IMatinib for PAin in Chronic Treatment of Sickle Cell Anemia (IMPACT SCA): A Pilot Study of Imatinib in Patients With Sickle Cell Anemia and Recurrent Vaso-occlusive Pain
Phase: PHASE1
Conditions: Sickle Cell Disease
Sponsor: Indiana University

 
COVER PAGE 
 
Title: IMatinib for PAin in Chronic Treatment of Sickle Cell Anemia (IMPACT SCA): 
A Pilot Study of Imatinib in Patients with Sickle Cell Anemia and Recurrent Vaso-occlusive Pain 
 
NCT03997903 
 
June 25, 2024 v10.4 

version 10.4 1 
 
IMatinib for PAin in Chronic Treatment of Sickle Cell Anemia (IMPACT SCA): 
A Pilot Study of Imatinib in Patients with Sickle Cell Anemia and Recurrent Vaso-occlusive Pain 
 
 
Principal Investigator Indiana University School of Medicine: 
Seethal A. Jacob, MD, MS 
Assistant Professor of Pediatrics 
Riley Hospital for Children, Rm 4340 
705 Riley Hospital Drive 
Indianapolis, Indiana 46202 
Email: seejacob@iu.edu 
Phone: 317-944-8785 
Fax: 
317-948-0616 
 
Principal Investigator Cincinnati Children’s Hospital: 
Charles T. Quinn, MD, MS 
Professor of Pediatrics 
Cincinnati Children’s Hospital Medical Center 
Division of Hematology 
3333 Burnet Ave 
Cincinnati, OH 45229 
Email: charles.quinn@cchmc.org 
Phone: 513-803-3086 
Fax: 
513-636-3549 
 
Sub-investigators Indiana University School of Medicine: 
Meghan Drayton-Jackson, DO 
Assistant Professor of Pediatrics 
Riley Hospital for Children 
 
Jennifer Kaericher, NP 
Riley Hospital for Children 
Sub-investigators Cincinnati Children’s Hospital: 
Theodosia Kalfa, MD, PhD 
Associate Professor of Pediatrics 
Cincinnati Children’s Hospital 
Sub-investigators Purdue University: 
Philip Low, PhD 
Professor of Chemistry and Director of the Purdue Center for Drug Discovery 
 
Faculty Biostatistician: 
Susan M. Perkins, PhD 
Indiana University, Indianapolis, IN 
 
Medical and Data Coordinating Center: 
Indiana University, Indianapolis, IN 
 
Funding Sponsor: 
Purdue University 
CTSI University of Cincinnati 

version 10.4 2 
 
ABSTRACT 
IMatinib for PAin in Chronic Treatment of Sickle Cell Anemia (IMPACT SCA) is a prospective, open-label Phase I/II 
study of imatinib to prevent pain in individuals with Sickle Cell Anemia (SCA). SCA is the most common severe 
inherited hematologic disorder worldwide with only one disease-modifying medication (hydroxyurea) licensed so far for 
its management. Although sickle hemoglobin polymerization is the initial trigger for the sickle cell shape deformation 
leading to vaso-occlusive pain episodes, we have shown that increased production of reactive oxygen species (ROS) in 
sickle red blood cells (RBCs) and inhibition by ROS of both major RBC tyrosine phosphatases, leads to phosphorylation 
of the major membrane-spanning protein, band 3. This phosphorylation results in dissociation of the RBC cytoskeleton 
from the lipid bilayer, release of free hemoglobin and emergence of circulating microparticles that contribute 
significantly to activation of the vascular endothelium and stimulation of the blood coagulation cascade, promoting the 
vasoocclusive events. Imatinib, a well-studied tyrosine kinase inhibitor, has been shown in our preclinical studies to inhibit 
band 3 phosphorylation in sickle RBCs and prevent the consequent microparticle release and hemolysis of these cells in 
vitro. We propose an early phase clinical trial of daily imatinib treatment on patients with SCA and recurrent vaso-
occlusive crises to evaluate both the biochemical and clinical effects, with the goal to re-purpose this well-tolerated 
targeted medication for preventive management in SCA. 

version 10.4 3 
 
STUDY FLOW DIAGRAM 
 
 
Study flow schema with an outline of patient visits and corresponding evaluations. 
Begin imatinib within 2 weeks of baseline visit date 

version 10.4 4 
 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................................... 1 
ABSTRACT AND STUDY FLOW DIAGRAM ......................................................................................... 2 - 3 
TABLE OF CONTENTS ............................................................................................................................. 4 
LIST OF ABBREVIATIONS ...................................................................................................................... 5 
1.0 
INTRODUCTION/SIGNIFICANCE ............................................................................................ 6 
2.0 
RATIONALE FOR DEVELOPMENT......................................................................................... 7 
3.0 
BACKGROUND .......................................................................................................................... 7 
4.0 
STUDY OBJECTIVES ................................................................................................................. 10 
5.0 
INVESTIGATIONAL PLAN ....................................................................................................... 11 
6.0 
TREATMENT PLAN ................................................................................................................... 13 
7.0 
GRADING OF ADVERSE EVENTS ......................................................................................... 15 
8.0 
DEFINITION OF DOSE-LIMITING TOXICITY ....................................................................... 17 
9.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS ............................................................... 18 
10.0 
SUPPORTIVE CARE AND CONCOMITTANT THERAPY ..................................................... 18 
11.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED ...................................... 20 
12.0 
AGENT INFORMATION ............................................................................................................ 23 
13.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY ................................................. 24 
14.0 
OFF-STUDY CRITERIA .............................................................................................................24 
15.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 24 
16.0 
INCLUSION OF CHILDREN, WOMEN, AND MINORITIES ................................................. 25 
17.0 
CORRELATIVE STUDIES ........................................................................................................ 25 
18.0 
DATA MANAGEMENT .............................................................................................................. 25 
19.0 
PROCEDURES AND INSTRUCTIONS ..................................................................................... 26 
REFERENCES ............................................................................................................................................. 28 
APPENDICES .............................................................................................................................................. 30 

version 10.4 5 
 
Abbreviations 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
CHR 
CML 
complete hematologic response 
Chronic Myelogenous Leukemia 
CRF 
case report/record form 
CS&E 
Clinical Safety and Epidemiology 
GIST 
gastrointestinal stromal tumor 
Hb 
HR 
hemoglobin 
hematologic response 
IEC 
Independent Ethics Committee 
IFN 
Interferon alpha 
IRB 
IDS 
IP 
Institutional Review Board 
Investigational Drug Services 
Investigational Product 
ITT 
intention-to-treat 
IULN 
Institutional Upper Limit of Normal 
NCI 
National Cancer Institute 
NIH 
National Institutes for Health 
od 
omnia die / once a day 
PDGF 
platelet-derived growth factor 
Ph + 
Philadelphia chromosome positive 
po 
per os / by mouth / orally 
PP 
per protocol 
PS 
performance status 
qd 
RBC 
RBCM 
quaque die / every day 
red blood cell(s) 
red blood cell membrane 
SAE 
serious adverse event 
SCF 
stem cell factor 
SCA 
SCD 
Sickle cell anemia 
Sickle cell disease 
SOP 
VOC 
Standard Operating Procedure 
Vaso-occlusive crisis 
WBC 
White Blood Cell Count 

version 10.4 6 
 
1.0 
INTRODUCTION 
 
Sickle cell anemia (SCA) is a severe and devastating, chronic hematological disorder that affects nearly 100,000 persons 
in the United States and millions more worldwide.1-3 Data from 2001-2005 reveals that annual healthcare costs related 
to sickle cell disease management in the U.S. exceeds $1.1 billion.4 While supportive care and disease-modifying 
therapies such as hydroxyurea have mitigated patient suffering and early death from sickle cell-related complications, 
many patients continue to suffer from anemia, recurrent vaso-occlusive painful episodes which lead to chronic organ 
damage, acute chest syndrome, and strokes.3 Although life expectancy for SCA patients in the western world has 
increased from 14 to approximately 50 years since 1973,2 the quality of life for survivors remains compromised by 
damage to their brain, kidneys, eyes, lungs and other organs.5-8 In some patients, the frequent requirement of opioids for 
pain episodes leads to opioid dependence, further limiting their quality of life.8,9 Pain caused by vaso-occlusion is the 
most frequent cause of hospitalization for patients with SCA and approximately 5.2% of patients with 3-10 painful events 
per year make up 33% of all hospitalizations.10 Pain rate also correlates with early death in sickle cell patients older than 
20 years of age.2 
The pathophysiology of vaso-occlusive crisis in sickle cell disease is complex and involves sickling of RBCs caused by 
polymerization of the deoxygenated Hemoglobin S (HbS), consequent red blood cell (RBC) rigidity, impaired 
microvascular blood flow, ischemia-reperfusion injury, vascular endothelial cell activation and increased blood cell- 
endothelium interactions.11-13 Consequence of frequent vaso-occlussive events over time is end-organ damage.2,14,15 
Previous research has provided solid evidence that an important contribution to vaso-occlusive events in SCA derives 
from RBC membrane instability that leads to intravascular hemolysis and release of membrane fragments or 
microparticles.16-21 Blebbing-off of plasma membrane fragments not only releases RBC membrane-derived 
microparticles that are known to be prothrombotic,19,21,22 but also reduces the cell’s surface-to-volume ratio,23,24 thereby 
concentrating HbS inside the cell and augmenting its propensity to 
polymerize. Concurrently, release of free hemoglobin from the 
fragmenting RBC activates the vascular endothelium to express 
adhesion receptors,25 thereby increasing retention of WBC and RBC 
in the microvasculature26-29 and further aggravating vaso- occlusive 
propensities.30,31 
 
Our studies have shown that increased reactive oxygen species 
(ROS) in sickle RBCs inhibit both of their major tyrosine 
phosphatases,32-35 leading to phosphorylation of the major 
membrane-spanning protein, band 3 (Figure 1).36-38 This results in 
dissociation of the RBC cytoskeleton from the lipid bilayer causing 
membrane fragmentation, microparticle release, and the escape of 
free hemoglobin into the bloodstream.38,39 This release of free 
hemoglobin 
and 
the 
circulating 
microparticles 
contribute 
prominently to activation of the vascular endothelium and 
stimulation of the blood coagulation cascade, respectively. 
Together, these two processes strongly promote the vaso-occlusive 
events that plague patients with sickle cell disease. 
 
 
 
 
 
 
 
 
 
Figure 1. Band 3 in RBC membrane is regulated by tyrosine 
phosphorylation by Syk kinase and de-phosphorylation by 
RBC tyrosine phosphatases. ROS, which are increased in 
SCD, inhibit these phosphatases. The phosphorylation of 
tyrosines 8, 21, and 359 in the cytoplasmic loop of band 3 
leads to displacement of the glycolytic enzyme complex, 
binding of the band 3 cytoplasmic loop to its SH2 domain and 
rupture of the band 3-ankyrin bridge to the RBC cytoskeleton. 

version 10.4 7 
 
Imatinib, a well-studied tyrosine kinase inhibitor, has been shown in our preclinical studies to suppress band 3 
phosphorylation in sickle RBCs and to prevent the consequent fragmentation, microparticle release, and hemolysis of 
these cells in vitro. Additionally, in two published case-reports, patients with SCA, who incidentally developed chronic 
myelogenous leukemia (CML), experienced cessation of vaso-occlusive pain episodes upon initiation of treatment with 
imatinib for their CML, followed by recurrence of vaso-occlusive crises whenever imatinib therapy was inadvertently 
interrupted.40,41 Therefore, we hypothesize that imatinib, as an inhibitor of tyrosine phosphorylation of band 3, will 
ameliorate SCA symptoms by preventing RBC membrane destabilization and consequently intravascular 
hemolysis and microparticle release, which in turn would activate adhesion receptors on the endothelium and 
trigger the coagulation cascade, respectively. Since imatinib is approved for use in children and can be taken for years 
without serious adverse events, we hypothesize that it could constitute a well-tolerated treatment for SCA that will 
function by a novel mechanism to inhibit vaso-occlussive crisis, pain, and chronic organ damage. 
 
2.0 
RATIONALE FOR DEVELOPMENT 
 
Although preventive and supportive management, including prophylactic antibiotics to prevent serious infections from 
encapsulated organisms, opioids and non-steroidal anti-inflammatory medications to control painful episodes, blood 
transfusions to dilute out sickle RBCs, and hydroxyurea as a fetal Hgb inducer and disease-modifying therapy have 
mitigated patient suffering and extended life expectancy of patients with SCA, many patients still continue to suffer from 
anemia and recurrent vaso-occlusive painful episodes which lead to chronic organ damage and compromise quality of 
life.1-3 Bone marrow transplant,42,43 and in clinical trial settings gene therapy44-46 are curative treatments, available in US 
and Europe, but are not feasible for all patients and not free of undesirable toxicities. New experimental therapies in the 
pipeline include new fetal Hb inducers, nitric oxide generators, statins and drugs that elevate the affinity of hemoglobin 
for oxygen.47,48 Unfortunately, each of the well-established therapies (even hydroxyurea as monotherapy) may have 
limited efficacy or undesirable toxicities, while many of the experimental therapies, though promising in some cases, 
will likely require years before they can be routinely implemented in sub-Saharan Africa, for example, where 75% of 
the sickle cell patients reside. 
Clearly, the need for more, safe, easily administered, inexpensive and effective SCA therapeutic options is high, in order 
to improve morbidity and early mortality in the 14 million patients suffering of sickle cell disease across the world. In 
this protocol, we will explore whether imatinib can inhibit in vivo a tyrosine kinase-mediated mechanism that induces 
erythrocyte membrane destabilization, an important biological factor in the clinical manifestations of sickle cell disease. 
Results from this study will inform a future Phase II-B trial with imatinib to assess clinical outcomes in patients with 
sickle cell disease. 
 
3.0 
BACKGROUND 
 
3.1 
Vaso-Occlusion and Sickle Cell Disease 
 
Sickle cell disease is characterized by recurrent attacks of vaso-occlusive painful events that often manifests as severe 
pain, acute chest syndrome, or priapism. Approximately 5.2% of patients with 3-10 painful events per year make up 33% 
of all hospitalizations.10 Pain rate also correlates with early death in sickle cell patients older than 20 years of age.2 The 
pathophysiology of vaso-occlusion in sickle cell disease is complex, and involves not only the “sickling” of RBCs due 
to polymerization of deoxygenated HbS, but also increased cellular adhesiveness of sickle RBCs.26-28 Previous research 
has provided solid evidence that an important contribution to vaso-occlusive events in SCD derives from the RBC 
membrane instability that leads to intravascular hemolysis and release of membrane fragments or microparticles.16- 

version 10.4 8 
 
21,49,50 Blebbing off of plasma membrane fragments not only releases RBC membrane-derived microparticles that are 
known to be prothrombotic,18,21,22,31 but also reduces the cell’s surface-to-volume ratio, thereby concentrating HbS inside 
the cell and augmenting its propensity to polymerize. Concurrently, release of hemoglobin from the fragmenting RBC 
increases free heme in the circulation which activates the vascular endothelium to express adhesion receptors,15,25,30 
thereby increasing retention of WBC and RBC in the microvasculature26,27,29,51 and further aggravating vaso-occlusive 
propensities. 
The organ failure and extreme pain commonly associated with SCD derive to a substantial degree from the above 
obstruction of blood vessels and associated inflammation.1 In search for a safe and effective SCD therapy with a novel 
target mechanism, we have focused on finding a method to stabilize the RBC membrane against the vesiculation and 
intravascular hemolysis that have been shown to contribute to the development of vaso-occlusion and subsequent clinical 
manifestations of SCD.30,31,52 
3.2 
Preclinical Studies with Imatinib 
Our preclinical studies have implicated phosphorylation of band 3 in the RBC membrane as integral to the development 
of vaso-occlusive events in patients with SCA (Figure 1). Band 3 is phosphorylated by the tyrosine kinase Syk, which 
can be inhibited by imatinib. 
Some of the initial steps in the chain of molecular events leading to vascular obstruction and pain crisis in patients with 
sickle cell disease are the following: 
1) 
sickle erythrocytes have elevated levels of Reactive Oxygen Species (ROS) generation due to auto-oxidation of 
Hb S that denatures into hemichromes (partially denatured Hb complexes preceding Heinz body formation),53 as well as 
due to increased production of ROS by erythrocyte NADPH oxidase which is activated by inflammatory cytokines36 
2) 
ROS inhibit both of the RBC’s major tyrosine phosphatases which have active site cysteines that are highly 
sensitive to oxidants (Figure 1)32-35,54 
3) 
in the absence of functioning tyrosine phosphatases, the major membrane-spanning protein, band 3, becomes 
phosphorylated on tyrosines 8, 21, and 359 by Syk tyrosine kinase15,38,39 
4) 
this phosphorylation of band 3, which is absent in healthy HbA erythrocytes (Figure 2), causes dissociation of 
the RBC cytoskeleton from the lipid bilayer, leading to membrane weakening and fragmentation, leading to a storm of 
microparticle release (Figure 3) and free hemoglobin 
escape into the bloodstream38,39 
As noted above, this release of free hemoglobin and 
circulating microparticles contributes prominently to 
activation of the vascular endothelium and 
stimulation of the blood coagulation cascade, 
respectively. Together, these two processes strongly 
promote the vaso-occlusive events that plague 
patients with SCD. Based on these considerations, 
we hypothesized that a tyrosine kinase inhibitor that 
inhibits Syk and blocks tyrosine phosphorylation of 
band 3 on tyrosine 8, 21, and 359 will ameliorate the 
symptoms of SCD by preventing RBC membrane 
destabilization and the consequent intravascular 
Figure 2. Anti-phosphotyrosine immunoblot of band 3 protein in control 
and sickle red blood cells before and after treatment in vitro with 1 μM 
imatinib for 3 hours. C= Control cells; C+I= Control cells + Imatinib; S= 
sickle cells; S+I= Sickle cells + Imatinib. Data with samples from five 
different patients with Sickle Cell Disease. Note the strong tyrosine 
phosphorylation of band 3 in sickle cells and the paucity of 
phosphorylation in normal cells at baseline. 
hemolysis, microparticle release, and decrease in RBC surface-to-volume ratio that enhances RBC sickling and vaso- 
occlusion.23,24 
In search for a tyrosine kinase inhibitor that might suppress the tyrosine phosphorylation of band 3 in sickle cells, we 
screened Eli Lilly’s tyrosine kinase library (provided by Dr. Philip Hipskind of Eli Lilly) for suppressors of band 3 
tyrosine phosphorylation. Five kinase inhibitors were found to potently inhibit the aforementioned band 3 tyrosine 

version 10.4 9 
 
phosphorylation. Importantly, when the identities of the inhibitors were revealed to us at the end of the study, one 
inhibitor stood out from the rest because it was already approved by the FDA for use in children. This tyrosine kinase 
inhibitor was imatinib (Gleevec), an orally bioavailable inhibitor 
of a group of tyrosine kinases, including Bcr-Abl, PDGFR, and c- 
Kit, that is employed for treatment of chronic myelogenous 
leukemia (CML), gastrointestinal stromal tumors, clonal 
hypereosinophilic syndrome and D816V-negative mastocytosis. 
Most relevant to the proposed study, however, is the fact that even 
though imatinib must be taken by CML patients daily for the rest 
of the patient’s life (or until resistant mutations emerge), it has an 
excellent safety record with limited adverse events.55,56 Based on 
these considerations, imatinib was selected as a medication 
possible to be re-purposed for SCD, with the goal to inhibit band 
3 tyrosine phosphorylation, RBC membrane vesiculation, 
microparticle formation and hemolysis and interrupt the chain of 
molecular events aggravating vaso-occlusion. 
3.3 
Clinical Experience with Imatinib 
Two highly relevant sets of studies in which imatinib has been 
intentionally or unintentionally used to treat an erythrocyte- 
related disease should be mentioned here. 
3.3.1 
Imatinib to treat P.falciparum malaria 
First, imatinib has been used to treat P. falciparum malaria both 
in human whole blood cultures of the parasitemia in vitro and in 
malaria patients in Vietnam in vivo.57,58 Importantly, imatinib was 
selected for this application because the malaria parasite induces 
band 3 tyrosine phosphorylation shortly before its egress from the 
erythrocyte during its intra-erythrocyte life cycle.57,58 The parasite 
does this in order to weaken the RBC membrane to facilitate its 
escape from its host RBC (i.e. the parasite exploits 
Figure 3. Incubation of RBCs with ortho-vanadate (o-v, 
phosphatase inhibitor) for increasing time intervals 
induces membrane vesiculation (A) associated with band 
3 tyrosine phosphorylation (B). C. Glycophorin A (GPA)- 
positive microparticles, derived from RBC membrane, 
determined by flow cytometry in the plasma of patients 
with sickle cell disease versus normal control (HbA) 
volunteers. GPA is a sialoglycoprotein that spans the 
RBC membrane and is easily identified by flow cytometry. 
the same tyrosine kinase-induced RBC membrane destabilization seen in SCA). Both in in vitro studies and in the clinical 
application in vivo, imatinib was successful in blocking band 3 tyrosine phosphorylation and parasite egress, thereby 
terminating the parasitemia. Moreover, no drug related adverse events have been observed to date in malaria patients 
treated with imatinib. 
3.3.2 
Imatinib to treat SCA patients with CML 
The second relevant set of studies concerns the use of imatinib to treat CML in patients who coincidentally also suffered 
from SCA. Anticipating that someone with SCA must have at some time contracted CML, we scrutinized the literature 
for case reports of SCD patients who were treated with imatinib to control their CML. Two such case reports were found. 
Importantly, upon treatment with imatinib, none of the patients in either of the papers experienced any further symptoms 
of SCA. 40,41 40,41 In fact, in one published report, the investigator noted that if the patient missed several days of imatinib, 
vaso-occlusive crises recurred, and stopped “immediately when the patient took imatinib again”.41 The authors of one of 
the articles speculate that imatinib may somehow suppress inflammatory cells, but they offer no data to support this 
hypothesis. Based on our data, we hypothesize that imatinib treatment of those patients prevented SCA- associated vaso-
occlusive painful events via inhibition of Syk-induced RBC membrane destabilization. 
 
3.4 
Overview of Proposed Study 
 
In this protocol, we propose to evaluate the biochemical effects of imatinib on sickle RBCs. Patients will be 
administered imatinib mesylate orally following the guidelines previously established for use of imatinib in other 

version 10.4 10 
 
disorders. The biochemical effects of imatinib on sickle RBCs will be examined, including changes in their levels of 
band 3 tyrosine phosphorylation and the abundances of RBC-derived microparticles in their blood. In addition, the 
patients will be monitored for symptoms of SCD. As noted in Fig. 2, we expect band 3 tyrosine phosphorylation to 
decrease dramatically in patients treated with imatinib. We also anticipate a reduction in the numbers of RBC-derived 
microparticles in circulation (quantitated by assaying the number of glycophorin A positive microparticles in 
peripheral blood samples by flow cytometry; see Fig. 1). Most importantly, we expect to see a reduction in the 
frequency of vaso-occlusive crises, and possibly acute chest syndrome and utilization of opioids. The study duration is 
planned as 6 months in order to provide adequate time for potential change in the primary endpoints (e.g. percent 
irreversibly sickled cells). 
 
4.0 
STUDY OBJECTIVES 
 
4.1 
Primary Aims 
 
4.11 
To examine the biochemical effects of imatinib by: 
a. quantitation of band 3 phosphorylation and microparticle release from sickle RBCs 
b. functional RBC analysis 
 
As noted in Figure 2, we expect band 3 tyrosine phosphorylation to decrease dramatically in patients treated with 
imatinib. We also anticipate a reduction in the numbers of RBC-derived microparticles in circulation (quantitated by 
assaying the number of glycophorin A positive microparticles in peripheral blood samples by flow cytometry; see Figure 
3B). We will evaluate for improvement in the red cell cytoskeleton mechanics by ektacytometry (which should improve 
due to reduced loss of RBC membrane as a consequence of decreased band 3 phosphorylation), oxygenscan, and 
determination of percent irreversibly sickled cells.59,60 
 
4.2 
Secondary Aims 
 
4.21 
To assess the effect of imatinib on the frequency of vaso-occlusive pain events in patients with sickle 
cell disease 
4.22 
To assess the effect of imatinib on the amount of opioid use, frequency of acute chest syndrome, and 
number of hospitalizations 
4.23 
To assess the tolerability and toxicity of imatinib in patients with sickle cell disease 
 
The clinical outcome will be a secondary aim due to the relatively short duration of the study; we expect to see a reduction 
in the frequency of vaso-occlusive crises, utilization of opioids, and number of hospitalizations and possibly in the 
incidence of acute chest syndrome and other SCA-associated complications. 
 
4.3. Endpoints 
 
4.31 
Primary Endpoints: 
a. 
Biochemical Effects to RBCs (see Section 17) 
i. 
Band 3 Phosphorylation 
ii. 
Microparticle Release 
b. 
Functional RBC analysis (see Section 17) 
i. 
Percent Irreversibly Sickled Cells at Month 6 
ii. 
Ektacytometry 
iii. 
OxygenScan to evaluate for altered susceptibility to sickling 
 
4.32 
Secondary Endpoints: 
a. 
Clinical Outcomes 

version 10.4 11 
 
i. 
Vaso-occlusive Crisis (VOC) 
i. 
Defined as an acute episode of pain lasting greater than 24 hours, with no 
medically determined cause other than a vaso-occlusive event that resulted in 
treatment with oral or parenteral opiate agents and/or parenteral nonsteroidal anti- 
inflammatory agents. 
ii. To be documented in pain diary by patient/guardian and reviewed at each visit 
iii. Measured by pain scale (1-10) or Wong-Baker Faces scale based on age: 
ii. 
Acute Chest Syndrome 
i. 
Defined as respiratory distress (hypoxia, shortness of breath, chest pain, 
tachypnea) with evidence of an infiltrate on chest x-ray 
ii. Will be reviewed at each visit, as well as extracted from the EMR by each site 
iii. 
Opioid Use 
i. 
Defined as both oral and parenteral opioid use 
ii. Oral use will be documented in pain diary by patient/guardian and reviewed at 
each visit. 
iii. Frequency of refills and parenteral opioid use will be extracted from the EMR by 
each site 
iv. 
Hospitalizations 
i. 
Defined as an emergency room or clinic visit resulting in an inpatient admission 
or observation for a sickle cell-related event (e.g. vaso-occlusive pain, acute chest 
syndrome, etc). 
ii. Will be reviewed at each visit, as well as extracted from the EMR by each site 
v. 
Assessment of tolerability and evaluation for any toxicities of imatinib in patients 
with SCA 
 
 
5.0 
INVESTIGATIONAL PLAN 
 
5.1 
Study Design 
 
This will be an open label nonrandomized pilot study to determine the effect of imatinib on band 3 phosphorylation, 
microparticle release from sickle RBCs, and percent irreversibly sickled cells obtained from adolescent and young 
adult patients with Hemoglobin SS Disease or S-Beta 0 Thalassemia before, during, and after 6 months of treatment 
with imatinib. We will also look at clinical outcomes during treatment (pain) and before treatment. Clinical outcomes 
before treatment will be collected via retrospective chart review. 
 
5.2 
Study Population 
 
5.2.1 Inclusion criteria 
 
1. Age: patients must be ≥18 years of age and ≤30 years of age at the time of study entry. 
2. Diagnosis: Patients must have documented diagnosis of Hemoglobin SS Disease or S-Beta 0 Thalassemia by 
either HPLC or Hemoglobin Electrophoresis 
3. Disease status: Patients must have at least 2 documented episodes of vaso-occlusive pain in the prior year as 
defined by an acute episode of pain lasting greater than 24 hours, with no medically determined cause other than 
a vaso-occlusive event that resulted in treatment with oral or parenteral opiates or with a parenteral nonsteroidal 
anti-inflammatory drug. 
4. Performance Level: Karnofsky ≥80 for patients >10 years of age and Lansky ≥80 for patients ≤10 years of age. 
Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
5. Organ function requirements: 

version 10.4 12 
 
a. Adequate bone marrow function defined as 
i. Peripheral absolute neutrophil count (ANC) ≥1000/µL 
ii. Platelet count ≥100,000/ µL (transfusion independent) 
b. Adequate renal function defined as 
i. Creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2 or 
ii. A serum creatinine based on age/gender as follows 
 
Table 1: Maximum serum creatinine allowed for eligibility 
Age 
Maximum Serum 
Creatinine (mg/dL) 
Male 
Female 
2 to <6 years 
0.8 
0.8 
6 to <10 years 
1 
1 
10 to <13 years 
1.2 
1.2 
13 to <16 years 
1.5 
1.4 
≥16 years 
1.7 
1.4 
The threshold creatinine values were derived from the Schwartz formula for estimating GFR 
(Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC. 
 
c. 
Adequate Liver Function Defined As: 
 
i. 
SGPT (ALT <2.5 upper limit of normal. For the purpose of this study, the ULN for SGPT is 45 
U/L 
ii. 
Serum albumin ≥2 g/dL 
d. 
Adequate cardiac function defined as: 
i. Shortening fraction or ejection fraction greater than the LLN (institutional norm), and 
ii. Corrected QT interval ≤450 msec 
 
6. Informed Consent: All patients must sign a written informed consent. Assent, when appropriate, will be 
obtained according to institutional guidelines. 
 
 
5.2.2 Exclusion criteria 
1. 
Chronic transfusion protocol. 
a. Patients currently on a chronic transfusion protocol are not eligible 
2. 
Hydroxyurea Intolerance 
a. Patients who are ineligible for hydroxyurea due to persistent marrow suppression (e.g. 
thrombocytopenia, neutropenia) 
3. 
Pregnancy or Breast-Feeding 
a. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive 
potential may not participate unless they have agreed to use an effective contraceptive method. 
4. 
Concomitant Medications 
a. Investigational Drugs: Patients who are currently receiving another investigational drug. 
b. Anti-cancer agents: Patients who are currently receiving other anti-cancer agents. 
c. The following CYP3A4 inducers are prohibited 14 days before the start of imatinib and during the study 
with imatinib: rifampin, rifabutin, carbamazepine, Phenobarbital, phenytoin, St. John’s wort, efavirenz, 
and tipranavir. 

version 10.4 13 
 
d. The following CYP3A4 inhibitors are prohibited 7 days before the start of imatinib and during the study 
with imatinib: azole antifungals (itraconazole, ketoconazole); clarithromycin, erythromycin, diltiazem, 
verapamil, HIV protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfainavir); delavirdine. 
5. 
Patients who have an uncontrolled infection. 
6. 
Prior use of Imatinib: Patients who have previously received imatinib are not eligible for study. 
7. 
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring 
requirements of the study. 
8. 
Patient is < 5 years free of a malignancy. Existence of any other malignant disease is not allowed. 
9. 
Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., 
congestive heart failure, myocardial infarction within 6 months of study). 
10. Patients with a history of QT prolongation, need for concomitant use of anti-arrhythmics or other agents 
known to prolong QT interval, or electrolyte derangement that cannot be corrected to within normal limits 
prior to initiation of study drug. 
11. Patients with a family history of sudden cardiac death. 
12. Patient has a severe and/or uncontrolled medical disease other than sickle cell disease (i.e., uncontrolled 
diabetes, chronic renal disease, or active uncontrolled infection). 
13. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). 
14. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. 
15. Patient had a major surgery within 2 weeks prior to study entry. 
 
5.3. Sample Size 
A total of 40 participants will be enrolled. Thirty subjects will be recruited at Riley Hospital for Children with 10 of 
the subjects having sickle cell anemia and up to 20 normal donor subjects enrolled for specimen shipping purposes. 
Ten subjects with sickle cell anemia will be recruited at Cincinnati Children’s Hospital. This sample size has been 
determined by the primary endpoints (See Section 15 for details). 
 
5.4 Recruitment Strategy 
Subjects will be recruited through the Pediatric Hematology/Oncology clinic at Indiana University School of 
Medicine, Pediatric Hematology/Oncology clinic at Cincinnati Children’s Hospital and Cincinnati CTSI. Study 
subjects will be compensated for their participation with a $50 gift card provided at the end of each monthly visit. 
 
6.0 TREATMENT PROGRAM 
 
All patients with sickle cell anemia will be treated in the same group. There will not be a randomization. 
Patients will receive Imatinib orally once daily for 6 months. 
The starting dose for subjects will be 340 mg/m2/day with a maximum dose of 600 mg daily. Drug doses will be 
rounded to nearest 50 mg according to the dosing table in Appendix A. Dosing should be based on the body surface 
area (BSA) obtained at each clinic appointment. Drug will be dispensed as a 30-day supply at each visit. Patients will 
be asked to bring the prescription bottle with them to each visit to assist with monitoring compliance. 
 
Clinic visits will occur at initiation of imatinib and then every 30 days +/- 7 days. Monthly visits will consist of 
interim history, assessing for adverse side effects and compliance. Participants will be asked to have blood drawn (see 
Section 11) 2 weeks +/- 3 days after initiation of the drug. Additionally, during the first two months of drug 
administration, patients will be called or texted a survey link weekly for follow-up safety assessments, except for the 
participant’s in-clinic visits at week 2, 4 and 8. The survey link will come via an app, called Twilio, that allows 
REDCap the capability to send SMS text messages to survey respondents. If the patient is unable to be reached by 
phone for at least 3 of the 4 weekly assessments each month, they will be asked to be seen in clinic for a safety 
assessment. If the patient is unable to do so, they will be removed from protocol therapy for protocol non-compliance. 
The 1 month, 3 month, 6 month, and 1-month off-therapy visits will consist of a comprehensive history and physical 

version 10.4 14 
 
exam, as well as laboratory and diagnostic studies documented in Section 10. The other visits (2, 4 and 5-month visits 
post treatment initiation) will be research-nurse visits, with a provider available to sign the next month’s prescription. 
 
Patients will be given a copy of the “Patient Pain Journal” at each visit which will need to completed and returned at 
the next visit. This journal should be reviewed with the treating physician and/or research nurse at each clinic 
appointment while on study. Patients should be instructed to use the journal to record any occurrence of pain episodes 
(see definition in Section 5.3), the duration, and necessary interventions. They will be asked to score their pain on a 
scale of 1-10. Additionally, it will be used to record the date and time of each imatinib dose as well as observed side 
effects and supportive treatments used while on study. 
 
Opioid use, hospitalizations, and occurrence of acute chest syndrome (see definitions in Section 5.3) will be reviewed 
at each study visit, as well. This information will also be extracted from the EMR at each site to confirm 
patient/guardian report. 
 
6.1 Dosage: 
 
Mylan will supply Imatinib as 100 mg tablets packaged in bottles for an exposure period of up to 6 months or so long 
as the patient remains on study. The starting dose for subjects will be 340 mg/m2 with a maximum dose of 600 mg 
daily. Tablets can be broken in half, and therefore, drug doses will be rounded to nearest 50 mg according to the 
dosing table in the Appendix A. Dosing should be based on the body surface area (BSA) obtained at each clinic 
appointment. 
 
The prescribed dose should be administered at the same time each morning, orally, with a meal and a large glass of 
water. Patients should keep normal eating habits, however a low-fat (i.e. continental) breakfast is recommended and 
avoiding xanthine (e.g. caffeine) or grapefruit containing food or beverages. If vomiting occurs > 15 minutes after 
administration of the dose, no additional trial medication should be taken that day in an effort to replace the material that 
has been vomited. 
 
In the absence of dose limiting toxicity (DLT), patients may receive a total of 6 months of therapy. Continuing 
treatment beyond this period will be at the discretion of the investigator and may become the financial responsibility of 
the patient if no alternative method of obtaining or paying for the drug can be identified at that time. Medication labels 
will comply with the legal requirements of the US and will be printed in English. The storage conditions for Imatinib 
will be described on the medication label. Bottles must be stored in a safe, secure location. 
 
See Section 8 and 9 for dose-limiting toxicities and dose reductions/modifications. If the toxicity resolves to meet 
study parameters within 14 days of drug discontinuation, the patient may resume treatment with the dose reduced by 
from 340 mg/m2 to 260 mg/m2. Treatment should resume 14 days from drug discontinuation even if toxicity has 
resolved before 14 days in order to allow for a full 2-week rest period before resuming drug. Subjects who fail to 
recover to a </= grade 2 or baseline within 14 days of AE onset will permanently discontinue study drug. This does 
not include the following AEs: nausea and fatigue (does not require dose reduction or discontinuation). Upon 
restarting drug, the dose will be reduced to 260 mg/m2 (see table in Appendix A) and not re-escalated in subsequent 
cycles. A maximum of 2 dose reductions (340 mg/m2 to 260 mg/m2 to 200 mg/m2) will be allowed before permanent 
discontinuation of study drug. 
 
6.2. Drug Accountability: 
IU Health Investigational Drug Services (IDS) is a division of the Pharmacy Department whose purpose is to assist 
investigators in procurement, dispensing, and accountability for investigational drugs. All patients treated on this 
study will have investigational drug coordinated through the IDS. 
 
The Principal Investigator will be ultimately responsible for the investigational product (IP) and the conduct of the 
study. The PI will delegate functions to IDS that are appropriate. 

version 10.4 15 
 
6.2.1 IDS Role and Delegated Functions 
 
Protocols: IDS will maintain a copy of the protocol and investigator’s brochure. All protocols that involve IDS must 
have Institutional Review Board (IRB) approval. IDS should be notified when changes have been submitted to the 
IRB and have access to the appropriate computer website/program to find the protocol amendments or update. 
 
IP Inventory: IDS will provide for adequate inventory including monthly checks, arrange for IP shipments, confirm 
all shipments as received in good condition and maintain records of all shipments. 
 
IP Shipments: IDS will document all IP receipt, dispensing, destruction in accordance with IDS policy and sponsor 
requirements. To guaranteed accurately and timely delivery and immediate shipment confirmation, IP should be 
shipped directly to IDS: 
Investigational Drug Services 
IUSCC Room C2102 
550 North University Boulevard 
Indianapolis, IN 46202 
 
Storage: IDS will ensure proper storage of all IP in accordance with manufacturer or sponsor recommendations. 
Storage temperatures will be monitored according to IDS and IU Health monitoring systems. 
 
Disposal: Disposal of IP will be in accordance with IDS and IUPUI procedures for Hazardous Waste Disposal. All 
disposal will be recorded on drug accountability records. 
 
IP Accountability: IDS will maintain complete records on of all IP received, dispensed, disposed. Accountability 
Records will follow standard IDS or NCI Accountability templates unless sponsor required forms are mandated. 
 
IP Preparation, Labeling and Administration: IDS staff will write internal standard operating procedures which 
include: 
 
Detailed preparation instructions including IV administration and expiration dating 
 
Proper labeling of prepared IP to comply with Pharmacy Department, Hospital, State or Federal Regulation. 
 
IDS will design and or approve any prescription or physician orders to be used for the IP to assure all appropriate 
Pharmacy and Hospital regulations are met. 
 
Study Conclusion and Record Retention: At the conclusion of the study, IDS will ensure final disposition of the IP 
and provide all accountability records, shipping and receipt records, prescriptions and essential study correspondence 
to the principal investigator for final storage with all study related records. 
 
For more complete details on IDS procedures for various functions please consult the IDS Manual of Operations. 
 
7.0 GRADING OF ADVERSE EVENTS 
 
An adverse event (AE) is defined as any unintended or abnormal clinical observation that is not of benefit to the 
patient. Either the condition was not present prior to exposure to test medication, or it has worsened in intensity or 
frequency following exposure to test medication. Adverse events will be graded according to the National Cancer 
Institute (NCI) Common Terminology Criteria v4.03 (CTCAE): 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Any suspected or confirmed dose-limiting toxicity should be reported immediately (within 24 hours) to the principal 
investigator. 

version 10.4 16 
 
Principal investigators (PI) must report to the IRB as soon as possible, but in all cases within 5 working days from 
notification of any event that appears on the List of Events that Require Prompt Reporting to the IU IRB. 
 
7.1 List of Events that Require Prompt Reporting to the IUPUI IRB. Any of the following: 
 
1.1.1 Event (including adverse events, injuries, side effects during the research study), which in the 
opinion of the PI 
 
1.1.1.1 
caused harm to one or more subjects or others, or placed one or more subjects or 
others at increased risk of harm; AND 
1.1.1.2 
was unexpected; AND 
1.1.1.3 
was related to the research procedures 
 
Note: After the study is closed with the IRB, these events should only be reported if they are 
profound or they demonstrate long-term risks that would necessitate notifying subjects. 
 
1.1.2 Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard 
to a research subject (e.g. purposeful and for subject safety) (on-site only) 
 
1.1.3 Complaint of a subject that indicates unexpected risks, or complaint that cannot be resolved by 
the research team (on-site only) 
 
1.1.4 Interim findings and safety monitoring reports that indicate an unexpected change to the risks 
or potential benefits of the research, in terms of severity or frequency 
 
1.1.5 Publication in the literature that indicates an unexpected change to the risks or potential benefits 
of the research 
 
1.1.6 Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research study 
 
1.1.7 Noncompliance (as defined in this policy and on-site only) 
 
Serious Adverse Events (SAE) and unanticipated problems involving risk to subjects or others (UPIRSOs) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• death 
• a life-threatening adverse experience 
• inpatient hospitalization or prolongation of existing hospitalization++ 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect 
 
Other important medical events may also be considered an SAE when, based on appropriate medical judgment, they 
jeopardize the subject or require intervention to prevent one of the outcomes listed. 
 
++ 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 

version 10.4 17 
 
• 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 
 
Any serious or immediately life-threatening adverse experience, including those resulting in death, occurring while the 
subject is receiving study drug, or within 30 days of the subject’s last dose of protocol therapy, regardless of the 
treating physician’s opinion regarding drug relationship, will be reported by telephone and/or e-mail (within 24 hours 
of the event) to the Study PI and appropriate parties. 
 
Serious adverse events are to be reported via Oncore on the SAE Form within 5 business days of event notification. 
 
Study principal investigators are be notified of serious adverse events via email within 5 business days of 
event notification. 
 
 
Instructions for rapid notification of unexpected serious adverse events reporting procedures 
 
When an unexpected serious adverse event occurs, the investigator (study chair) must complete the FDA MedWatch 
3500a form in English and assess the relationship to study treatment. 
 
Follow-up information should describe whether the event has resolved or continues, if and how it was treated, and 
whether the patient continued or discontinued study participation. The MedWatch form and fax confirmation sheet must 
be retained. Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary or spontaneous 
termination, details of the birth, and the presence or absence of any congenital abnormalities or birth defects. 
 
8.0 DEFINITION OF DOSE-LIMITING TOXICITY (DLT) 
 
DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to imatinib. 
 
1. 
Non-hematologic dose-limiting toxicity 
• 
Any Grade 4 non-hematologic toxicity 
• 
Any Grade 3 non-hematologic toxicity with the specific exception of: 
o Grade 3 ALT that return to levels that meet initial eligibility criteria within 7 days of study 
drug interruption and that do not recur upon rechallenge with study drug. Note: For the 
purposes of this trial the ULN for ALT is defined as 45 U/L. 
o Grade 3 AST 
o Grade 3 fever or infection <5 days duration 
o Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to 
oral supplementation within 14 days of initiating supplementation 
o Asymptomatic Grade 3 elevations in amylase or lipase resolving to <Grade 1 within 7 days of 
study drug interruption and that do not recur upon re-challenge with study drug 
• 
Grade 2 or greater left ventricular systolic dysfunction OR an absolute decrease in shortening fraction 
of 8 percentage points from baseline. 
• 
Grade 2 allergic reactions that necessitate discontinuation of study drug will not be considered a dose 
limiting toxicity. 
• 
Any Grade 2 non-hematological toxicity that persists for ≥7 days and is considered sufficiently 
medically significant or sufficiently intolerable by patients that it requires treatment interruption. 
• 
Any adverse event requiring interruption of study drug for >7 days or which recurs upon drug re- 
challenge. 
 
2. Hematologic dose limiting toxicity 

version 10.4 18 
 
• 
Grade 3 thrombocytopenia with Grade 3 or 4 hemorrhage 
• 
Grade 4 thrombocytopenia (platelet count <25,000/mm3) or 
• 
Grade 4 neutropenia. 
 
9.0 
DOSE MODIFICATIONS FOR ADVERSE EVENTS 
The study PIs must be notified of any dosage modification. 
1.  Dose modifications for hematological toxicity (Of note, such adverse events have been observed in patients 
with CML (chronic myelogenous leukemia), likely contributed by concurrent morbidities). 
a. If a patient experiences Grade 3 neutropenia (ANC<1000) or Grade 3 thrombocytopenia (platelets 
<50,000/mm3) with or without Grade 1 or 2 non-CNS hemorrhage, the treatment will be withheld. 
Counts should be checked twice weekly during this time. If the toxicity resolves to meet on study 
parameters within 14 days of drug discontinuation, the patient may resume treatment with the dose 
reduced as mentioned in Section 6.1. Treatment should resume 14 days from drug discontinuation 
even if toxicity has resolved before 14 days in order to allow for a full 2-week rest period before 
resuming drug. 
b. If a patient experiences Grade 1 CNS hemorrhage or Grade 3 or > non-CNS hemorrhage, the 
treatment will be withheld. Treatment will not be resumed and the participant will discontinue study 
drug permanently. 
c. If toxicity does not resolve to meet on study parameters within 14 days of drug discontinuation, the 
patient must be removed from protocol therapy. 
d. If dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced dose (maximum 
of 2 dose reductions allowed), the patient must be removed from protocol therapy. 
e. Myeloid growth factors will not be used on study. 
 
2. 
Dose modifications for non-hematological toxicity. 
a. If a patient experiences non-hematologic DLT as defined in Section 8, the treatment will be withheld. 
If the toxicity resolves to meet on study parameters within 14 days of drug discontinuation, the patient 
may resume treatment with the dose reduced as mentioned in Section 6.1 (see Appendix A). 
Treatment should resume 14 days from drug discontinuation even if toxicity has resolved before 14 
days. Doses reduced for toxicity will not be re-escalated, even if there is minimal or no toxicity with 
the reduced dose. 
b. If toxicity does not resolve to meet on study parameters within 14 days of drug discontinuation, the 
patient must be removed from study. 
c. If dose-limiting toxicity recurs in a patient who has resumed treatment at the reduced dose level, the 
patient must be removed from protocol therapy. 
d. Dose modifications for left ventricular systolic dysfunction: Left ventricular systolic dysfunction will 
be graded according to CTCAE criteria but will also take into account absolute changes in shortening 
fraction. 
 
Grade 1 left ventricular systolic dysfunction: Continue imatinib at current dose level and repeat 
echocardiogram in 30 days. 
 
Grade 2 left ventricular systolic dysfunction OR >8 absolute percentage point decrease in shortening 
fraction: hold study drug and repeat echocardiogram in 7 days. If repeat echocardiogram confirms 
toxicity, patient will be taken off-protocol therapy and should be referred to a cardiologist. If repeat 
echocardiogram does not confirm toxicity, patient may restart therapy with repeat echocardiogram 14 
days after restart. If any two echocardiograms demonstrate Grade 2 dysfunction OR >8 absolute 

version 10.4 19 
 
percentage point decrease in shortening fraction, patients will be taken off-protocol therapy and should 
be referred to a cardiologist. 
 
≥Grade 3 left ventricular systolic dysfunction: Off-protocol therapy. Referral to cardiologist. 
 
10.0 SUPPORITIVE CARE AND OTHER CONCOMITANT THERAPY 
In general, concomitant medications and therapies deemed necessary for the supportive care and safety of the patient are 
allowed, provided their use is documented in the patient records and on the appropriate case report form. Concomitant 
medication use will be reviewed at each visit to assess for potential interaction with Imatinib. If a medication that has 
the potential to interact with imatinib is identified at initial screening, the investigator will determine whether it is in the 
best interest of the subject to continue with participation in the trial. If the potential interaction poses a risk that is deemed 
unacceptable, the subject will either stop the concomitant medication and wait an appropriate amount of time to allow 
clearance of this medication prior to taking Imatinib or, if the concomitant medication is unable to be discontinued, then 
the subject will be excluded from participation in the trial. In the event a subject is prescribed a medication with the 
potential for interaction with Imatinib during the course of participation in the trial and the potential risk is deemed too 
high then the subject will be instructed not to start this medication or will have to be withdrawn from study. All subjects 
will be instructed to discuss any new medications with the investigator or study personnel prior to taking in order to 
reduce the possibility of serious drug interactions. 
 
10.1 Investigational Agents: no other investigational agents may be given while the patient is on study. 
 
10.2 Concomitant Medications 
 
Drugs that may increase imatinib plasma concentrations 
Caution is recommended when administering imatinib with inhibitors of the cytochrome P450 isoenzyme CYP3A4 
family (e.g., ketoconazole, itraconazole, erythromycin, and clarithromycin). Substances that inhibit CYP3A4 activity 
may decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib 
when the compound was co-administered with ketoconazole, a CYP3A4 inhibitor. 
 
Drugs that may decrease imatinib plasma concentrations 
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations. 
Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. 
John's Wort) may reduce exposure to imatinib. There was a significant decrease in exposure to imatinib when imatinib 
was co-administered with rifampicin, an inducer of CYP3A4. 
 
Drugs that may have their plasma concentration altered by imatinib 
Imatinib increases the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating 
inhibition of CYP3A4 by imatinib. Particular caution is recommended when administering imatinib with CYP3A4/5 
substrates with a narrow therapeutic window (e.g., cyclosporine or pimozide). Imatinib will increase plasma 
concentrations of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel 
blockers, certain HMG-CoA reductase inhibitors, etc.). 
In vitro, imatinib inhibits the activity of cytochrome P450 isoenzyme CYP2D6 at concentrations similar to those that 
affect CYP3A4/5 activity. Systemic exposure to substrates of CYP2D6 is expected to be increased when co-administered 
with imatinib. No specific studies have been performed and caution is recommended. 
 
Corticosteroids may induce CYP3A4 and are not routinely recommended on-study unless deemed absolutely necessary. 
Discussion with the principal investigator is not required prior to initiating corticosteroids. 

version 10.4 20 
 
 
A list of drugs metabolized by CYP3A4/5 and CYP2D6 is provided in Appendix B. 
 
Concomitant treatment with dysrhythmic drugs, i.e., terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, 
haloperidol, risperdone, and indapamide, is not recommended. 
 
10.3 Concurrent Anticancer Therapy: Concurrent cancer therapy, including chemotherapy, radiation therapy 
immunotherapy, or biologic therapy may NOT be administered to patients receiving study drug. If these treatments are 
administered the patient will be removed from protocol therapy. 
 
 
 
11.0      EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Subjects will be prescreened for potential eligibility prior to initial clinic visit. All entry/eligibility laboratory and 
imaging studies will be performed at or within 2 weeks of the initial visit. Baseline EKG to rule-out prolonged QTc, 
and if needed, echocardiogram, is required within 2 weeks of starting protocol therapy. If eligibility studies are drawn 
but the participant was not able to be enrolled/initiate study drug (e.g. hospitalized) in this timeframe, all eligibility 
laboratory studies will need to be repeated. EKG and ECHO do not need repeated unless there are new clinical 
concerns. Each study visit will occur approximately 4 weeks (+/- 1 week) after the previous. 

version 10.1 21 
 
 
STUDIES TO BE OBTAINED 
Baseline 
2 Weeks 
1 Month 
2 Months 
3 Months 
4 Months 
5 Months 
6 Months 
1 month Off 
Study 
Phone Assessment (Weekly) 
X 
X 
History 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam with vital signs 
X 
X 
X 
X 
X 
Height, weight, BSA 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
CBC/platelet with differential, 
Reticulocyte Count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HPLC or Hemoglobin EP 
X 
Ektacytometry, 
OxygenScan, F% correlation, 
Blood Viscosity# 
X 
X 
X 
X 
X 
% ISCs (irreversibly sickled cells) 
X 
X 
X 
X 
X 
D-dimer 
X 
X 
X 
X 
X 
Urine Pregnancy test (female) 
X 
X 
X 
X 
CMP^, Mag, Phos, Uric Acid, 
Amylase, Lipase and tryptase 
X 
X 
X 
X 
X 
Biochemical 
Analysis Sample 
X 
X 
X 
X 
X 
EKG* 
X 
X 
Echocardiogram* 
X 
Patient Pain Journal 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table 2. Studies to confirm eligibility and monitor safety and efficacy on imatinib 
 
*During study treatment, monitor for signs and symptoms of arrhythmia and for edema and fluid retention that may cause congestive heart failure. 
Obtain EKG/echocardiogram and cardiology consult as clinically indicated. 
 
#Blood samples for these studies to be sent to Cincinnati 

version 10.1 22 
 
^ CMP should include Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), BUN, Calcium, Chloride, Carbon Dioxide, Creatinine, Glucose, 
Potassium, Sodium, Total Bilirubin, Total Protein, and a calculation of eGFR. 

version 10.4 23 
 
12.0 AGENT INFORMATION 
Imatinib Mesylate 
1. Chemistry 
Imatinib mesylate, a phenylaminopyrimidine derivative, is designated chemically as 4-[(4-12 Methyl-1- 
piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-13 phenyl]benzamide 
methanesulfonate and its structural formula is: 
 
 
It was originally found as an inhibitor of the tyrosine kinase activity of the BCR-ABL1 fusion gene (oncoprotein), 
the product of the Philadelphia chromosome. Imatinib mesylate has also shown activity in blocking the tyrosine 
kinase activity of c-kit, the stem-cell factor receptor, and of PDGFR, the platelet-derived growth factor receptor 
and cellular events mediated by PDGF and SCF. Our studies have demonstrated that it also has significant 
blocking activity of Syk, the tyrosine kinase that phosphorylates band 3 in erythrocytes. 
 
2. Mechanism of Action 
Imatinib (STI571), a phenylaminopyrimidine derivative, is a selective inhibitor of the tyrosine kinase activity of 
the BCR-ABL1 fusion gene (oncoprotein), the product of the Philadelphia chromosome. Imatinib mesylate has 
also shown high activity in blocking the tyrosine kinase activity of stem-cell factor receptor (SCF), c-kit and 
platelet-derived growth factor PDGF and cellular events mediated by PDGF and SCF. The ability of imatinib to 
inhibit BCR-ABL1 tyrosine kinase activity is related to its occupancy of the kinase pocket of the protein, which 
blocks access to ATP and prevents substrate phosphorylation inhibiting BCR- ABL dependent cellular 
proliferation. Imatinib has caused apoptosis or arrest of growth in hematopoietic cells expressing BCR-ABL1. 
 
Imatinib is well-absorbed after oral administration; maximum plasma concentrations are achieved 2 to 4 hours 
after administration. The elimination half-lives of imatinib and its major active metabolite, the N-desmethyl 
derivative, are approximately 18 and 40 hours, respectively. The elimination half-life of the parent drug in 
children is approximately 15 hours. Imatinib is approximately 95% protein-bound, mostly to albumin and alpha- 
1- acid glycoprotein. CYP3A4 is the major enzyme responsible for metabolism. CYP1A2, CYP2D6, CYP2C9, 
and CYP2C19 play minor roles in metabolism. Drugs metabolized by these same enzymes should be avoided or 
used with caution to avoid unwanted drug interactions. Severe hepatic impairment (bilirubin >3-10 times ULN) 
increases AUC by 45% to 55% for imatinib and its active metabolite, respectively. Elimination is predominately 
in the feces, mostly as metabolites. 
 
3. Supplier 
 
Mylan Pharmaceuticals 

version 10.4 24 
 
13.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY 
 
1. Adverse Events requiring removal from study 
2. Refusal of further protocol therapy by patient/parent/guardian. 
3. Non-compliance that in the opinion of the investigator does not allow for ongoing participation, including <70% 
of drug prescribed being taken. Compliance will not be contingent on completion of the pain journal as this not 
the primary endpoint of the study. 
4. Physician determines continued protocol therapy is not in the patient’s best interest. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below). 
Ongoing adverse events, or adverse events that emerge after the patient is removed from protocol therapy, but within 
30 days of the last dose of investigational agent, must be followed and reported via RDE and AERS (if applicable). 
Follow-up data will be required unless consent is withdrawn. 
 
14.0 OFF STUDY CRITERIA 
 
1. Thirty days after the last dose of the investigational agent. 
2. Death 
3. Lost to follow-up 
4. Withdrawal of consent for any further data submission. 
5. Enrollment onto another therapeutic study 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 Sample Size Justification 
This sample size has been determined by the primary endpoint of microparticle released at 6 months with an 
adjustment to the alpha level to account for the fact there are five primary endpoints. From Figure 1, the mean 
(standard deviation) of number of microparticles released is 140,000 (75,000) and it is anticipated that treatment with 
imatinib will decrease that amount at least 50% to 70,000. A two-sided paired t-test with alpha level 0.05/5 = 0.01 will 
have 89% power to detect this difference when the sample size is 20 subjects (assuming the pre/post treatment 
correlation is 0.5). We estimate a sample size of 20 patients total (10 patients from each site) would be feasible to 
recruit and would meet these statistical criteria to provide adequate data to assess effect. 
 
15.2 Safety evaluation 
The assessment of safety will be based mainly on the frequency of adverse events, particularly adverse events leading to 
discontinuation of treatment and on the number of significant laboratory abnormalities. 
 
Adverse events will be summarized by presenting the number and percentage (as appropriate) of patients having any 
adverse event by body system, type of adverse event, and maximum severity according to CTCAE grade. Those adverse 
events which result in death, discontinuation or are otherwise classified as dose limiting will be presented separately. 
 
Laboratory data will be summarized using the NCI CTCAE version 4.03 criteria. 
 
15.3 Safety Monitoring 
DLTs (see Section 8 for definition) will be continuously monitored. If the stopping rule is met, enrollment will be 
halted, and a data safety meeting will be convened to determine whether or not the study should be continued. 
Sequential boundaries will be used to monitor dose-limiting toxicity rate. The accrual will be halted if excessive 
numbers of dose-limiting toxicities are seen, that is, if the number of dose-limiting toxicities is equal to or 
exceeds bn out of n patients with full follow-up (see table below). This is a Pocock-type stopping boundary that yields 
the probability of crossing the boundary at most [probability of early stopping] when the rate of dose-limiting toxicity 
is equal to the acceptable rate [event probability θ]. 

version 10.4 25 
 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- - 3 4 4 4 5 5 5 6 6 6 7 7 7 8 8 8 9 9 
 
This boundary is equivalent to testing the null hypothesis, after each patient, that the DLT rate is equal to 0.2, using a 
one-sided level 0.021430 test61. 
 
15.4 Efficacy evaluation 
Descriptive statistics will be calculated for all endpoints before, during, and after treatment. Changes before and 6 
months after treatment in biochemical endpoints will be tested with two-sided paired t-tests. This analysis will be 
supplemented with single group repeated measures ANOVA to test for effects over time since there are 3 measures on 
treatment. Many secondary endpoints are counts (e.g. frequency of refills of opioids, number of hospitalizations). 
Depending on the distributions of these outcomes, we will either: 1) dichotomize and compare with McNemar’s test; 
2) treat as ordinal and compare with a Cochran-Mantel-Hazensel type test; or 3) treat as continuous and conduct either 
paired t-test or Wilcoxon signed rank tests. Since the pain measure will depend on age, we will only statistically 
analyze when there are at least 6 participants using a single-group repeated measures ANOVA model. Otherwise, only 
graphical descriptions will be used. 
 
16.0 INCLUSION OF CHILDREN, WOMEN, AND MINORITIES 
 
The study is open to all participants regardless of gender or ethnicity. Efforts will be made to extend the accrual to a 
representative population. If differences in outcome that correlate to gender, racial, or ethnic identity that are outside of 
the expected distribution for this patient population are noted, accrual may be expanded or additional studies may be 
performed to investigate those difference more fully. 
 
17.0 CORRELATIVE STUDIES (Please see Lab Manual) 
 
18.0 DATA MANAGEMENT AND DATA SAFETY MONITORING 
 
18.1 Monitoring and Reporting Guidelines 
Investigators will conduct continuous review of data and patient safety. As accrual warrants, review meetings will take 
place monthly and will include principal investigators Seethal Jacob, MD, MS; Charles Quinn, MD, Theodosia Kalfa, 
MD, PhD, study coordinators and clinical research nurses. Monthly meetings will include review of data, the number 
of patients, significant toxicities as described in the protocol, and responses observed. 
18.21. Early Study Closure 
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or benefits) to the 
subject warrant early closure of the study, the Compliance Officer must be notified within 1 business day via email, 
and the IRB must be notified within 5 business days. Alternatively, the investigators may initiate suspension or early 
closure of the study based on their monthly reviews. 
 
18.3 Oversight of Study Progress 
Data collection and data management for this study will be conducted with the support of the Center for Cancer and 
Blood Disorders Clinical Research Office and the Data Management Core at Indiana University School of Medicine. 
This team will be responsible for assisting the PI in assuring protocol compliance as well as reviewing, transcribing and 
tracking of all clinical and safety related data. 

version 10.4 26 
 
18.31. Continuing Review 
All Continuing Reviews will be reviewed annually or as dictated by the Institutional Review Board. 
 
18.4 Study Data Management 
Primary data will be collected from treatment or test results included in the subject’s medical record or source 
documentation given by the subject (i.e, patient diary). Patients will be registered in OnCore. Data will be entered on 
the Case Report Forms (CRFs) developed for this study stored electronically in REDCap. This database will be backed 
up automatically every week. Quality assurance steps will include: 1) built-in range checks; 2) testing of the database 
by the study team prior to moving to production mode; and 3) review and verification of all by the principal 
investigator and the research manager. Specific data questions will be given to the appropriate personnel who will 
then investigate and resolve the questions with the help of the investigator as necessary. Additionally, the following 
quality control methods will be used: 1) single entry of data with random checks of accuracy; and 2) extraction and 
cleaning of data that will be used for analysis every 6 months. 
 
Data will be recorded on the CRFs and will be kept confidential with only the principal investigator, co-investigators, 
statisticians, IRB and the research personnel having access to individually identifiable data. The CRFs will be locked 
in a cabinet in a secure area with limited access to the building. 
 
Data from this study will be retained for a minimum of 7 years for health data per Indiana State law. Following this 
period, paper will be shredded and permanently deleted from any computers. 
 
Identifiable data will be shared only between research team members approved on the “Investigator List” in any of the 
following ways: encrypted email, US postal service or trackable courier services (i.e. FedEX), fax in a secured area, 
shared drive with password protection, personal delivery by authorized research personnel and/or private telephone 
conversations to authorized personnel. 
 
19.0 PROCEDURES AND INSTRUCTIONS 
 
19.1 Administrative Procedures 
 
19.1.1 Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must be approved by all the principal 
investigators before implementation. Amendments significantly affecting the safety of subjects, the scope of the 
investigation or the scientific quality of the study, require additional approval by the IRB. 
 
Amendments affecting only administrative aspects of the study do not require formal protocol amendments or IRB 
approval but the IRB of each center must be kept informed of such administrative changes. 
 
19.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as described in: 
 
21.21. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
21.22. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
21.23. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning informed 
consent and IRB regulations). 
21.24. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in 
Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 
1989, Somerset West 1996). 

version 10.4 27 
 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
 
19.3 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other information to subjects, 
must be reviewed by a properly constituted Institutional Review Board/Independent Ethics Committee (IRB/IEC/REB). 
 
19.4 
Informed Consent 
The investigator must explain to each subject (or legally authorized representative) the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort it may entail. 
Each subject must be informed that participation in the study is voluntary and that he/she may withdraw from the study 
at any time and that withdrawal of consent will not affect his/her subsequent medical treatment or relationship with the 
treating physician. 
 
This informed consent should be given by means of a standard written statement, written in non-technical language. The 
subject should read and consider the statement before signing and dating it, and should be given a copy of the signed 
document. If the subject cannot read or sign the documents, oral presentation may be made or signature given by the 
subject’s legally appointed representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed consent has been obtained. 

version 10.4 28 
 
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version 10.4 31 
 
APPENDIX A: IMATINIB TABLETS DOSING GUIDELINES 
Imatinib 340mg/m2/day 
Body Surface Area (m2) 
Total Daily Dose (Rounded to 
Nearest 50 mg) 
Recommended Administration 
≤ 0.36 
100 mg 
1 x 100 mg tablet once daily 
0.37 – 0.51 
150 mg 
1 ½ x 100 mg tablets once daily 
0.52 – 0.66 
200 mg 
2 x 100 mg tablets once daily 
0.67 – 0.81 
250 mg 
2 ½ x 100 mg tablets once daily 
0.82 – 0.95 
300 mg 
3 x 100 mg tablets once daily 
0.96 – 1.10 
350 mg 
3 ½ x 100 mg tablets once daily 
1.11 – 1.25 
400 mg 
4 x 100 mg tablets once daily 
1.26 – 1.39 
450 mg 
4 ½ x 100 mg tablets once daily 
1.4 – 1.54 
500 mg 
5 x 100 mg tablets once daily 
1.55 – 1.69 
550 mg 
5 ½ x 100 mg tablets once daily 
≥1.70 
600 mg 
6 x 100 mg tablets once daily 
 
Imatinib 260mg/m2/day 
Body Surface Area (m2) 
Total Daily Dose (Rounded to 
Nearest 50mg) 
Recommended Administration 
≤ 0.29 
50 mg 
½ x 100mg tablet once daily 
0.3 – 0.48 
100 mg 
1 x 100mg tablet once daily 
0.49 – 0.67 
150 mg 
1 ½ x 100mg tablet once daily 
0.68 – 0.86 
200 mg 
2 x 100mg tablet once daily 
0.87 – 1.05 
250 mg 
2 ½ x 100mg tablet once daily 
1.06 – 1.24 
300 mg 
3 x 100mg tablet once daily 
1.25 – 1.44 
350 mg 
3 ½ x 100mg tablet once daily 
1.45 – 1.63 
400 mg 
4 x 100mg tablet once daily 
1.64 – 1.82 
450 mg 
4 ½ x 100mg tablet once daily 
1.83 – 2.01 
500 mg 
5 x 100mg tablet once daily 
≥ 2.02 
550 mg 
5 ½ x 100mg tablet once daily 
 
Imatinib 200mg/m2/day 
Body Surface Area (m2) 
Total Daily Dose (Rounded to 
Nearest 50mg) 
Recommended Administration 
≤ 0.37 
50 mg 
½ x 100mg tablet once daily 
0.38 – 0.62 
100 mg 
1 x 100mg tablet once daily 
0.63 – 0.87 
150 mg 
1 ½ x 100mg tablet once daily 
0.88 – 1.12 
200 mg 
2 x 100mg tablet once daily 
1.13 – 1.37 
250 mg 
2 ½ x 100mg tablet once daily 
1.38 – 1.62 
300 mg 
3 x 100mg tablet once daily 
1.63 – 1.87 
350 mg 
3 ½ x 100mg tablet once daily 
1.88 – 2.12 
400 mg 
4 x 100mg tablet once daily 
2.13 – 2.37 
450 mg 
4 ½ x 100mg tablet once daily 
≥ 2.38 
500 mg 
5 x 100mg tablet once daily 

version 10.4 32 
 
APPENDIX B: Drugs known to be metabolized by CYP450 isoenzymes 2D6 and 3A4 
CYP2D6 
Substrates 
Amitriptyline (hydroxylation) 
Methamphetamine 
Amphetamine 
Metoclopramide 
Betaxolol 
Metoprolol 
Bisoprolol 
Mexitetine 
Brofaromine 
Mianserin 
Buturolol 
Mirtazapine (hydroxylation) 
Bupropion 
Molindone 
Captopril 
Nortriptyline (hydroxylation) 
Carvedilol 
Olanzapine (minor, hydroxymethylation) 
Cevimeline 
Ondansetron 
Chlorpheniramine 
Orphenadrine 
Chlorpromazine 
Oxycodone 
Cinnarizine 
Papaverine 
Clomipramine (hydroxylation) 
Paroxetine (minor pathway) 
Clozapine (minor pathway) 
Penbutolol 
Codeine (hydroxylation, o-demelhylation) 
Pentazocine 
Cyclobenzaprine (hydroxylation) 
Perhexiline 
Cyclophosphamide 
Perphenazine 
Debrisoquin 
Phenformin 
Delavirdine 
Pindolol 
Desipramine 
Promethazine 
Dexfenfluramine 
Propafenone 
Dextromethorphan (o-demethylation) 
Propranolol 
Dihydrocodeine 
Quetiapine 
Diphenhydramine 
Remoxipride 
Dolasetron 
Risperidone 
Donepezil 
Ritonavir (minor) 
Doxepin 
Ropivacaine 
Encainide 
Selegiline 
Fenlluramine 
Sertindole 
Flecainide 
Sertratine (minor pathway) 
Fluosetine (minor pathway) 
Sparteine 
Fluphenazine 
Tamoxifen 
Halofantrine 
Thioridazine 
Haloperidol (minor pathway) 
Tiagabine 
Hydrocodone 
Timolol 
Hydrocortisone 
Tolterodine 
Hydroxyamphetamine 
Tramadol 
Imipramine (hydroxylation) 
Trazodone 
Labetalol 
Trimipramine 
Loratadine 
Tropisetron 
Maprotiline 
Venlafaxine (o-desmethylation) 
m-Chlorophenylpiperazine (m-CPP) 
Yohimbine 
Meperidine 
Methadone 
Inhibitors 
Amiodarone 
Methadone 

version 10.4 33 
 
Celecoxib 
Chloroquine 
Chlorpromazine 
Cimelidine 
Citalopram 
Clomipramine 
Codeine 
Delavirdine 
Desipramine 
Dextropropoxyphene 
Diltiazem 
Doxorubicin 
Entacapone (high dose) 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol 
Labetalol 
Lobeline 
Lomustine 
Mibefradil 
Moclobemide 
Nortluoxeline 
Paroxetine 
Perphenazine 
Propafenone 
Quinacrine 
Quinidine 
Ranitidine 
Risperidone (weak) 
Ritonavir 
Sertindole 
Sertraline (weak) 
Thioridazine 
Vaiprolc acid 
Venlafaxine (weak) 
Vinblastine 
Vincristine 
Vinorelbine 
Yohimbine 
 
 
CYP3A3/4 
Substrates 
Acetaminophen 
Chlorpromazine 
Alfentanil 
Cimetidine 
Alosetron 
Cisapride 
Alprazolam 
Citalopram 
Amiodarone 
Clarithromycin 
Amitriptyline (minor) 
Clindamycin 
Amlodipine 
Clomipramine 
Anastrozole 
Clonazepam 
Androsterone 
Clozapine 
Antipyrine 
Cocaine 
Astemizole 
Codeine (demethylation) 
Atorvastatin 
Cortisol 
Benzphetamine 
Cortisone 
Bepridil 
Cyclobenzaprine (demethylation) 
Bexarotene 
Cyclophosphamide 
Bromazepam 
Cyclosporine 
Bromocriptine 
Dapsone 
Budesonide 
Dehydroepiandrostendione 
Bupropion (minor) 
Delavirdine 
Buspirone 
Desmethyldiazepam 
Busutfan 
Dexamethasone 
Caffeine 
Dextromethorphan (minor, N-demethylation) 
Cannabinoids 
Diazepam (minor; hydroxylation, N-demethylation) 
Carbamazepine 
Nefazodone 
Cevimeline 
Nelfinavir 
Cerivastatin 
Nevirapine 
Digitoxin 
Nicardipine 

version 10.4 34 
 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erythromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Flutamide 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
Ifosfamide 
Imipramine 
Indinavir 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 

version 10.4 35 
 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, Goldman MP, Lance 
LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 2000: 1364-1371