminases, bilirubin, and alkaline 
phosphatase will be checked every 2 weeks during the first month of therapy and then monthly thereafter. The 
number of RBC transfusions and platelet transfusions will be recorded at each visit, and hematologic response data 
will be collected monthly. Lab studies may be performed by the local oncologist. Safety assessments will be 
performed at all study visits with ophthalmologic and audiometric examinations performed at baseline and as 
indicated (at least yearly). A bone marrow aspirate or biopsy will be obtained after 3 months of treatment and 6 
months following initiation of deferasirox. Patients will be followed for an additional 30 days after discontinuation of 
deferasirox to assess for toxicity. 
Table 2 Summary of Study Related Monitoring: 
Test 
Minimal Frequency* 
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Serum creatinine, GFRA 
Pretreatment (within 30 days) baseline. Every 2 
weeks during the first month and then monthly 
thereafter. 
Urine protein/creatinine ratio (spot-check) 
Pretreatment (within 30 days) baseline and at 6 
months and 12 months 
Serum Ferritin 
Pretreatment (within 30 days) baseline and then 
monthly thereafter 
Serum transaminases, bilirubin, alkaline 
phosphatase 
Prior to therapy (within 30 days). Every 2 weeks 
during the first month and then monthly thereafter 
CBC with differential 
Pretreatment (within 7 days) baseline and monthly 
thereafter 
Bone Marrow Aspirate or Biopsy 
Pretreatment (within 30 days) baseline 
(screening) and at 3 months and 6 months post-
initiation 
Auditory and ophthalmic testing 
Prior to therapy (within 3 months). Annually 
thereafter. 
Hepatotrophic viruses: Hep B surface 
antibody, Hep B surface antigen, Hep C 
antibody, and HCV PCR 
Pretreatment (within 30 days) 
Pregnancy test urine or serum 
Pretreatment (within 7 days of start of deferasirox) 
in women of child bearing potential 
*Testing should be performed more frequently if clinically .ndicated 
"Estimated GFR with the MDRD formula 
Please see Study Calendar (Appendix F) which will be supplied to the patients to assist with follow up and 
scheduling of necessary testing. 
7.4 Duration of Follow-Up 
Patients will remain treated on study for a maximum of one year. The primary endpoint of hematologic improvement 
in the erythroid lineage based upon the modified IWG criteria (Appendix G) will be assessed at 6 months. At the 
end of 6 months patients who do not respond will be offered the option of alternative treatments including enrollment 
into clinical trials if possible. The goal is for patients to complete at least 6 months of therapy; however, patients 
may be removed/withdrawn from the study prior to 6 months as detailed in Section 7.7. Patients will be followed 
for 30 days following last dose of study related therapy. At the end of one year patients may continue to receive 
deferasirox but not as part of this trial and they will not be followed for outcomes or toxicities. 
7.5 Concomitant Medication and Supportive Care Guidelines 
Supportive care measures (e.g. antibiotic prophylaxis and treatment, transfusions) should be carried out according 
to institutional practice guidelines or the preference of the attending physician. 
7.5.1 Permitted Concomitant Therapy 
1. All study participants will be allowed, as medically justified, access to RBC and platelet transfusions. 
Concurrent use of an ESA will be allowed if the patient has been on a stable dose for two months prior to 
screening and continuation of ESA is medically justified. Combination therapy with a TPO-mimetic (such 
as Eltrombopag or Romiplostim) and/or G-CSF is allowed as long as the patient has been on a stable dose 
for two months prior to screening. G-CSF will be allowed in the setting of an acute infection if medically 
justified. Lenalidomide concurrent use is allowed if they have been on a stable dose for at least 3 months 
of duration. HMA concurrent use is allowed if they have been on a stable dose for at least 6 months. 
7.5.2 Permitted Concomitant Therapy Requiring Caution or Action 
• 
Concomitant use of UGT inducers decreases deferasirox systemic exposure. Avoid the concomitant use of 
potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) with deferasirox. If you must 
administer deferasirox with 1 of these agents, consider increasing the initial dose of deferasirox by 50%, and 
monitor serum ferritin levels and clinical responses for further dose modification Concomitant use of bile acid 
sequestrants decreases deferasirox systemic exposure. Avoid the concomitant use of bile acid sequestrants 
(e.g., cholestyramine, colesevelam, colestipol) with deferasirox. If you must administer deferasirox with 1 of 
these agents, consider increasing the initial dose of deferasirox by 50%, and monitor serum ferritin levels and 
clinical responses for further dose modification 
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• 
Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs 
are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is 
administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, 
eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, 
sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) 
• 
Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) 
concentration when these drugs are coadministered. If deferasirox and repaglinide are used concomitantly, 
consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely 
monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other CYP2C8 
substrates 
• 
Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, 
melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An 
increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or 
other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow 
therapeutic index (e.g., tizanidine) with deferasirox. Monitor theophylline concentrations and consider 
theophylline dose modification if you must coadminister theophylline with deferasirox. Closely monitor patients 
for signs of exposure related toxicity when deferasirox is coadministered with other drugs metabolized by 
CYP1A2. 
7.5.3 Prohibited Concomitant Therapy 
• 
Any investigational drug other than study medication is NOT permitted during the study. 
• 
The concomitant administration of deferasirox and aluminum-containing antacid preparations has not been 
formally studied. Although deferasirox has a lower affinity for aluminum than for iron, avoid use of deferasirox 
with aluminum-containing antacid preparations due to the mechanism of action of deferasirox. 
7.6 Dose Modifications 
7.6.1 Based on Concomitant Medications 
As stated in Section 7.5.1 deferasirox will be adjusted based upon concomitant medications which interferes with 
metabolism. 
7.6.2 Change in Patient's Weight 
The dose of study medication should be adapted using during the study if the change (increase or decrease) in 
body weight exceeds 10% of the body weight compared to the baseline visit or the last dose adjustment due to 
change in patient's body weight 
7.6.3 Renal Impairment 
Serum creatinine and proteinuria should be monitored during the study as stated in Table 2. 
Deferasirox can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing 
experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced 
stages of their hematological disorders. In the clinical trials, deferasirox-treated patients experienced dose-
dependent increases in serum creatinine. 
Measure serum creatinine and determine the glomerular filtration rate (GFR, estimated by the MDRD method) 
before initiating therapy in all patients. 
Deferasirox is contraindicated in patients with an estimated GFRIess than 40 mUminute or serum creatinine greater 
than 2 times the age-appropriate upper-limit-of-normal (ULN). Renal tubular damage, including Fanconi's Syndrome, 
has been reported in patients treated with deferasirox, most commonly in children and adolescents with beta-
thalassemia and serum ferritin levels <1500 mcg/L. 
Deferasirox will be administered and dosed at the discretion of the treating clinician based on renal function as 
measured by serum creatinine and via the estimated GFR. 
Intermittent proteinuria of unclear significance was also noted in clinical trials with deferasirox. The level of 
proteinuria will be measured per Table 2 (at baseline before treatment, at 6 months and again at 12 months)strictly 
for monitoring. Deferasirox will be administered and dosed at the discretion of the treating clinician based on the 
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results of monitoring for proteinuria. However, given the intermittent nature of proteinuria experienced with 
deferasirox and its unclear significance, there is no contraindication to the administration of deferasirox based on 
level of proteinuria. 
7.6.4 Changes in Serum Ferritin 
Goal serum ferritin of < 100 ng/mL and deferasirox dose adjustment will be at the discretion of the treating clinician 
based on the monthly serum ferritin level (in addition to other variables as detailed above including renal function, 
hepatic function, blood counts, and clinical condition / performance status). 
7.6.5 Skin Disorders 
Rashes may occur during deferasirox treatment. For rashes of mild to moderate severity, deferasirox may be 
continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt 
treatment with deferasirox. Reintroduction at a lower dose with escalation may be considered after resolution of the 
rash. Severe skin reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme, have been 
reported during deferasirox therapy. If SJS or erythema multiforme is suspected,. discontinue deferasirox 
immediately and do not reintroduce deferasirox therapy. 
7.6.6 Hepatic Impairment 
Liver function tests should be monitored during the duration of the trial as indicated in Table 2. 
Deferasirox can cause hepatic injury, fatal in some patients. Hepatic toxicity appears to be more common in patients 
greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including 
liver cirrhosis and multiorgan failure. 
Consider dose modifications or interruption of treatment for severe or persistent elevations. 
Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic 
toxicity. In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox 
exposure was increased compared to patients with normal hepatic function. The average total (free and bound) 
AUC of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients 
with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact 
of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient. 
Avoid the use of deferasirox in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate 
(Child-Pugh B) hepatic impairment, the starting dose should be reduced by 50%. Closely monitor patients with mild 
(Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require 
dose titration. 
7.6.7 Auditory or Ocular Toxicity 
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported with deferasirox 
treatment. Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of deferasirox 
treatment and at ,regular intervals thereafter (every 12 months). If disturbances are noted, dose reduction or 
interruption may be considered. 
7.6.8 Hypersensitivity Reactions 
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients 
receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of 
treatment. If reactions are severe, deferasirox should be discontinued. 
7.6.9 Cytopenias 
There have been post-marketing reports (both spontaneous and from clinical trials) of cytopenias in patients treated 
with deferasirox. Most of these patients had pre-existing hematological disorders that are frequently associated with 
bone marrow failure. The relationship of these episodes to treatment with deferasirox is uncertain. In line with the 
standard clinical management of such hematological disorders, complete blood counts will be monitored regularly. 
Given the nature of this particular clinical trial in the setting of MDS patients, dose interruptions or modifications in 
patients who develop cytopenias or have worsening of cytopenias are at the discretion of the treating clinician. 
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7.6.10 Gastrointestinal Ulceration, Hemorrhage, and Perforation 
GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic 
malignancies and/or low platelet counts. Nonfatal upper Cl irritation, ulceration and hemorrhage have been reported 
in patients, including children and adolescents, receiving deferasirox. Monitor for signs and symptoms of GI 
ulceration and hemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a 
serious Cl adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when 
administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as 
nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There 
have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome). 
7.6.11 Hypersensitivity 
Deferasirox may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of 
the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue deferasirox 
and institute appropriate medical intervention. deferasirox is contraindicated in patients with known hypersensitivity 
to deferasirox. 
7.7 Criteria for Removal/Withdrawal 
A patient may be discontinued from protocol-prescribed therapy under the following circumstances: 
• 
Consent withdrawal at the patient's own request or at the request of their legally authorized representative; 
• 
Any event that, in the judgment of the PI or designee, poses an unacceptable safety risk to the patient; 
• 
If, in the PI or designee's opinion, continuation in the study would be detrimental to the patient's well-being; 
• 
Significant deviation from inclusion/exclusion criteria, in the opinion of the PI or designee; 
• 
A positive pregnancy test at any time during the study; 
• 
An intercurrent illness that, in the judgment of the PI or designee, would affect assessments of the clinical 
status to a significant degree and requires discontinuation of therapy, or 
• 
Completion of the study 
• 
Evidence of disease progression to a higher stage of MDS or AML as defined by WHO criteria 
Once the attending physician has met and discussed the decision with the patient and/or family member, the Notice 
of Withdrawal from a Research Study form (Appendix H) should be filled out. 
• 
Once completed, the form should be faxed to FHCRC Research Coordinator at 206-667-2284. 
• 
It is the responsibility of the PI or designee to complete the Notice of Withdrawal From a Research Study 
Form (see Appendix H) and fax it to the FHCRC Research Coordinator at (206) 667-2284. 
Study treatment is defined as "any activity involving a patient described in a protocol that is not part of their routine 
medical care". Patients that withdraw from study treatment will be asked permission to continue to record survival 
data up to the protocol-described end of the subject follow-up period as it is important to the integrity of the final 
study analysis. 
Patients that are withdrawn from the protocol will not be replaced as this is intent to treat analysis. 
8.0 GUIDELINES FOR ADVERSE EVENT REPORTING 
8.1 Adverse Event Reporting/Institutional Policy 
The following guidelines are the minimum Cancer Consortium IRB adverse event (AE) reporting guidelines. 
Protocol-specific additional reporting requirements for adverse events are addressed in Section 8.2. 
In accordance with institutional policy, all adverse events which in the opinion of the PI are unexpected and related 
or possibly related to the research and serious or suggest that the research places research participants or others 
at greater risk of physical or psychological harm than was previously known or recognized be reported to the IRB 
within 10 calendar days of learning of the problem. 
Definitions:  
Adverse Event (AE) - Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product, medical treatment or procedure and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including 
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an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, medical treatment or procedure whether or not considered related to the medicinal product. 
Life-threatening AE — Any adverse event that places the patient or subject, in view of the investigator, at immediate 
risk of death from the reaction. 
Unexpected AE — An adverse event is "unexpected" when its nature (specificity), severity, or frequency are not 
consistent with (a) the known or foreseeable risk of adverse events associated with the research procedures 
described in the Protocol-related documents, such as the IRB-approved research protocol, informed consent 
document and other relevant sources of information such as product labeling and package inserts; and are also not 
consistent with (b) the characteristics of the subject population being studied including the expected natural 
progression of any underlying disease, disorder or condition any predisposing risk factor profile for the adverse 
event. 
.Attribution - The following are definitions for determining whether an adverse event is related to a medical product, 
treatment or procedure: 
• 
An adverse event is "related or possibly related to the research procedures" if in the opinion of the PI, 
it was more likely than not caused by the research procedures. 
• 
Adverse events that are solely caused by an underlying disease, disorder or condition of the subject or by 
other circumstances unrelated to either the research or any underlying disease, disorder or condition of the 
subject are not "related or possibly related." 
• 
If there is any question whether or not an adverse event is related or possibly related, the adverse event 
should be reported. 
The Cancer Consortium Expedited Reporting Form should be completed for all adverse events that meet the 
expedited reporting requirements. The AE form (see Appendix I) should be faxed to the FHCRC Research 
Coordinator at (206) 667-2284 within 10 business days of study staff awareness. All available information should 
be submitted. 
8.2 Study-Specific AE Capture 
Please refer to the package insert of deferasirox for a listing of specific expected AEs. 
AEs will be reviewed and captured in the source documentation. AEs occurring from enrollment through 30 days 
after the last administration of the study treatment will be captured in protocol-specific case report forms (Appendix 
J). 
The following events are not recorded as AEs in this study: 
• 
Disease progression or relapse. 
• 
Planned medical or surgical procedures in and of themselves, including those that require hospitalization 
(e.g., surgery, endoscopy, biopsy procedures) are not considered AEs. 
• 
Abnormal laboratory values grade < 3 (CTCAE v4.03). 
In accordance with institutional policy, all SAEs which in the opinion of the PI or designee meet all three of the 
following criteria will be reported to the IRB within 10 calendar days of learning of the problem: 
1. unexpected 
2. 
related or possibly related to the research 
3. 
serious or suggests that the research places research participants or others at greater risk of physical or 
psychological harm than was previously known or recognized 
All other SAEs and deaths, not meeting the expedited reporting criteria, will be reported to the IRB as part of the 
annual continuation review report to the IRB. 
9.0 Serious Adverse Events 
9.1 Definitions 
Serious adverse event (SAE) is defined as one of the following: 
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• 
Is fatal or life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Constitutes a congenital anomaly/birth defect 
• 
Is medically significant, i.e., defined as an event that jeopardizes the patient or may require medical or surgical 
intervention to prevent one of the outcomes listed above 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Note that hospitalizations for the following reasons should not be reported as serious adverse events: 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study 
and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the patient's general condition 
• 
Note that treatment on an emergency outpatient basis that does not result in hospital admission and involves 
an event not fulfilling any of the definitions of a SAE given above is not a serious adverse event 
9.2 Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided 
informed consent and until at least 30 days after the patient has stopped study treatment must be reported to the 
study PI and/or study coordinator within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to the study PI and/or study coordinator if 
the investigator suspects a causal relationship to the study treatment. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely 
.unrelated to a previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all applicable 
sections of the form must be completed in order to provide a clinically thorough report. The investigator must assess 
and record the relationship of each SAE to each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form in English, and send the completed, signed form by fax (206-667-2284) 0 within 24 
hours to the study PI and study coordinator.. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, using a new 
SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original 
report. Each re-occurrence, complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation. 
9.3 Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to the 
study PI and/or study coordinator within 24 hours of learning of its occurrence. The pregnancy should be followed 
up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
9.4 Duration and Grade of AE Capture 
AEs will be captured starting with the initiation of study treatment through 30 days after the last administration of 
the study treatment. 
9.4.1 AE Grading 
Toxicities will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
Citing the website under this section in the protocol rather than printing the entire document is sufficient unless the 
study is modifying the criteria. The scale in its entirety can be found at: 
http://evs.nci.nih.pov/ftp1/CTCAE/CTCAE 4.03 2010-06-14 QuickReference 8.5x11.pdf 
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10.0 DATA AND SAFETY MONITORING PLAN 
The PI of the study will have primary responsibility for ensuring that the protocol is conducted as approved by the 
FHCRC Scientific Review Committee and Institutional Review Board. The PI will ensure that the monitoring plan is 
followed, that all data required for oversight of monitoring are accurately reported to the FHCRC/UW Cancer 
Consortium Data and Safety Monitoring Committee (DSMC), that all adverse events are reported according to the 
protocol guidelines, and that any adverse reactions reflecting patient safety concerns are appropriately reported. 
The PI or designee will personally review with the Research Nurse the clinical course of all the enrolled patients 
weekly. A delegation log of authority will be kept to delineate the role of co-investigators (Appendix K). 
Under the provisions of the Institutional Data Safety and Monitoring Plan, the Cancer Consortium Clinical Research 
Support Office provides monitoring for Good Clinical Practice and compliance by qualified monitors unaffiliated with 
the conduct of the study. Monitoring visits are conducted in accordance with the Cancer Consortium Data and 
Safety Monitoring Plan. 
This protocol will also be monitored by a dedicated DSMB on a semi-annual basis. Enrollment, response and 
toxicity data will be reviewed. The DSMB has the authority to terminate the study, hold enrollment, or suggest 
modifications to the protocol as indicated. 
An annual review of the progress of the study with respect to the monitoring plan will be performed by the DSMC. 
The DSMC will review the number of subjects and unanticipated problems. The DSMC will also review DSMB 
reports regarding accrual, stopping rules, protocol adherence to the data and safety monitoring plan, as well as 
DSMB recommendations. If the DSMC finds a study to be continuing accrual in violation of the study design or the 
recommendation of the DSMB, the DSMC has the authority to suspend trial accrual. 
11.0 STUDY AGENT INFORMATION 
11.1 Background Investigational drug: Deferasirox 
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with 
high affinity in a 2:1 ratio. Two molecules of deferasirox form a complete complex with Fe3+. 
The high potency of deferasirox in mobilizing tissue iron and promoting iron excretion was demonstrated both in 
vitro and in vivo model systems. Deferasirox is eliminated from the body by hepatic glucuronidation and biliary 
excretion. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these 
metals. 
Deferasirox was first approved for the treatment of chronic iron overload due to blood transfusions (transfusional 
hemosiderosis) in adults and pediatric patients aged 2 years and older in the United States in November 2005 and 
is currently approved for this indication in more than 100 countries, including the European Union, Switzerland and 
Japan. Deferasirox has also been approved in more than 60 countries for the treatment of chronic iron overload in 
patients with non-transfusion dependent thalassemia aged 10 years and older. 
11.2 Deferasirox Preparation and Administration 
Deferasirox is for oral use and will be administered per manufacturers labeling for iron chelation.. 
12.0 ASSESSMENT OF EFFICACY AND TOXICITY 
12.1 Efficacy Parameters 
The primary endpoint is the proportion of patients that achieve erythroid hematologic improvement as defined by 
the modified IWG response criteria(39) at 6 months. Please see Appendix G for a table defining the response 
criteria for this study. 
12.2 Method and Timing 
All patients will be screened for eligibility following consent. Screening must be completed within 30 days of start 
of therapy. If the time period between screening assessments and start of therapy is greater than 30 days then 
screening tests must be repeated. The most recent screening labs prior to start of therapy will be considered the 
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baseline assessment upon which response by the modified IWG criteria will be based. Screening assessments will 
consist of CBC with differential, ferritin, hepatic and renal function tests and a bone marrow aspirate or biopsy. 
Women of child bearing potential must have a urine or serum pregnancy test performed within 7 days of start of 
deferasirox. 
Follow up tests will consist of monthly CBC with differential, monthly ferritin levels, and monthly renal and hepatic 
function tests while the patient remains enrolled in the trial. Bone marrow aspiration or biopsy will be repeated at 
3 months and 6 months following the start of deferasirox, and as clinically indicated. If at any point a patient is 
suspected to have disease progression, a bone marrow biopsy or aspirate may be obtained to document this 
progression. Physical exams and detailed history will be obtained on a monthly basis to screen for potential 
toxicities. The primary endpoint of hematologic improvement in the erythroid lineage will be assessed at 6 
months following start of deferasirox. The secondary endpoints of hematologic improvement in granulocytes and 
platelets will also be assessed at 6 months. At the end of 6 months patients who do not respond will be offered 
the option of alternative treatment options including enrollment into clinical trials if possible. 
12.3 Other Parameters 
The secondary endpoints change in RBC transfusion requirements, change in serum ferritin, and safety and 
tolerability will be assessed in a continuous fashion during the entire duration of the study. Patients will remain on 
study for a maximum of one year. Patients will be assessed for AE and SAEs while they remain enrolled into the 
study. Patients will have an end of study visit day 30 following completion or withdrawal from the study. 
13.0 DATA MANAGEMENT/CONFIDENTIALITY 
Study data will be recorded in a password-protected research database. Case report forms are generated from the 
database for review by the PI and study monitors. Clinical Statistics maintains a subject database at FHCRC to 
allow storage and retrieval of subject data collected from a wide variety of sources. The investigator will ensure that 
data collected conform to all established guidelines for coding, collection, key entry and verification. Each subject 
is assigned a unique patient number to assure subject confidentiality. Subjects will not be referred to by this number, 
by name, or by any other individual identifier in any publication or external presentation. The licensed medical 
records department, affiliated with the institution where the subject receives medical care, maintains all original 
inpatient and outpatient chart documents. Subject research files are scanned and stored in a secure database 
(OWL). OWL records are maintained by the FHCRC data abstraction staff. Access is restricted to personnel 
authorized by the Division of Clinical Research. 
-17- 
 
IRB Approved 
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9422 
14.0 ETHNIC and GENDER DISTRIBUTION: TARGETED ENROLLMENT 
Projected Target Accrual 
ETHNIC AND GENDER DISTRIBUTION CHART 
TARGETED / PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
9 
14 
23 
Ethnic Category Total of All Subjects* 
10 
15 
25 
Racial Categories 
American Indian / Alaska Native 
0 
0 
0 
Asian 
1 
1 
2 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
0 
0 
0 
White 
9 
14 
23 
Racial Categories: Total of All Subjects* 
10 
15 
25 
*The "Ethnic Category Total of All Subjects" must be equal to the "Racial Categories Total of All Subjects 
The projected accrual is based on demographic trends of the referral population and not on any perceived 
advantage or disadvantage of the intervention based on race, gender or ethnicity. 
15.0 STATISTICAL CONSIDERATIONS 
We estimate the rate of hematologic response to iron chelation with deferasirox to be 0.25 based on previously 
published studies in patients with MDS and iron overload. The null hypothesis that the true response rate is 0.05 
will be tested against a one-sided alternative. The accrual goal is for a total of 25 patients. The null hypothesis will 
be rejected if 4 or more responses are observed in 25 patients. This design yields a type I error rate of 0.0336 and 
power of 0.9008 when the true response rate is 0.25. Descriptive statistics will be performed and the planned 
number of patients is estimated based on the patients we have that would meet eligibility criteria. 
16.0 TERMINATION OF THE STUDY 
The PI may terminte the study at any time. The IRB and FDA also have the authority to terminate the study should 
it be deemed necessary. There is no planned interim analysis of this study and there are no early stopping rules in 
place for excessive toxicity. The study will be monitored by a designated DSMB which will meet every 6 months to 
review the protocol accrual and results including toxicity. The DSMB has the independent authority to terminate 
the study at their discretion. This information will be included in the consent form. 
-18- 
IRB Approved 
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9422 
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decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte 
colony-stimulating factor: significant effects on quality of life. Br J Haematol 2003 Mar;120(6):1037-46. 
(12) Haase D, Germing U, Schanz J, PfeilstOcker M, NOsslinger T, Hildebrandt B, et al. New insights into the 
prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 
2124 patients. Blood 2007 Dec 15;110(13):4385-95. 
(13) Komrokji RS, Lancet JE, Swern AS, Chen N, Paleveda J, Lush R, et at Combined treatment with 
lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood 2012 Oct 
25;120(17):3419-24. 
(14) Lyons RM, Cosgriff TM, Modi SS, Gersh RH, Hainsworth JD, Cohn AL, et al. Hematologic response to 
three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes. J Clin Oncol 
2009 Apr 10;27(11):1850-6. 
(15) Garcia-Manero G, Jabbour E, Borthakur G, Fader! S, Estrov Z, Yang H, et al. Randomized open-label 
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(16) Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. 
Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the 
cancer and leukemia group B. J Clin Oncol 2002 May 15;20(10).2429-40. 
(17) Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, FineIli C, Giagounidis A, et al. Efficacy of azacitidine 
compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009 Mar;10(3).223-32. 
(18) Labbert M, Suciu S, Baila L, Rater BH, Platzbecker U, Giagounidis A, et al. Low-dose decitabine versus 
best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) 
ineligible for intensive chemotherapy: final results of the randomized phase III study of the European 
Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study 
Group. J Clin Oncol 2011 May 20;29(15):1987-96. 
(19) Shenoy N, Vallumsetla N, Rachmilewitz E, Verma A, Ginzburg Y. Impact of iron overload and potential 
benefit from iron chelation in low-risk myelodysplastic syndrome (Review). Blood 2014 Aug 7;124(6):873-
81. 
(20) Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, et al. Prognostic factors and life 
expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical 
decision making. J Clin Oncol 2005 Oct 20;23(30):7594-603. 
(21) Garcia-Manero G, Shan J, Faderl S, Cortes J, Ravandi F, Borthakur G, et al. A prognostic score for 
patients with lower risk myelodysplastic syndrome. Leukemia 2008 Mar;22(3):538-43. 
(22) Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP, et al. Prognostic impact of elevated 
pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 
2007 May 15;109(10):4586-8. 
(23) Platzbecker U, Bornhauser M, Germing U, Stumpf J, Scott BL, Kroger N, et al. Red blood cell transfusion 
dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de 
novo myelodysplastic syndrome (MDS). Biol Blood Marrow Transplant 2008;14(11):1217-25. 
(24) Alessandrino EP, Della Porta MG, Bacigalupo A, Malcovati L, Angelucci E, van Lint MT, et al. Prognostic 
impact of pre-transplantation transfusion history and secondary iron overload in patients with 
myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study. 
Haematologica 2010 Mar;95(3):476-84. 
(25) Armand P, Kim HT, Rhodes J, Sainvil MM, Cutler C, Ho VT, et al. Iron overload in patients with acute 
leukemia or MDS undergoing myeloablative stem cell transplantation. Biol Blood Marrow Transplant 2011 
Jun,17(6):852-60. 
(26) Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent 
prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J 
Clin Oncol 2007 Aug 10;25(23):3503-10. 
(27) Leitch HA, Leger CS, Goodman TA, Wong KK, Wong DHC, Ramadan KM, et al. Improved survival in 
patients with myelodysplastic syndrome receiving iron chelation therapy. Clinical Leukemia 2008 
Aug,2(3):205-11. 
(28) Leitch HA. Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using 
iron chelation therapy (Review). Leuk Res 2007 Dec;31 (Suppl. 3):S7-S9. 
(29) Neukirchen J, Fox F, Kundgen A, Nachtkamp K, Strupp C, Haas R, et al. Improved survival in MDS 
patients receiving iron chelation therapy - a matched pair analysis of 188 patients from the Dusseldorf 
MDS registry. Leuk Res 2012 Aug;36(8).1067-70. 
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(30) Rose C, Brechignac S, Vassilief D, Pascal L, Stamatoullas A, Guerci A, et al. Does iron chelation therapy 
improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GEM 
(Groupe Francophone des Myelodysplasies). Leuk Res 2010 Jul;34(7):864-70. 
(31) Lyons RM, Marek BJ, Paley C, Esposito J, Garbo L, DiBella N, et al. Comparison of 24-month outcomes 
in chelated and non-chelated lower-risk patients with myelodysplastic syndromes in a prospective 
registry. Leuk Res 2014 Feb;38(2):149-54. 
(32) Gattermann N, FineIli C, Porta MD, Fenaux P, Ganser A, Guerci-Bresler A, et al. Deferasirox in iron-
overloaded patients with transfusion-dependent myelodysplastic syndromes: Results from the large 1-
year EPIC study. Leuk Res 2010 Sep;34(9):1143-50. 
(33) Gattermann N, FineIli C, Della Porta M, Fenaux P, Stadler M, Guerci-Bresler A, et al. Hematologic 
responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. 
Haematologica 2012 Sep;97(9):1364-71. 
(34) List AF, Baer MR, Steensma DP, Raza A, Esposito J, Martinez-Lopez N, et al. Deferasirox reduces serum 
ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J 
Clin Oncol 2012 Jun 10;30(17):2134-9. 
(35) Improta S, Villa MR, Volpe A, Lombardi A, Stiuso P, Cantore N, et al. Transfusion-dependent low-risk 
myelodysplastic patients receiving deferasirox: Long-term follow-up. Oncology Letters 2013 
Dec;6(6):1774-8. 
(36) Maurillo L, Breccia M, Buccisano F, Voso MT, Niscola P, Trape G, et al. Deferasirox chelation therapy in 
patients with transfusion-dependent MDS: a 'real-world' report from two regional Italian registries: Gruppo 
Romano Mielodisplasie and Registro Basilicata. Eur J Haematol 2015 Mar 12;[Epub ahead of print; doi: 
10.1111/ejh.12476]. 
(37) Jabbour E, Garcia-Manero G, Taher A, Kantarjian HM. Managing iron overload in patients with 
myelodysplastic syndromes with oral deferasirox therapy (Review). Oncologist 2009 May;14(5):489-96. 
(38) Gattermann N. Guidelines on iron chelation therapy in patients with myelodysplastic syndromes and 
transfusional iron overload (Review). Leuk Res 2007 Dec;31 Suppl 3:S10-S15. 
(39) Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans P, Nimer SD, et al. Clinical 
applications and proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006 Jul 15;108(2):419-25. 
(40) Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the 
World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and 
important changes. Blood 2009 Jul 30;114(5):937-51. 
(41) Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982 Dec;5(6):649-55. 
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Unbalanced abnormalities  
Balanced abnormalities 
—7 or del(7q) 
—5 or del(5q) 
i(17q) or t(17p) 
—13 or del(13q) 
del(11q) 
del(12p) or t(12p) 
del(9q) 
idic(X)(q13) 
t(11;16)(q23;p13.3) 
t(3;21)(q26.2;q22.1) 
t(1;3)(p36.3;q21.1) 
t(2;11)(p21;q23) 
inv(3)(q21q26.2) 
t(6;9)(p23;q34) 
Complex karyotype (3 or more chromosomal abnormalities) involving one or 
more of the above abnormalities. 
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APPENDIX A: World Health Organization (WHO) Classification of Myelodysplastic Syndromesoo 
Disease  
Blood findings  
BM findings 
Refractory cytopenia with unilineage dysplasia  Unicytopenia or bicytopenia*  
Unilineage dysplasia: w 10% of the cells in one myeloid 
(RCUD): (refractory anemia [RA]; refractory  No or rare blasts ( < 1%)t  
lineage 
neutropenia [RN]; refractory thrombocytopenia  
<5% blasts 
[RT])  
< 15% of erythroid precursors are ring sideroblasts 
Refractory anemia with ring sideroblasts (RARS) 
Refractory cytopenia with multilineage dysplasia 
(RCMO) 
Anemia  
w 15% of erythroid precursors are ring sideroblasts 
No blasts  
Erythroid dysplasia only 
<5% blasts 
Cytopenta(s)  
Dysplasia in  10% of the cells in a• 2 myeloid lineages 
No or rare blasts (< 1%)t  
(neutrophil and/or erythroid precursors and/or 
No Auer rods  
megakaryocytes) 
< 1 x 109/ monocytes  
< 5% blasts in marrow 
No Auer rods 
15% ring sideroblasts 
Refractory anemia with excess blasts-1 (RAEB-1)  Cytopenia(s)  
Unilineage or multilineage dysplasia 
<5% blastst  
5%-9% blastst 
No Auer rods  
No Auer rods 
< 1 x 109/ monocytes 
Refractory anemia with excess blasts-2 (RAEB-2)  Cytopenia(s)  
Unilineage or multilineage dysplasia 
5%-19% blastst  
10%-19% blastst 
Auer rods -24  
Auer rods ±$ 
< 1 x 109/ monocytes 
Myelodysplastic syndrome--unclassified  
Cytopenias  
Unequivocal dysplasia in < 10% of cells in one or more myeloid 
(MDS-U)  
< 1% blastst  
lineages when accompanied by a cytogenetic abnormality 
considered as presumptive evidence for a diagnosis of 
MDS (see Table 6) 
<5% blasts 
MDS associated with isolated del(5q)  
Anemia  
Normal to increased megakaryocytes with hypolobated nuclei 
Usually normal or increased platelet count  < 5% blasts 
No or rare blasts (< 1%)  
Isolated del(5q) cytogenetic abnormality 
No Auer rods 
*Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U. 
tlf the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is RAEB-1. Cases of RCUD and RCMD with 
1% myeloblasts in the blood should be classified as MDS-U. 
$Cases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as RAEB-2. Although the finding of 5% to 19% blasts in the 
blood is, in itself, diagnostic of RAEB-2, cases of RAEB-2 may have < 5% blasts in the blood it they have Auer rods or 10% to 19% blasts in the marrow or both. Similarly, cases 
of RAEB-2 may have < 10% blasts in the marrow but may be diagnosed by the other 2 findings, Auer rod + and/or 5% to 19% blasts in the blood. 
Recurring Chromosomal Abnormalities Considered as Presumptive Evidence of MDS 
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APPENDIX B 
REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS-R) (8)  
IPSS-R Cvtoaenetic Risk Grou s 
Cytogenetic 
prognostic 
subgroups 
Cytogenetic abnormalities 
Very good 
-Y, del(11q) 
Good 
Normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate 
(Int) 
del(7q), +8, +19, i(17q), any other single or double 
independent clones 
Poor 
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 
abnormalities 
3 
Very poor 
Complex: >3 abnormalities 
IPSS-R Pro nostic Score Values 
Prognostic 
variable 
0 
0.5 
1 
1.5 
2 
3  . 
4 
Cytogenetics 
Very 
Good 
Good 
Int 
Poor 
Very 
Poor 
BM Blast % 
5 2 
>2 - <5% 
5-10% 
> 10% 
Hemoglobin 
.?. 10 
8 -<10 
<8 
Platelets 
100 
50 - <100 
<50 
ANC 
0.8 
<0.8 
/ 
IPSS-R Pro nostic Risk Cate ories/Scores 
RISK CATEGORY 
RISK SCORE 
Very Low 
1.5 
Low 
>1.5 - 3 
Intermediate 
>3 - 4.5 
High 
>4.5 - 6 
Very High 
>6 
IPSS-R: Pro nostic Risk Cateaorv Clinical Outcomes* 
Total ' Ve  Low 
Low 
Int 
Hi.h 
Ve  Hi.h 
Pts (h)) 
7012 
1332(19) 
2665(38) 
1402(20) 
912(13) 
701(10) 
Survival* 
8.8 
5.3 
3.0 
1.6 
0.8 
AML 25%^ I  I  NR  1  10.8  I  3.2  I  1.4  I  0.7 
*Medians, years ^Median time to 25% AML evolution 
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9422 
APPENDIX C: Eastern Cooperative Oncology Group Performance Statue')  
ECOG PERFORMANCE STATUS 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more 
than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
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9422 
APPENDIX D 
Clinical Research Division 
Research Subject Registration Fax Coversheet 
Date: 
TO:  MDS Protocol 9422 Research Coordinator 
FAX:  (206) 667-2284 
RE:  RESEARCH SUBJECT REGISTRATION FORM 
FROM: 
FAX: 
PHONE: 
THE INFORMATION CONTAINED IN THIS TRANSMISSION IS INTENDED ONLY FOR THE ADDRESSEE OR THE ADDRESSEE'S AUTHORIZED 
AGENT THE FAX CONTAINS INFORMATION THAT MAY BE PRIVILEGED, CONFIDENTIAL AND EXEMPT FROM DISCLOSURE. IF THE 
READER OF THE MESSAGE IS NOT 771E INTENDED RECIPIENT OR RECIPIENT'S AUTHORIZED AGENT THEN YOU ARE NOTIFIED THAT ANY 
DISSEMINATION, DISTRIBUTION OR COPYING OF THIS INFORMATION IS PROHIBITED. 
IF YOU HAVE RECEIVED 771IS INFORMATION IN ERROR, PLEASE NOTIFY THE SENDER BY TELEPHONE, AND RETURN THE ORIGINAL AND 
ANY COPIES OF 711E MESSAGE BY MAIL TO THE SENDER AT FRED HUTCHINSON CANCER RESEARCH CENTER, 1100 FAIRVIEW AVE N. LF-
210, SEATTLE, WA 98109 
41 i 
FRED HUTCH 
*0 CURES START HERE" 
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foam FRED HUTCH 
.41.10 
CURES START HERE' 
Clinical Research Division 
Research Subject Registration Form 
16.1 Protocol Number: 9422 
Research Subject Name:  
 
Date of Birth: 
Month Day Year 
Ethnicity: (Choose one) 0 Hispanic or Latino (A person of Cuban, Mexican, Puerto Rican, South or Central American, or 
other Spanish culture or origin, regardless of race. Term "Spanish Origin" can also be used in addition to 
"Hispanic" or "Latino" 
0 Not Hispanic or Latino 
O Refused to Report 
Race: (check all that apply) 0 American Indian/Alaska Native (A person having origins in any of the original peoples of 
North, Central, or South America, and who maintains tribal affiliations or community attachment) 
LI Asian (A person having origins in any of the original peoples of the Far East, Southeast, Asia, or the 
Indian subcontinent including, for example, Cambodia, China, India Japan, Korea, Malaysia, Pakistan, the 
Philippine Islands, Thailand and Vietnam) 
O Native Hawaiian/Pacific Islander (A person having origins in any of the original peoples of 
Hawaii, Guam, Samoa or other Pacific Islands) 
0 Black/African American (A person having origins in any of the black racial groups of Africa. 
O White (A person having origins in any of the original peoples of Europe, the Middle East or North 
Africa) 
LI Unknown 
O 
Refused to Report 
Gender:  
O Male 
O Female 
O Unknown or Refused to Report 
HIPAA Authorization: (check one) 
LI Protocol covered under general HIPAA authorization 
Z Protocol specific HIPAA authorization required for 
this protocol. (Attach and submit with this form) 
Name of person completing form (Please Print) 
Name  
Phone Number 
Date Submitted  
Time 
ATTACH SIGNED CONSENT AND SEND TO DATA MANAGEMENT WITHIN 10 HOURS OF CONSENTING. 
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9422 
Appendix E.: Protocol 9422 Eligibility Checklist 
A.  Inclusion Criteria: All answers must be yes for the patient to be eligible 
1.  Yes fl 
 No  L1  Patient signed IRB approved consent form. 
Date: 
IRB file number:  
 
Date of IRB approval:  
 
2. Yes LI  No  LI  Diagnosis of MDS by WHO criteria (Appendix A) 
3. 
Yes El No  IPSS-R of very low, low or intermediate risk (Appendix B). 
4. Yes 111 No  Baseline serum ferritin level 100 ng/mL 
5  Yes El No fl  ECOG PS 0-2 (Appendix C) 
6. Yes El No El  Age 
18 years 
7. Yes LI  No El  Hemoglobin 10.0 g/dL 
8. 
Yes LI  No  LI  Adequate organ function. Please check yes if patient meets ALL of the following criteria. 
Yes El No El  Hepatic: Bilirubin 1.5 times upper limits of normal (ULN), alanine 
transaminase (ALT), and aspartate transaminase (AST) 5 3.5 times ULN 
Yes El No El Renal: Serum creatinine 5 1.5 X ULN and estimated GFR > 40 mUmin 
9. 
Yes  No  Males and females with reproductive potential must agree to use medically approved 
contraceptive precautions during the study and for 3 months following the last dose of 
deferasirox 
10. Yes El No LI  Females with childbearing potential must have a negative urine pregnancy test 5 7 days 
before the first dose of deferasirox and must also not be breastfeeding 
11. Yes El No LI  Reliable and willing to make themselves available for the duration of the study and are 
willing to follow study procedures 
B. Exclusion criteria: Each of the following questions must be marked no for the patient to be eligible 
1. 
Yes El No El  If the patient is currently receiving ESA (for example, erythropoietin) with plans to continue 
during study: Less than 2 months duration of ESA therapy prior to start of study therapy and no dose 
escalation within 2 months of start of study therapy. 
2. 
Yes LI  No  LI  If the patient is being treated with GCSF and/or a TPO-mimetic (for example, Eltrombopag 
or Romiplostim) with plans to continue during the study: Less than 2 months duration of GCSF or the TP0-
mimetic treatment prior to start of study therapy; or GCSF and/or TPO-mimetic has been added to ESA 
therapy within 2 months of start of study therapy. 
3. 
Yes El No LI  If patient is being treated with Lenalidomide with plans to continue during the study: Stable 
dose for less than 3 months prior to start of study therapy. 
4. 
Yes LI  No El  If patient is being treated with HMA (for example, Azacitidine or Decitabine) with plans to 
continue during the study: Stable dose for less than 6 months prior to start of study therapy.. 
5. 
Yes El No El  Currently enrolled in, or discontinued within the last 14 days from a clinical trial involving 
an investigational product or non-approved use of a drug, or concurrently enrolled in any other type of 
medical research judged not to be scientifically or medically compatible with this study 
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9422 
6. 
Yes El No LI  Presence of 0% blast by morphologic examination of bone marrow aspirate or biopsy 
7. 
Yes LI  No  LI  Platelets 50,000 
8. Yes 11 No fl  Presence of microcytosis on screening CBC (MCV < 81 fL) 
9. 
Yes LI  No El 	
Active GI ulceration or hemorrhage 
10. Yes  No El 	
Have serious preexisting medical conditions that, in the opinion of the PI or designee would 
preclude participation in the study (for example a GI disorder causing clinically significant symptoms such 
as nausea, vomiting, and diarrhea, or malabsorption syndrome) 
11. Yes El No  Known hypersensitivity to deferasirox 
12. Yes LI  Non  History of non-transfusional.hemosiderosis. 
13. Yes 111 No El  Prior hematopoietic stem cell transplant for the diagnosis of MDS 
14. Yes El No El 	
A second primary malignancy that in the judgment of the PI or designee may affect the 
interpretation of results 
15. Yes  No  Have an active fungal, bacterial, and/or known viral infection including human 
immunodeficiency virus (HIV) or viral (A, B, or C) hepatitis 
16. Yes El No El  Currently using aluminum-containing antacid products 
17. Yes El No LI  History of clinically significant auditory or ocular toxicity to ICT 
Signature of person completing this form:  
 Date:  
 
Signature of PI or Designee 
Date: 
-28- 
 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019


9422 
APPENDIX F 
9422 Study Calendar 
Procedure 
Screening 
Phase 
Treatment Phase 
Follow-up phase 
Screening 
within 30 
days 
Cycle 1  Cycle 2-6  Cycle 7-12 
Day 1  Day 1  Day 1 
At End of 
6 cycles 
Primary 
Endpoint 
At End of 1 
year 
30 days 
after last 
dose 
Medical History 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Transfusion History 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test* 
X 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine, estimated GFRA 
X 
X (every 2 
weeks) 
X 
X 
X 
X 
X 
Urine protein/creatinine ratio (spot-
check) 
X 
X 
X 
X 
Serum Ferritin 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow Aspiration or Biopsy 
X** 
X" (at 3 and 6 
months) 
X 
Hematologic Improvement 
according to modified IWG criteria 
X 
X 
X 
X 
X 
Hepatotrophic Virology 
X 
Serum transaminases, bilirubin, 
alkaline phosphatase 
X 
X (every 2 
weeks) 
X 
X 
X 
X 
X 
Auditory and Ophthalmic Testing 
X 
X 
*Pregnancy test only in women of child baring potential may consist of urine or serum pregnancy test and must be completed within 7 days of day 1 
^Estimated creatinine clearance with the MDRD formula; 
Hep B Surface antibody, Hep B surface antigen, Hep C antibody, and HCV PCR 
** Research samples: use preservative-free heparin in the syringe and place in sterile, preservative-free red-top tube. Send to hematopathology lab at SCCA 
-29- 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019


9422 
APPENDIX G 
Modified IWG Response Criteria(39) 
Modified IWG Response Criteria for Hematologic Improvement 
Hematologic Improvement*  
Response criteria (responses must last at least 8 wk)t 
Erythroid response (pretreatment, < 11 g/dL) 
Platelet response (pretreatment, < 100 x 109/L) 
Neutrophil response (pretreatment. < 1.0 x 109/L) 
Progression or relapse after Hlt 
Hgb increase by 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared 
with the pretreatment transfusion number in the previous 8 wk. Only RBC transfusions given for a Hgb of s 9.0 g/dL 
pretreatment will count in the RBC transfusion response evaluationt 
Absolute increase of a• 30 x 109/L for patients starting with > 20 x 109/L platelets 
Increase from <20 x 109/L to > 20 x 109/L and by at least 100%f 
At least 100% increase and an absolute increase > 0.5 x 109/Lt 
At least 1 of the following: 
At least 50% decrement from maximum response levels in granulocytes or platelets 
Reduction in Hgb by a- 1.5 g/dL 
Transfusion dependence 
Deletions to the IWG response criteria are not shown. 
To convert hemoglobin levels from grams per deciliter to grams per liter, multiply grams per deciliter by 10. 
Hgb indicates hemoglobin; RBC: red blood cell; HI: hematologic improvement. 
'Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) 1 week apart (modification). 
tModification to IWG response criteria. 
tin the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), gastrointestinal bleeding, hemolysis, and so forth. It is 
recommended that the 2 kinds of erythroid and platelet responses be reported overall as well as by the individual response pattern. 
Modified IWG Response Criteria for altering natural history of MDS 
Category 
Response criteria (responses must last at least 4 wk) 
Complete remission (CR) 
Bone marrow: 5 5% myeloblasts with normal maturation of all 
cell lines 
Partial remission (PR) 
All CR criteria if abnormal before treatment except: 
- Bone marrow blasts decreased by 5. 50% over pretreatment 
but still > 5% 
- Cellularit  and morsholoiy not relevant 
Stable disease (SD) 
Failure to achieve at least PR, but no evidence of progression 
Disease Progression (DP) 
For patients with: 
- Less than 5% blasts:  50% increase in blasts to > 5% blasts 
- 5%-10% blasts:  50% increase to > 10% blasts 
- 10%-20% blasts: ? 50% increase to > 20% blasts 
- 20%-30% blasts:  50% increase to > 30% blasts 
Relapse after CR or PR 
At least 1 of the following: 
- Return to pretreatment bone marrow blast percentage 
- Decrement of ?. 50% from maximum remission/response 
levels in granulocytes or platelets 
- Reduction in Hgb concentration by .1.5 g/dL or transfusion 
dependence 
-30- 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019


Seattle ' 
Cancer Care 
Alliance 
Fred Hutch •Seattle Chadren's • UW Mediclee 
APPENDIX H 
9422 
/IP 
wit484  FRED HUTCH 
uebiep 
CURES START HERE 
Notification of Withdrawal From a Research Study 
This form must be completed and routed when a study participant notifies you of his/her withdrawal 
from a Fred Hutchinson Cancer Research Center (FHCRC) Clinical Research Division Protocol. 
Research Subject Name 
9422 
Protocol Number or Title 
Hospital No. (U-number)  UPN/Study No. 
Bart Scott, MD 
Principal Investigator  Current Attending 
Person(s) 
Responsibility 
Initial person who receives 
the participant's notification 
of withdrawal (e.g., Team 
Nurse, Study Nurse or 
Study Coordinator) 
Cl 
CI 
0 
Complete Notification of Withdrawal From a Research Study form. 
If appropriate, notify other members of participant's care team. 
Fax the completed form to FHCRC (206-667-2284). 
Attending Physician 
0 
0 
0 
Acknowledge the notice from the participant or responsible adult on 
behalf of a pediatric participant to withdraw from a research study if 
appropriate. 
Meet with participant/family member and discuss reasons for withdrawal 
and the risks and benefits of withdrawing from the study if appropriate. 
If a meeting occurs with the participant/family, document discussion wid 
participant/family in the participant's medical record. 
Primary Provider 
0 Review medical orders and discontinue any upcoming research study-
related orders. 
I ensure that the above providers and staff have been notified of their responsibilities. 
Signature 
Printed Name 
Date 
 For FHCRC Data Management Use   
Sent to PI on 	
(date) 	Sent to Study Coordinator on 	
(date) 
Sent to SCCA HIM on 	
(date) 
-31- 
 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019


9422 
APPENDIX I 
Fred Hutchinson Cancer Research Center 
Clinical Research Division 
Institutional Review Office 
SERIOUS ADVERSE EVENT REPORT 
FHCRC Unique Patient Number: 
El FHCRC/SCCA ['Other 
Gender [Wale ID Female 
FHCRC Principal Investigator 
Date of Report: 
FHCRC Protocol Number:  9422 
FHCRC IR File Number:  9422 
Age: 
Bart Scott,MD 
Phone number: 206-667-1990 
Mail stop: D1-100  
['Initial Report  Follow-up Report # 
Date Serious Adverse Event Started: 
Date Ended: 
Adverse Event: 
Date Study Staff became aware of event: 
12 Other: 
or ['Ongoing (if ongoing- must submit follow-up report) 
Outcomes attributed to adverse event: (Check all that apply) 
CI Death  /  / 
 12 Disability 
12 Life-threatening  
12 Congenital Anomaly 
CI Hospitalization (initial or prolonged)  CI Required intervention to prevent permanent impairment/damage 
Describe the Serious Adverse Event including a summary of all relevant clinical information. 
(Or attach a Med Watch Form or other SAE reporting form if one has been completed.) 
I2 Continued next page 
[I Follow-up Report Required  ICI Final Report (PI must sign final report) 
Completed by:  
Date: 
The PI has determined that the consent form must be revised: ['Yes': No 
Signature of PI or Designee:  
Date: 
-32- 
 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019


9422 
APPENDIX J 
Protocol 9422 ADVERSE EVENTS 
Patient Name: 
CTC Category 
Adverse Event 
Start Date End Date 
Ongoing 
YIN 
Grade 
3,4, 
Death 
SAE 
YIN 
-33- 
 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019


9422 
FHCRC/UW Study Personnel Signature and Delegation of Authority Log 
Sponsor: 
FHCRC / UW 
Principal Investigator: 
Bart L. Scott, MD 
Protocol Number/Title: 
9422 / A Phase II Study of Deferasirox in Patients with Myelodysblastic Syndromes who are Anemic with Iron 
Overload  
. 
IND #: 
N/A 
Name (print) 
Title and 
Position (e.g. 
Investigator, 
Study 
Coordinator) 
Initials 
Signature 
Responsibilities 
See Codes 
below *List all 
that apply 
Start Date of 
Study 
Responsibility 
End Date of 
Study 
Responsibility 
Pl's 
Initials 
and Date 
** 
*Responsibility Codes:  01=Administer informed consent  
05=Data base entries & corrections  09= 
02= Determine eligibility  
06=Study drug accountability  10= 
03=Assess adverse events  
07=SAE reporting  
11= 
04=CRF entries & corrections  
08=IRB submission, renewals,  12= 
modifications 
**Investigator's initials indicate review and approval of responsibilities for the person listed on that line 
-34- 
IRB Approved 
Document Release Date: 10/02/2019
Printed on 10/3/2019