Clinical trial NCT00674479
Conditions: Acute Myeloid Leukemia Acute Lymphocytic Leukemia Myelodysplastic Syndrome Chronic Myelogenous Leukemia
Keywords: Advanced Hematologic Malignancies Cancer Blood Bone marrow Lymph nodes JAK kinase inhibitor INCB018424 phosphate Acute Myeloid Leukemia AML Acute Lymphocytic leukemia ALL Myelodysplastic Syndrome MDS Chronic myelogenous leukemia - Blast Crisis CML INCB018424
Sponsor: M.D. Anderson Cancer Center
Start date: 2008-05-12; Completion date: 2017-03-23
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if ruxolitinib can help to control advanced hematological malignancies. The safety of this drug will also be studied.

Detailed description:
The Study Drug:

Ruxolitinib is designed to block the protein product of a mutated (changed) gene that may be important in cancer cell growth and survival.

Study Drug Administration:

If you are found to be eligible to take part in this study, every day of each 28-day cycle you will take ruxolitinib by mouth 2 times a day (in the morning and evening).

On Day 1 of each cycle, the morning dose of study drug should not be taken until you visit the clinic unless the doctor says differently.

If the doctor thinks it is necessary, your dose of study drug may be raised or lowered.

Study Visits:

On Day 1 of Cycle 1, the following tests and procedures will be performed:

* You will be asked to list any drugs you may be taking and if you have experienced any side effects.
* You will have a physical exam, including measurement of your vital signs.

On Days 8, 15, and 22 of Cycle 1 (+/- 2 days), the following tests and procedures will be performed (these can be done at your local physician's office):

* Your medical history will be reviewed, including any drugs you may be taking.
* You will be asked if you have experienced any side effects.
* You will have a physical exam, including measurement of your vital signs.
* Blood (about 2 tablespoons) will be drawn for routine tests.

On Day 1 of Cycles 2-4 (+/- 2 days) and then once every 3 months, the following tests and procedures will be performed:

* Your medical history will be reviewed, including any drugs you may be taking.
* You will be asked if you have experienced any side effects.
* You will have a physical exam, including measurement of your vital signs.
* You will have a performance status evaluation.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* If the doctor thinks it is necessary, blood (about 1 tablespoon) will be drawn to check the status of the disease.
* If the doctor thinks it is necessary, you will have a bone marrow biopsy/aspirate to check the status of the disease.
* During these visits, you will also be receiving your new supply of medication.

On Days 8, 15, and 22 of Cycles 2 and 3, blood (about 2 tablespoons) will be drawn for routine tests at your local doctor's office.

On Day 1 of Cycles 4, 7, and every 6th cycle after that (Cycles 13, 19, 25, and so on), you will have a bone marrow aspiration or biopsy to check the status of the disease. On Day 1 of Cycle 4, the bone marrow aspiration/biopsy will also look at the genes and chromosomes of the leukemia cells. If there is not enough information from the biopsy/aspirate, leftover blood will be used to look at this gene and chromosome information.

Every 2 weeks of Cycles 4-7, blood (about 2 tablespoons) will be drawn for routine tests.

You will be called once a month while you are on study. During this phone call you will be asked how you are doing, if you have experienced any side effects, and if you are taking the study drug at the correct dose and time. This phone call will take a few minutes. You will be sent a card in the mail to remind you about any study visits you need to complete.

Women who are able to become pregnant will have a urine pregnancy test if there is a suspicion of pregnancy. If the test is positive, they will then have a blood (about 1 teaspoon) pregnancy test.

Length of Study:

You may stay on study for as long as you are benefitting. You will be taken off study if you experience intolerable side effects or the disease gets worse.

End-of-Study Visit:

After you go off study you will have an end-of-study visit. At this visit, the following tests and procedures will be performed:

* Your medical history will be reviewed, including any drugs you may be taking.
* You will be asked if you have experienced any side effects.
* You will have a physical exam, including measurement of your vital signs.
* You will have a performance status evaluation.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* If the doctor thinks it is necessary, blood (about 1 tablespoon) will be drawn to check the status of the disease.
* If the doctor thinks it is necessary, you will have a bone marrow biopsy/aspirate to check the status of the disease.
* Women who are able to become pregnant will have a urine pregnancy test. If the test is positive, they will then have a blood (about 1 teaspoon) pregnancy test.

This is an investigational study. Ruxolitinib is FDA approved and commercially available to treat myelofibrosis. Giving ruxolitinib to patients with advanced hematological malignancies is investigational.

Up to 120 patients will take part in this study. All will be enrolled at M. D. Anderson.

Arms: arm 1: The starting dose of INCB018424 will be 25 mg by mouth twice daily.
Interventions: intervention 1: INCB018424
Intervention descriptions: intervention 1: Starting dose: 25 mg by mouth (po) twice daily for 7 days each week for 4 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
2007-0925
October 14, 2008
Page 1
Protocol Page
Phase II Study of INCB018424 in Patients with Advanced Hematologic Malignancies
2007-0925
Core Protocol Information
Short Title 
Phase II Study of INCB018424
Study Chair: 
Farhad Ravandi-Kashani
Additional Contact:
Kwann C. Vigilant
Maria E. Diaz-Pines-Mateo
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-745-0394
Unit:
428
Full Title: 
Phase II Study of INCB018424 in Patients with Advanced Hematologic Malignancies
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 03/23/2017
Version:
16
Submitted by:
Farhad Ravandi-Kashani--11/19/2015 11:45:43 AM
OPR Action:
Accepted by:  Julie Arevalo -- 11/24/2015 2:27:48 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2007-0925
October 14, 2008
Page 2
Protocol Body
 


Protocol Number 2007-0925 
October 13, 2008 
Page 1 of 36 
 
MDACC Protocol #2007-0925:  
 
 
TITLE:  PHASE II STUDY OF INCB018424 IN PATIENTS WITH ADVANCED 
HEMATOLOGIC MALIGNANCIES 
 
 
Protocol No: 
 
Principal Investigator: 
 
 
 
Farhad Ravandi-Kashani, M.D. 
 
Co-Principal Investigator: 
 
 
Jorge Eduardo Cortes, M.D. 
Hagop M. Kantarjian, M.D. 
 
Co-Investigators: 
 
 
 
Srdan Verstovsek, M.D., Ph.D. 
Stefan Faderl, M.D. 
Guillermo Garcia-Manero, M.D. 
Gautham Borthakur, M.D. 
Jan A. Burger, M.D., Ph.D. 
Susan M. O’Brien, M.D. 
Charles A. Koller, M.D. 
Alessandra Ferrajoli, M.D. 
Marina Konopleva, M.D., Ph.D. 
William G. Wierda, M.D., Ph.D. 
Deborah Ann Thomas, M.D. 
Zeev Estrov, M.D. 
Xuelin Huang, M.D., Ph.D. 
 


Protocol Number 2007-0925 
October 13, 2008 
Page 2 of 36 
 
  TABLE OF CONTENTS 
 
Page 
1. Objectives .................................................................................................................. 3 
 
2. Background ............................................................................................................... 3 
2.1  Diseases to be studied ........................................................................................ 3 
2.2  INCB018424 Phosphate ..................................................................................... 3 
2.3  Rationale ............................................................................................................. 5 
 
3. Patient eligibility ........................................................................................................ 7 
3.1 Inclusion criteria ................................................................................................... 7 
3.2 Exclusion criteria .................................................................................................. 8 
 
4. Treatment plan ........................................................................................................... 9 
4.1  Dose of INCB018424 and Treatment Cycle ........................................................ 9 
4.2  Administration of INCB018424 .......................................................................... 11 
4.3  Supportive Care Guidelines .............................................................................. 11 
4.4  Duration of Therapy .......................................................................................... 12 
4.5  Dosing Delays/Dosing Modifications ................................................................. 12 
4.6  Concomitant medications .................................................................................. 13 
 
5. Study procedures .................................................................................................... 13 
5.1  Screening .......................................................................................................... 13 
5.2  Study Procedures ............................................................................................. 15 
 
6. Response definitions .............................................................................................. 22 
 
7.  Pharmacokinetic and Pharmacodynamic Methods ............................................. 25 
7.1  Pharmacokinetic Methods ................................................................................. 25 
7.2  Pharmacodynamic Methods .............................................................................. 25 
7.3  Bone Marrow Aspiration, Biopsy and Cytogenetics .......................................... 26 
 
8. Regulatory and Reporting Requirements ............................................................. 27 
8.1  Expedited Adverse Event Reporting ................................................................. 29 
 
9. Statistics .................................................................................................................. 29 
9.1  Study Population ............................................................................................... 29 
9.2  Efficacy and PK/PD Variables ........................................................................... 30 
9.3  Safety Analysis ................................................................................................. 31 
9.4  Study Definitions ............................................................................................... 31 
9.5  Reporting and Exclusions ................................................................................. 32 
 
10. Ethics ...................................................................................................................... 33 
10.1  Institutional Review Board ............................................................................... 33 
10.2  Informed Consent ........................................................................................... 33 
References ................................................................................................................... 36 


Protocol Number 2007-0925 
October 13, 2008 
Page 3 of 36 
 
1. OBJECTIVES 
 
This study is a phase II study of the JAK kinase inhibitor INCB018424 phosphate in 
patients with advanced hematological malignancies who have failed prior therapy.  
The objectives of the proposed study are: 
 
Primary:  
To observe the anti-tumor effects of INCB018424 in patients with   
relapsed/refractory AML, ALL, and MDS (including CMML), and blast phase  
or tyrosine kinase refractory CML.  
 
Secondary: 
1. To determine the safety and tolerability in patients with relapsed/refractory  
AML, ALL, and MDS (including CMML), and blast phase or tyrosine kinase 
refractory CML.  
 
2. To determine the pharmacokinetics and preliminary pharmacodynamic 
activity including the modulation of signal transducer and activator of 
transcription (STAT) protein phosphorylation.  
 
2. BACKGROUND 
 
2.1 Diseases to be studied 
 
Despite progress in leukemia therapy, most adult patients with leukemia still 
die from disease progression, and improvements in therapy are still required 
for pediatric patients with resistant or relapsed leukemia. For patients with 
acute myeloid leukemia (AML) who fail to achieve a complete remission 
(CR) with first attempts at induction or who have relapsed disease, current 
therapy is inadequate with a true long term cure rate of less than 10% and 
therefore, new agents are needed.1 Adult patients with acute lymphocytic 
leukemia (ALL) who fail to achieve a CR with first attempts at induction or 
who have relapsed disease have a true long term cure rate of less than 
10%.2 Patients with chronic myelogenous leukemia (CML) who enter blastic 
phase having received prior imatinib therapy or who fail imatinib therapy for 
blastic phase have a median survival of 3 to 9 months with current 
therapies.3 Similarly, patients with CML who have failed two or three 
tyrosine kinase inhibitors have few alternative options. 
 
2.2 INCB018424 Phosphate 
2.2.1 Drug Product 
INCB018424 phosphate is an inhibitor of the Janus kinase family of protein 
tyrosine kinases (JAKs) that is currently being developed for treatment of 
myeloproliferative disorders under IND No. 77,456.  Unless otherwise 


Protocol Number 2007-0925 
October 13, 2008 
Page 4 of 36 
 
noted, INCB018424 phosphate is referred to throughout this IND as 
INCB018424.  INCB018424 Phosphate Tablets 5 and 25 mg (free base 
equivalent), as disclosed in IND No. 77,456, will be used in the proposed 
studies described in this IND. Additional details of the CMC characterization 
of INCB018424 may be found in the Clinical Investigators Brochure (CIB). 
IND No. 77,455 was submitted to the FDA Division of Anesthesia, 
Analgesic, and Rheumatology Products to develop INCB018424 Phosphate 
Capsules for the treatment of patients with rheumatoid arthritis.  Phase 1 of 
this study (Study INCB 18424-132) has safely completed the short term (10 
day) dosing of normal volunteers with the 25 mg BID doses of INCB018424 
that are proposed to be used in this study.   
2.2.2 In Vitro Pharmacology of INCB018424 
INCB018424 is a potent inhibitor of all JAK family members (IC50 values < 5 
nM), with modest selectivity for JAK2. It does not significantly inhibit a broad 
panel of 26 other kinases when tested at concentrations approximately 100 
fold higher than its potency against the various JAKs.  Moreover, in cell-
based assays relevant to the pathogenesis of MPDs and cancer, such as 
cytokine-induced JAK-STAT signaling, cytokine-driven tumor cell 
proliferation as well as growth of a cell line expressing the JAK2V617F 
mutation, INCB018424 demonstrates excellent potency (IC50 values of ~ 80-
150 nM).  This effect is not due to general cytotoxicity, because 
INCB018424 (up to 20 µM) had no significant effect on the growth of 
cytokine-independent cell lines.  In addition, INCB018424 inhibits cytokine-
induced JAK/STAT phosphorylation in human whole blood with an IC50 
value of ~ 300 nM, providing a useful biomarker of INCB018424 
pharmacological activity. Additional details as to the in vitro pharmacology of 
INCB018424 may be found in the Clinical Investigators Brochure (CIB). 
2.2.3 In Vivo Pharmacology of INCB018424 
Treatment of mice with orally administered INCB018424 resulted in a dose-
dependent suppression of STAT3 phosphorylation and tumor growth in the 
cytokine-dependent multiple myeloma INA-6 xenograft model at doses ≥ 10 
mg/kg BID.  Moreover, oral administration of INCB018424 inhibited JAK 
pathway signaling, tumor cell growth and splenomegaly in mice resulting 
from intravenous inoculation of a BaF3 cell line engineered to express 
JAK2V617F (BaF3-JAK2V617F).  Additional details as to the in vivo 
pharmacology of INCB018424 may be found in the Clinical Investigator’s 
Brochure (CIB).  
 
Pharmacological data obtained in both in vitro and in vivo model systems 
support the potential utility of orally administered INCB018424 in the 
treatment of JAK-dependent hematological malignancies. 
 


Protocol Number 2007-0925 
October 13, 2008 
Page 5 of 36 
 
INCB018424 has been administered orally in single doses to healthy 
subjects in ongoing study INCB 18424-131.  In study INCB 18424-131, 
single oral doses of 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 200 mg have 
been administered with monitoring of adverse events, clinical laboratories, 
PK and pharmacodynamic parameters.  All single doses were well tolerated 
with no observed drug-associated adverse events.  The pharmacodynamic 
preliminary, unaudited draft data available indicate that single doses of 
INCB018424 are able to inhibit interleukin-6 induced STAT3 
phosphorylation in a dose dependent manner.  The 200 mg dose of 18424 
produced ~80-95% inhibition of STAT3 phosphorylation between 1-8 hours 
following dosing with levels returning to baseline by 48 hours.   
 
In study INCB 18424-132, multiple oral doses of 25 mg BID and 50 mg  
daily and BID have been administered with monitoring of adverse events, 
clinical laboratories, PK and pharmacodynamic parameters.  The 
preliminary unaudited pharmacodynamic draft data available indicate that 
multiple doses of INCB018424 are able to inhibit interleukin-6 induced 
STAT3 phosphorylation in a dose dependent manner, similar to data 
obtained in the single dose studies.  The data on day 1 and day 10 
demonstrated similar levels of inhibition of STAT3 phosphorylation, 
indicating a lack of cumulative biological activity.  From an evaluation of the 
safety data obtained in this study, the preliminary conclusion is that the 
INCB018424 50 mg BID dose is considered too high for healthy volunteers 
and patients without serious diseases.  Dosing in these populations should 
be limited to 25 mg BID or lower and up to 50 mg daily, although higher 
doses than 50 daily may be safe but have not been tested beyond single 
doses.  However, in patients with malignancies dose escalation could 
continue until the maximum tolerated dose is achieved due to the different 
benefit-risk ratio in these subjects and because these patients may respond 
differently.  
 
Under IND No. 77,456, INCB018424 has also been dosed to three patients 
with multiple metaplasia with myelofibrosis at 25 mg BID for over five 
months with clinical benefit but without notable toxicity.  In this study four 
patients have also been dosed at 50 mg INCB018424 BID but, according to 
protocol, dosing was halted after two of four subjects presented with 
significant reductions in peripheral blood neutrophils and platelets.  
Subsequently, according to protocol, three additional patients have been 
treated at the 25 mg BID dose for at least 1 month to establish this dose as 
the MTD in this population. 
 
2.3 Rationale 
 
The Jak family of kinases comprises four proteins (Jak1, Jak2, Jak3, and 
Tyk2) that can associate with cytokine receptor subunits, phosphorylate 
them, and in doing so create docking sites on the receptors for binding of 


Protocol Number 2007-0925 
October 13, 2008 
Page 6 of 36 
 
SH2-containing proteins. In general, Jaks consist of several domains (JH1-
JH7), including a tyrosine kinase domain, and the functional significance of 
these domains has been characterized by mutational analysis.  Jaks are 
able to associate with the cytokine receptors as well as with each other. 
Dimerization/oligomerization of cytokine receptor subunits as a result of 
ligand binding leads to juxtaposition of Jaks. This results in 
transphosphorylation and activation of their kinase activity and the 
phosphorylation of downstream signaling proteins such as Stats, Src-
kinases, and adaptors such as Shc, Grb2, and Cbl.4  
Abnormalities of Jak function have been associated with a number of 
disorders. For example, chromosomal translocations resulting in TEL-JAK2 
constructs lead to the constitutive activation of STAT5, IL-3-independent 
cellular proliferation, and leukemogenesis. The translocation 
t(9;12)(p24;p13) results in the fusion of the kinase catalytic region of JAK2 
with the transcription factor TEL generating the constitutively active TEL-
JAK2. Similarly, infection with oncogenic viruses such as human T-cell 
lymphotrophic virus, type I, and Abelson murine leukemia viruses results in 
enhanced kinase activity of Jaks, possibly accounting for their leukemogenic 
potential.  
The STAT transcription factors are coded by six known mammalian genes 
and include 10 different STAT proteins including different isomers of STATs 
1, 3, 4, and 5. Like other transcription factors STATs have a well-defined 
structure including a DNA-binding domain, a conserved NH2-terminal 
domain, a COOH-terminal transactivation domain, and SH2 and SH3 
domains. Their activation through tyrosine phosphorylation results in their 
dimerization and translocation into the nucleus where they activate specific 
genes.4  
Jak proteins activate a number of intracellular signaling proteins, among 
which STATs are the best defined. Binding of a cytokine to its receptor 
rapidly induces tyrosine phosphorylation of the cytoplasmic domains of the 
receptor by activated Jak kinases, thus providing a docking site for STAT 
proteins, which are then phosphorylated. This phosphorylation of STATs 
leads to their homo- or heterodimerization and translocation to the nucleus, 
followed by DNA binding and gene activation. The specificity for STAT 
phosphorylation is determined by the receptor docking sites and not the Jak 
kinases. Also, different STAT proteins have different DNA-binding affinities, 
resulting in activation of specific genes. STATs also interact with other 
transcription factors such as the p300/cyclic AMP-responsive element 
binding protein family of coactivators to activate genes. The transcriptional 
activity of STATs may also be regulated by the phosphorylation of their 
serine and threonine residues, although the implications of such regulation 
are not known.  


Protocol Number 2007-0925 
October 13, 2008 
Page 7 of 36 
 
STATs mediate diverse and sometimes opposite cellular events affecting 
growth, differentiation, and apoptosis. For example, STATs can mediate 
both growth arrest and cellular proliferation. Specifically, STAT1 mediates 
the growth-inhibitory effects of IFN- , through the induction of the CDKI 
p21waf1, whereas STAT5 mediates proliferative effects of IL-3 and GM-CSF. 
Similarly, phosphorylation of STAT3 can result both in IL-6- and IL-10-
induced growth arrest, and in GM-CSF- and IL-3-induced proliferation. 
STATs also modulate cellular differentiation and apoptosis. Reconstitution of 
STAT1 in STAT1-null U3A cells (which do not respond to TNF- ) restores 
basal caspase expression and renders them sensitive to TNF-induced 
apoptosis. Conversely, STAT3 and STAT5 mediate the antiapoptotic effects 
of IL-6 and IL-2, respectively. STAT1 activates the caspase cascade 
through up-regulation of Fas and FasL expression in response to IFN- . The 
exact mechanisms underlying these diverse effects are being elucidated.4  
Abnormalities of the JAK-STAT pathways have been described in a variety 
of leukemias and their inhibition can be a goal for leukemia therapy. 
 
3.  PATIENT ELIGIBILITY 
 
Patients in this trial can be of any race and either gender.   
 
3.1 Inclusion Criteria 
 
A. Must be at least 18 years of age. 
 
B. Patients must have relapsed/refractory leukemias for which no standard therapies 
exist. Patients with poor-risk myelodysplasia (MDS) [i.e. refractory anemia with 
excess blasts (RAEB-1 or RAEB-2) by WHO classification] and chronic 
myelomonocytic leukemia (CMML) who failed prior therapy are also candidates for 
this protocol. Relapsed/refractory leukemias include acute non-lymphocytic 
leukemia (AML) by WHO classification (i.e. ≥ 20% blasts), acute lymphocytic 
leukemia (ALL), or chronic myelogenous leukemia (CML) in blast crisis. Patients 
with CML who are resistant to at least two tyrosine kinase inhibitors and have no 
standard stem cell transplant option are also eligible. 
 
C. ECOG performance status of 0-2.  
 
D. A female of childbearing potential must have a negative serum or urine pregnancy 
test at screening.  Women of child-bearing potential (i.e., women who are pre-
menopausal or not surgically sterile) must use acceptable contraceptive methods 
(abstinence, intrauterine device [IUD], oral contraceptive or double barrier device), 
and must have a negative serum or urine pregnancy test within 2 weeks prior to 
beginning treatment on this trial.  Sexually active men must also use acceptable 
contraceptive methods for the duration of time on study. 


Protocol Number 2007-0925 
October 13, 2008 
Page 8 of 36 
 
 
E. Must be able and willing to give written informed consent. 
 
F. In the absence of rapidly progressing disease, the interval from prior treatment to 
time of study drug administration should be at least 2 weeks for cytotoxic agents, 
or at least one week for noncytotoxic agents.  Persistent clinically significant 
toxicities from prior chemotherapy must not be greater than grade 2.  
 
G. Patients must have the following clinical laboratory values unless considered due 
to leukemic organ involvement: 
1. Serum creatinine ≤ 2.0 mg/dl.  
2. Total bilirubin ≤ 1.5x the upper limit of normal unless considered 
due to Gilbert’s syndrome or hemolysis.  
3. Alanine aminotransferase (ALT), and aspartate aminotransferase 
(AST) ≤ 2.5x the upper limit of normal unless considered due to 
organ leukemic involvement (then ≤ 5x the upper limit of normal).  
 
H.  Patients with active CNS disease are included and will be treated concurrently 
with intrathecal therapy.  INCB018424 will not be administered by intrathecal 
route. 
 
 
3.2  Exclusion Criteria 
 
Patients with any one of the following criteria will not be eligible for study 
participation: 
 
A. Uncontrolled intercurrent illness including, but not limited to uncontrolled 
infection, symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements.  
 
B. Active heart disease including myocardial infarction within the previous 3 months, 
symptomatic coronary artery disease, arrhythmias not controlled by medication, 
or uncontrolled congestive heart failure. 
 
C. Current treatment or treatment within 2 weeks or 5 half-lives (whichever is 
longer) prior to the first dose of study medication with another investigational 
medication or current enrollment in another investigational drug protocol (unless 
there is evidence of rapidly progressive disease in which case a shorter interval 
from last therapy may be acceptable). 
 
D. Females who are pregnant or are currently breastfeeding. 
 
E. Patients receiving therapy with intermediate or high dose steroids greater than 
the equivalent of 10 mg prednisone per day are not allowed. 
 


Protocol Number 2007-0925 
October 13, 2008 
Page 9 of 36 
 
F. Evidence of active hepatitis or human immunodeficiency virus (HIV) infection 
determined by screening laboratory test results or results within prior 3 months. 
 
G. Any unresolved toxicity equal to or greater than Grade 2 from previous 
anticancer therapy, except for stable chronic toxicities not expected to resolve, 
such as peripheral neurotoxicity. 
 
H. Incomplete recovery from any prior surgical procedures or had surgery within 4 
weeks prior to study entry, excluding the placement of vascular access.  
 
I. Uncontrolled intercurrent illness or any concurrent condition that, in the 
Investigator’s opinion, would jeopardize the safety of the patient or compliance 
with the protocol. 
 
J. In patients who are receiving medications known to be inhibitors or inducers of 
CYP3A4 every effort will be made to change these medications to acceptable 
alternatives. If this is not safely possible, patients will be excluded from 
participation in the study. If a patient is already on the study, must be started on a 
CYP3A4 inhibitor, and is demonstrating benefit from the study, they will be seen 
twice weekly in the first cycle and weekly in the subsequent cycles for toxicity 
evaluation and their dose will be modified according to the table in section 4.5 in 
the event of a toxicity thought to be related to the study drug. A list of CYP3A4 
inducers and inhibitors is provided in Appendix I. 
 
 
4. TREATMENT PLAN 
 
4.1  Dose of INCB018424 and Treatment Cycle 
 
This is a phase II study of oral INCB018424 in patients with relapsed/refractory 
AML, ALL, and MDS (including CMML), and blast phase or tyrosine kinase 
refractory CML. The starting dose of INCB018424 will be 25 mg po twice daily, 
which has been determined to be the maximum tolerated dose in patients with 
myelofibrosis with myeloid metaplasia and a dose that is tolerated for ten days in 
normal human volunteers.   
 
INCB018424 will be administered orally at a dose of 25 mg BID for 7 days each 
week for 4 weeks (cycle number 1).  Patients will be evaluated after 1 full cycle of 
therapy (28 days) for response.  Responding patients or patients with stable 
disease will be allowed to continue on study at a dose of 25 mg INCB018424 BID 
until progression. The response assessment for the purpose of study statistical 
evaluation will be after two cycles (8 weeks) of therapy.  Patients with 
progressive disease, based on clinical and laboratory evaluation, will, at the 
discretion of the Investigator, either be removed from the study or, as long as the 
25 mg BID dose has been well tolerated, dose escalated to 50 mg INCB018424 
BID. In instances of dose escalation to 50mg BID, patients will be evaluated after 


Protocol Number 2007-0925 
October 13, 2008 
Page 10 of 36 
 
1 full cycle of therapy (28 days) for response and toxicity.  At that point, patients 
with continued progressive disease, based on clinical and laboratory evaluation, 
will be removed from the study.  In instances of dose escalation, the response 
assessment for the purpose of study statistical evaluation will be after two cycles 
(8 weeks) of therapy at the 50 mg BID dose.    
 
Patients with chronic phase CML who have failed at least 2 prior tyrosine kinase 
inhibitors and do not have a standard transplant option will be assessed for 
response after 3 months of therapy in the absence of loss of disease control and 
they may continue therapy if they demonstrate any clinical benefit. Patients with 
chronic phase CML will not be allowed to have the dose escalation as this 
population has less of a life-threatening disease situation. 
   
Patients who, in the opinion of the Investigator, are demonstrating cytopenias not 
thought to be related to disease progression and who may be receiving benefit 
from treatment may, at the discretion of the Investigator, be dose adjusted to a 
lower dose of INCB018424 BID or an equivalent dose given daily (see section on 
dose modifications below).  Studies in subjects with myelofibrosis with myeloid 
metaplasia using different doses and schedules of INCB18424 may be used as a 
guide to dose adjustments in this study. 
 
Patients will initiate the first cycle of therapy at MDACC. They will have weekly 
visits at their local physician’s office with physical exam and review of symptoms 
during cycle one. In the absence of intolerable side effects, patients may return to 
the local oncologist for laboratory tests, but only MDACC investigators can make 
treatment decisions.  Patients will return to MDACC every 4 weeks to be 
evaluated and receive their new supply of study medication.  For the second and 
third cycle, patients will return to MDACC every 4 weeks to be evaluated and 
receive their new supply of study medication.  Subsequently, patients will return 
to MDACC every three months. Because of drug stability issues, some patients 
may have to continue to be seen on a monthly basis to have the drug provided. 
 
For toxicity evaluation, patients enrolled in the study will be considered in 2 
cohorts (I) those with relapsed/refractory AML, ALL, and MDS (including CMML), 
and blast phase CML, and (II) those with chronic phase CML. At any time after 6 
patients are enrolled in cohort I (including AML, ALL, MDS, blast phase CML 
patients), if 30% or more patients experience grade 3 or 4 toxicity thought to be 
directly related to INCB018424 and lasting longer than 2 weeks, then we will stop 
that cohort of the trial. At any time after 6 patients are enrolled in cohort II 
(including chronic phase CML patients), if 15% or more patients experience 
grade 3 or 4 toxicity thought to be directly related to INCB018424 and lasting 
longer than 2 weeks, then we will stop that cohort of the trial. 
 
 
 
 


Protocol Number 2007-0925 
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4.2 Administration of INCB018424 
 
This is an open label, non-randomized, study of INCB018424, administered 
orally to patients with relapsed/refractory AML, ALL, and MDS (including 
CMML), and blast phase or tyrosine kinase refractory CML.  The study of 
INCB018424 in each disease listed will be conducted in two parts.  The first 
part is intended to enroll a maximum of 10 patients within each of the four 
disease categories included in this study and to identify whether significant 
benefit is observed.  If a minimum of one patient shows benefit that is 
considered significant, there will be an expanded cohort of 20 additional 
patients treated in that arm of the study.  
  
Patients will receive 50 mg/day administered orally in two divided doses (i.e., 
BID: every 12 hours ± 2 hours).  Within each arm of the study, three patients 
will be initially treated and observed for toxicity for one treatment cycle (28 
days) before the additional seven patients are entered. Dose reduction will be 
considered if the number of patients experiencing grade 3 or higher toxicities 
exceed 2/3, 3/4, 4/7, 5/10, 6/14, 7/18, 8/22, 9/26. Treatment will be 
administered primarily on an outpatient basis, but can be administered as an 
inpatient if the patient is hospitalized for other reasons.   
 
The 5 mg tablets have been shown to be stable when stored up to one month 
at 25ºC/60%RH and 40ºC/75%RH; the 25 mg tablets have been shown to be 
stable when stored for three months at 25º/60%RH and 40º/75%RH.  (25ºC = 
77ºF, 40ºC = 104ºF). 
 
 
 
4.3 Supportive Care Guidelines 
  
Supportive measures including erythropoietin, analgesics, blood transfusions, 
antimicrobials, and hematopoietic colony stimulating factors for treatment of 
cytopenias are permitted. 
 
Prophylactic use of hematopoietic colony stimulating factors  is not permitted.  
 
Other chemotherapy, investigational cytotoxic agents, radiation, or biologic 
therapy is prohibited while the patient is on study with the following exceptions 
during cycle 1: During the first 7 days of study only, patients may receive 
leukaphereses (not more than three procedures per week and not more than 
five procedures in total to control elevated blast and/or platelet counts and/or 
hydroxyurea (up to a maximum of 5 gm/day) for a maximum of 14 days.  
Intrathecal chemotherapy to treat isolated CNS involvement of leukemia is 
allowable. 
 
 
 


Protocol Number 2007-0925 
October 13, 2008 
Page 12 of 36 
 
 
4.4 Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
 
˜ 
Lack of objective response after 2 cycles of therapy (3 cycles if there is 
dose escalation to 50 mg BID after cycle 1) unless INCB018424 is 
considered to be of clinical benefit to the patient 
 
˜ 
Intercurrent illness that prevents further administration of treatment 
 
˜ 
Unacceptable adverse event(s) 
 
˜ 
Patient decides to withdraw from the study, or 
 
˜ 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 
4.5 Dosing Delays/Dose Modifications 
 
Dose Adjustments 
 
The dose of INCB018424 will be adjusted according to the guidelines shown 
in the following tables for INCB018424 - related clinically significant toxicity.  If 
a toxicity is not covered in the table, doses may be reduced or held at the 
discretion of the investigator for the patient’s safety.  Dose adjustments for 
hematological toxicity are based on the blood counts obtained in preparation 
for the day of treatment i.e. CBC within 3 days of Day 1 of that cycle.   
 
Patients will be withdrawn from the study if they fail to recover to CTC AE 
grade 0 to 2 (or within 1 grade of starting values for pre-existing laboratory 
abnormalities) from a treatment-related toxicity within 2 weeks (leading to 
treatment delay of > 2 weeks) unless the investigator feels that the patient 
should remain in the study because of evidence that the patient is/may 
continue deriving benefit from continuing study treatment. 
 
Patients with toxicities that are manageable with supportive therapy may not 
require dose reductions.  Patients requiring greater than 1 dose reduction of 
INCB018424 should be withdrawn from the study, unless INCB018424 is 
considered to be of clinical benefit to the patient. 
 
Dose modification for neutropenia and thrombocytopenia grade 4 persisting 
beyond 2 weeks of therapy is allowed if the treating physician believes them 
to be related to the treatment and not the underlying disease. The dose can 
be held until the AE is to grade 2 or lower; then INCB018424 will be restarted 
at 15 mg BID or an equivalent dose given daily. Alternatively, at the discretion 


Protocol Number 2007-0925 
October 13, 2008 
Page 13 of 36 
 
of the treating physician, the dose may be reduced to 15 mg BID without 
holding the drug if the treating physician believes that the cytopenia is related 
to a combined effect of the drug and uncontrolled disease. 
 
 
Dosing for INCB018424- Related Toxicities 
 
NCI CTC AE Grade 
INCB018424 
Grade 0-2 non-hematological toxicity 
No dose reduction. 
Grade 2 toxicities that are persistent and 
intolerable (e.g. stomatitis) can result in 
dose delays or dose reduction to 15 mg 
BID in Cycle 2 or beyond. 
Grade 
3-4 
clinically 
significant 
non-
hematological toxicity 
Hold until recover to NCI CTC AE grade 0-2 
If recovery occurs within 2 weeks after 
treatment has been held, dose should be 
reduced to 10 mg or 15 mg BID.  At the 
discretion of the investigator and if the 
patient is considered to be benefiting, the 
patient will receive an intermittent dose 
schedule, alternating treatment periods and 
recovery periods at the 25 mg BID dose. i.e 
alterations to the dose and schedule that is 
thought to be beneficial to the patient in the 
responding patients may be allowed after 
discussion with IRB, FDA and the PI. 
   
4.6  Concomitant medications 
 
INCB018424 is predominantly metabolized by CYP3A4. 
      The potential for INCB018124 to inhibit or induce human Cytochrome P450 
enzymes has been extensively investigated. The available data suggests that the 
potential for INCB018124 to cause clinical drug interaction via CYP inhibition is low. 
Furthermore, in vitro data suggest that the potential for INCB018124 to induce 
CYP3A4 is also low. Therefore there is little potential to interact with other drugs. 
 
5.  STUDY PROCEDURES 
 
5.1  Screening  
The following procedures are performed during screening, staging and workup 
(Table 5.1, below).  These procedures are to be performed within 4 weeks prior to 
study drug administration, except where indicated. 
 
 
 
 


Protocol Number 2007-0925 
October 13, 2008 
Page 14 of 36 
 
 
Table 5.1:  Procedures During Screening, Staging and Workup 
Procedures 
Specifics 
Informed consent 
 
Full History and Physical Examination 
History – present illness, all surgeries, all 
other medical illnesses, review of 
systems, allergies, all prior therapy for 
cancer and concurrent meds;  
F 
Physical exam – record weight, and 
note abnormalities in any major organ 
system (including but not limited to 
neurologic, head and neck, lymph 
nodes, cardiovascular, pulmonary, 
abdomen, extremities), note and 
measure sites of disease 
Vital signs (including temperature, pulse, and blood pressure)  
 
ECOG performance status 
 
Pregnancy test (females of child-bearing potential only) 
At screening, within 2 weeks prior to first 
dose 
Disease status (note: measurement of lesions assessed only by 
physical exam should be performed within 1 week prior to first dose)  
 
Note: Bone marrow biopsy or aspirate within 4 weeks prior to first 
dose of drug in all patients. Cytogenetics, immunohistochemistry, 
and histochemistries performed as indicated. 
Staging with bone marrow biopsy or 
aspirates.  
 
Lumbar punctures or radiographic 
investigations as appropriate to the 
disease. 
Serum chemistries (repeat if screening chemistries completed 
greater than 72 hours prior to the first dose) 
Sodium, potassium, chloride, CO2, blood 
urea 
nitrogen, 
creatinine, 
glucose, 
calcium, phosphate, magnesium, AST
and 
ALT, 
total 
bilirubin, 
alkaline 
phosphatase, total protein, albumin, uric 
acid, lactic dehydrogenase 
Urinalysis (including microscopic) 
 
CBC with platelets (repeat if screening test completed greater than 
24 hours prior to the first dose) 
 
PT/aPTT 
 
Chest X-ray PA-LAT 
 
HIV, Hepatitis B and C 
Results of test performed within past 3 
months acceptable 
 
 
PA-LAT = Posterior anterior - lateral.  


Protocol Number 2007-0925 
October 13, 2008 
Page 15 of 36 
 
5.2 Study Procedures 
 
Screening 
Phase 
Treatment Phase 
End 
of 
Treatment 
                      Cycle 1 
                        Cycle 2+3 
Subsequent Visits - 
For details see Footnotes 
Visit  
 
Day -28 to 
Day -1  
Day 
1  
Day 
8 
Day 
15 
Day  
22 
Day  
1 
Day  
8 
Day  
15 
Day  
22 
Day 1 
Day 15 
End of 
Studyo 
Evaluation – All evaluations have a 
+/- 2 day window except for bone 
marrow biopsy (see footnote i). 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consenta / Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical & medication historyb  
X 
X 
X 
X 
X 
X 
 
 
 
Xb 
 
X 
Physical examinationc   
X 
X 
X 
X 
X 
X 
 
 
 
Xc 
 
X 
Vital signsc   
X 
X 
X 
X 
X 
X 
 
 
 
Xc 
 
X 
Overall Response assessment (IWG-MRT)d 
  
 
 
 
 
X 
 
 
 
Xd 
 
X 
ECOG performance statuse 
X 
 
 
 
 
X 
 
 
 
Xe 
 
X 
Concomitant medication reviewf 
 
X 
X 
X 
X 
X 
 
 
 
Xf 
 
X 
Clinical laboratory testsg 
X 
 
X 
X 
X 
X 
 
X 
 
Xg 
 
X 
CBCh  
X 
 
X 
X 
X 
X 
X 
X 
X 
Xh 
Xh 
X 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
CXR 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
 
 
FSH testg 
X 
 
 
 
 
 
 
 
 
 
 
 
Serology / HIV laboratory testsg 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisg 
X 
 
 
 
 
 
 
 
 
 
 
 
BM aspiration, biopsy and cytogeneticsi 
X 
 
 
 
 
 
 
 
 
Xi 
 
 
Administer 1st dose of INCB018424j 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense INCB018424 study medicationj 
 
X 
 
 
 
X 
 
 
 
Xj 
 
 
PK sampling k 
 
X 
 
 
 
X 
 
 
 
 
 
 
PD biomarker sampling l 
 
X 
 
 
 
X 
 
 
 
Xl 
 
X 
Adverse 
event 
/ 
Intercurrent 
illness 
assessmentm 
 
X 
X 
X 
X 
X 
 
 
 
Xm 
 
X
Study medication compliancen 
 
 
X 
X 
X 
X 
 
 
 
Xn 
 
X 
a. Informed consent must be obtained at Screening.  At Screening and Day 1, assess eligibility for study entry and review eligibility for 
study entry on Day 1. 
b. Medical history will be done at each visit. Medication history will be obtained only at the screening visit. 
c. A complete examination will be performed at Screening and the End-of-Study Visit . A “targeted” examination will be performed at 
all other visits.  During the treatment phase, weekly visits at the local physician’s office are required during 1st cycle of therapy with 
a review of constitutional symptoms and physical exam, including transfusion requirement. During 2nd and 3rd cycles visits are 
every 4 weeks, and then every 3 months thereafter.  All examinations will include body weight.  On Day 1 of Cycle 1, before PK/PD 
blood-draws, the vital signs will be done as well as with the physical exams.  On all other clinical visits vital signs are taken once. 
Overall response assessments will be graded according to consensus criteria for treatment response.  


Protocol Number 2007-0925 
October 13, 2008 
Page 16 of 36 
 
d. Overall response assessments are required on Day 1 of Cycles 2, 3, and 4 and then every 3 months thereafter.  If the dose of 
INCB018424 is escalated to 50 mg BID after cycle 1, then overall response assessments are required on Day 1 of Cycles 3, 4, and 
5 and then every 3 months thereafter. 
e. ECOG performance criteria must be 0, 1 or 2 at screening.  ECOG assessment is required on Day 1 of 2nd and 3rd cycles and 
thereafter every scheduled subsequent visit on Day 1. 
f. 
All medications received within 30 days prior to the Screening Visit are to be recorded. Reassessments will be done weekly at the 
local physician’s office during 1st cycle of therapy and then every 4 weeks during 2nd and 3rd cycles and thereafter every 3 months 
during scheduled visits. 
g. Serum chemistry (Sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, calcium, phosphate, magnesium, 
AST or ALT, total bilirubin, alkaline phosphatase, total protein, albumin, uric acid, lactic dehydrogenase)  is required every week 
during the 1st cycle and every two weeks during Cycles 2 and 3, and at each scheduled subsequent visit.  Urinalysis is required 
only at screening and at the end of study visit.  Hepatitis serology and HIV laboratory test will be performed only during the 
Screening Visit if there are no results available from past 3 months. A pregnancy test will be obtained at screening.  Urine 
pregnancy test will then be performed if there is a suspicion of pregnancy. A serum pregnancy test will be performed to confirm 
positive results obtained from a urine test.  FSH test will only be performed on females who have been amenorrheic for >1 year, 
and if levels are elevated no further pregnancy testing is required for these female patients.   
h. Complete blood count (CBC) including absolute neutrophil count and platelet count are required weekly for Cycle 1, 2 and 3 and 
every two weeks for subsequent visits.   
i. 
Bone marrow aspiration or biopsy will be taken during the screening phase (within 4 weeks of starting drug), and at start of Cycle 4 
(± 7 days), Cycle 7 (± 7 days), and thereafter at start of each 6th subsequent cycle (+/- 7days).  Evaluation will include staining for 
fibrosis and cytogenetics if abnormal prior to therapy.   Cytogenetic studies will be repeated only in patients with abnormalities at 
baseline, on Day 1 of Cycles 4 and 7 and thereafter on Day 1 of each 6th subsequent cycle(+/-7days).  If unable to obtain BM 
aspirate, cytogenetics may also be done on peripheral blood collected for PD/PK analysis.  
j. 
Instruct patient that the dose is to be taken at 12 hour intervals at approximately the same time each day. The first dose of each 
day should be taken in the morning.   
k. For Cycle 1, PK samples to be collected on Day 1 at pre-dose, 0.5, 1, 1.5, 2, 4, 6, and if possible 8  hours after administration of the 
morning dose of INCB018424. For Cycles 2 and 3, a PK sample will be collected at pre-dose on Day 1.   
l. 
For Cycle 1, plasma and whole blood PD samples will be collected on Day 1 at pre-dose and 2, hours after administration of the 
morning dose of INCB018424.  For Cycles 2, 3, and each subsequent scheduled visit to MDACC, plasma and whole blood PD 
samples will be collected at pre-dose on Day 1.  Final PD sample will be collected at End-Of–Study visit. Not all samples may be 
collected on all patients.  See Appendix F. 
m. Adverse events (AEs) considered related to study medication must be followed until resolution, start of a different treatment therapy 
or no longer considered to be clinically relevant in the opinion of the investigator. During the treatment phase, AE assessment is 
required weekly at the local physician’s office during 1st cycle of therapy. During the 2nd and 3rd cycles assessments are required 
every 4 weeks, and then every visit thereafter. 
n. Compliance should be checked at each scheduled clinical visit.  Any unused drug in sealed bottles will be returned to Incyte or its 
designee.  MDACC will follow internal procedures to destroy and dispose of unused drug in open/unsealed bottles. 


Protocol Number 2007-0925 
October 13, 2008 
Page 17 of 36 
 
o. End-of-Study procedures are to be completed if patient completes study or at anytime patient terminates treatment early in the 
study. 


Protocol Number 2007-0925 
October 13, 2008 
Page 18 of 36 
 
 
5.2.1 Cycle 1 
 
5.2.1.1  Cycle 1 - Day 1 
 
Patients who meet all of the study entrance criteria and none of the exclusion 
criteria will return to the study site on Day 1.  The following procedures will be 
performed: 
 Review of eligibility criteria including laboratory results. 
 Review of prior/concomitant medications. 
 Targeted physical examination. 
 Record vital signs. 
 Intercurrent illness will be assessed pre-dose. 
 Administration of the 1st dose of the INCB018424.  
 Blood samples for plasma PK assessment will be drawn pre and post-
dose with exact time recorded as defined in the Study calendar.   PK 
samples to be collected on Day 1 at pre-dose, 0.5, 1, 1.5, 2, 4, 6, and if 
possible 8 hours after administration of the morning dose of INCB018424. 
If not feasible, all samples do not have to be drawn in all patients.  
 Blood sample for plasma and whole blood PD will be collected pre-dose, 
and 2 hours after administration of the morning dose of INCB018424.   
 Adverse events will be assessed post-dose.    
 Study medication for the first Cycle will be dispensed and the Study staff 
will instruct the patient regarding dosing regimen. 
 Patients will be instructed to call the Investigator or designated research 
staff if they experience any “troubling” signs and/or symptoms that are of 
moderate or greater severity.   
 Patients will be asked to return to the clinical site on Day 8.  Patients will 
be asked to bring the study medication. 
  
5.2.1.2 
Days 2 to 7 
 
Patients will self-administer study medication as instructed twice daily at 
approximately 12 hour intervals in an out-patient setting.  
  
5.2.1.3 
Day 8 ± 2  
 
The following procedures will be performed: 
 Review of medical history and concomitant medication. 
 Review of any adverse events. 
 Targeted physical examination and vital signs. 
 Blood sampling for blood serum chemistry tests, CBC with Differential, 
ANC, platelet count  
 Review all safety information and criteria for dosing interruptions to 
determine if patients should receive further doses.  


Protocol Number 2007-0925 
October 13, 2008 
Page 19 of 36 
 
 Patients will be instructed to call the Investigator or designated research 
staff if they experience any “troubling” signs and/or symptoms that are of 
moderate or greater severity. 
 Patients will be asked to return to the clinical site on Day 15.  
 
5.2.1.4 
Days 9 to 14 
 
Patients will self-administer study medication as instructed twice daily at 
approximately 12 hour intervals in an out-patient setting. 
 
5.2.1.5 
Day 15 ± 2  
 
The following procedures will be performed: 
 Review of medical history and concomitant medication. 
 Review of any adverse events. 
 Targeted physical examination and vital signs. 
 Blood sampling for blood serum chemistry tests, CBC with Differential, 
ANC, platelet count  
 Patients will be instructed to call the Investigator or designated research 
staff if they experience any “troubling” signs and/or symptoms that are of 
moderate or greater severity. 
 Patients will be asked to return to the clinic on Day 22.   
 Review all safety information and criteria for dosing interruptions (Section 
10.4) to determine if patients should receive further doses.  
 
5.2.1.6 
Days 16 to 21 
 
Patients will continue to self-administer study medication per instructions twice 
daily at approximately 12 hour intervals in an out-patient setting.     
 
5.2.1.7 
Day 22 ± 2  
 
The following procedures will be performed: 
 Review of medical history and concomitant medication. 
 Review of any adverse events. 
 Targeted physical examination and vital signs. 
 Blood sampling for the blood serum chemistry tests, CBC with Differential, 
ANC, platelet count  
 Patients will be instructed to call the Investigator or designated research 
staff if they experience any “troubling” signs and/or symptoms that are of 
moderate or greater severity. 
 Patients will be asked to return to the clinic on Day 1 of Cycle 2 (Day 28 to 
31 of Cycle 1).  Patients will be asked to bring all study medication with 
them to the visit.  


Protocol Number 2007-0925 
October 13, 2008 
Page 20 of 36 
 
 Due to PK and PD samples being collected at the next visit, patients will 
be asked to withhold their morning dose of study medication on Day 1 of 
Cycle 2. 
 Review all safety information and criteria for dosing interruptions (Section 
10.4) to determine if patients should receive further doses.  
 
5.2.1.8 
Days 23 to 27 
 
Patients will continue self-administering study medication per instructions twice 
daily at approximately 12 hour intervals in an out-patient setting.  
 
5.2.2  
Cycles 2 and 3 
 
5.2.2.1 
Day 1 ± 2 days 
 
The following procedures will be performed: 
 Review of medical history and concomitant medication. 
 Review of any adverse events. 
 Targeted physical examination and vital signs. 
 ECOG performance status. 
 Urine collection for pregnancy test on females of childbearing potential only. 
If positive then serum pregnancy test will be done. 
 Blood sampling for the following: 
o Blood serum chemistry tests, CBC with Differential, ANC, platelet 
count   
o PK analysis sample collection pre-dose 
o Plasma and whole blood PD marker analysis sample collection pre-
dose  
 Overall response assessment. 
 Administration of the morning dose of INCB018424.   
 A study medication tablet count will be done to assess compliance.  If patient 
qualifies for continued dosing, they will be provided with study medication for 
the next 4 weeks.  
 Patients will be asked to return to the clinic on Day 1 of Cycle 3 (Day 28 of 
Cycle 2 ± 2 days).  Patients will be asked to bring all study medication with 
them to the visit.  
 Due to PK and PD samples being collected at the next visit, patients will be 
asked to withhold their morning dose of study medication on Day 1 of Cycle 
3. 
 All procedures listed above, including dispensing of study medication for next 
4 weeks of Cycle 3, if patient qualifies for continued dosing, will be performed 
on Day 1 of Cycle 3 ± 2 days.  Patients will be asked to return to the clinic on 
Day 1 of Cycle 4 (Day 28 of Cycle 3 ± 2 days).  Patients will be asked to 
bring all study medication with them to the visit.  
 Due to PD samples being collected at the next visit, patients will be asked to 
withhold their morning dose of study medication on Day 1 of Cycle 4. 


Protocol Number 2007-0925 
October 13, 2008 
Page 21 of 36 
 
 Review all safety information and criteria for dosing interruptions to determine 
if patients should receive further doses.  
 Patients will be instructed to call the Investigator or designated research staff 
if they experience any “troubling” signs and/or symptoms that are of 
moderate or greater severity. 
 
5.2.2.2 
All Other Days 
 
Patients will be instructed to have the following tests done at their local clinical 
laboratory at the frequency listed below: 
 CBC with Differential, ANC, platelet count weekly i.e., Day 8, 15 and 22nd 
of Cycle 2 and 3. 
 Blood Chemistry Chem-20 test Panel, every two weeks i.e., Day 15 of 
Cycles 2 and 3. 
 The Investigator and/or research staff will immediately contact the patient 
to notify him/her to interrupt study medication if the laboratory test results 
meet the interruption criteria.  The Investigator will continue to review the 
laboratory test results and inform the patients about how to proceed 
regarding study medication (i.e., re-starting or continue to hold). 
 Patients will continue to self-administer study medication per instructions 
twice daily at approximately 12 hour intervals in an out-patient setting.  
 
5.2.3  
Each Subsequent Visit – Day 1 
 
 All study visit specific observations as outlined in “Study calendar” and 
described for Day 1 of Cycle 2 and 3 will be done for each subsequent 
visit on Day 1.   
 In addition, Day 1 of Cycle 4 the following procedures will be done: 
o Bone marrow aspiration or biopsy and cytogenetics (if abnormal 
prior to therapy) will be done (Cycle 4, Cycle 7 and each sixth 
subsequent cycle)   
o Plasma and whole blood PD biomarkers sample collection pre-dose 
o Cytogenetics may be performed on peripheral blood (if bone 
marrow aspiration is inadequate) 
 A 3-month supply of study medication will be dispensed on Day 1 of each 
subsequent visit to qualified patients who have not met any interruption 
criteria and showing clinical benefit from the therapy. 
 Patients will be instructed to return to the site every three months (+/- 7 
days) following Day 1 of Cycle 4 and bring their study medication including 
empty containers with them.  
 Patients will be instructed to go every two weeks for the next three months 
to their local laboratory to have blood drawn for CBC with Differential, 
ANC and platelet count.  
 Due to PD samples being collected at the next visit, patients will be asked 
to withhold their morning dose of study medication on Day 1 of each 
subsequent visit. 


Protocol Number 2007-0925 
October 13, 2008 
Page 22 of 36 
 
 Patients will be instructed to call the Investigator or designated research 
staff if they experience any “troubling” signs and/or symptoms that are of 
moderate or greater severity. 
 
5.2.4 Each Subsequent Visit – All Other Days 
 
 Review all safety information and criteria for dosing interruptions on a 
regular and on-going basis to determine if patients should receive further 
doses.  
 The Investigator and/or research staff will immediately contact the patient 
to notify him/her to interrupt study medication if the laboratory test results 
meet any interruption criteria.  The Investigator will continue to review the 
laboratory test results and inform the patients about how to proceed 
regarding study medication (i.e., re-starting or continue to hold). 
 The investigator and/or research staff will contact the patient on a regular 
monthly basis to assess the patient’s overall well-being, any new or 
worsening signs and/or symptoms, compliance with study medication and 
dosing instructions, compliance with the local laboratory schedule and to 
answer any questions that the patient might have. The investigator and/or 
research staff will remind the patient of their next scheduled visit and how 
to prepare for it (i.e., withhold their morning dose of study medication.) 
The investigator and research staff will be responsible for ensuring that all 
relevant information resulting from these monthly contacts is documented 
in the patient’s medical record and case report form, as appropriate. 
 
5.2.5 End of Study or Early Termination Visit  
 
 All study visit specific observations as outlined in “Study calendar” and 
described above for Day 1 of Cycles 2 and 3 will be done except: 
o Study medication will not be dispensed.  
o Blood draw for PK sampling will not be done. 
 
 
5.2.6 Duration of Participation and Number of Subjects 
 
The individual patient participation is expected to be 4-12 months.  A maximum 
total number of 30 patients can be recruited into each disease category arm of 
this study and therefore the maximum total number of patients potentially studied 
under this protocol would be 120. 
 
6.  
RESPONSE DEFINITIONS 
 
Patients will be assessed for efficacy at the end of each 28 day cycle of therapy, +/- 
4 days for the first 3 cycles, then 3 monthly thereafter. 
 
 


Protocol Number 2007-0925 
October 13, 2008 
Page 23 of 36 
 
6.1 
Acute leukemias, MDS, CML-BP, CMML: 
 
6.1.1 Complete remission:  The patient must be free of all symptoms related to 
leukemia and have an absolute neutrophil count >1x109/L and platelet count 
>100 x109/L, and normal marrow differential (< 5% blasts) in a normo- or 
hypercellular marrow. 
 
6.1.2 Partial remission: CR with 6-25% abnormal cells in the marrow or 50% 
decrease in bone marrow blasts.  
 
6.1.3 CRp: As per CR but platelet count <100 x109/L. 
 
6.1.4 Hematologic Improvement (HI) 
 
Hematologic improvement should be described by the number of  
 
    
individual, positively affected cell lines  
(e.g. HI-E; HI-E + HI-N; HI-E+ HI-P + HI-N). 
 
 
6.1.4.1 
Erythroid response (HI-E) 
Major response: For patients with pretreatment hemoglobin less 
than 11 g/dL, greater than 2 g/dL increase in hemoglobin; for 
RBC transfusion-dependent patients, transfusion independence.    
Minor response: For patients with pretreatment hemoglobin less 
than 11g/dL, 1 to 2 g/dL increase in hemoglobin; for RBC 
transfusion-dependent patients, 50% decrease in transfusion 
requirements. 
 
 
6.1.4.2 
Platelet response (HI-P) 
Major response: For patients with a pretreatment platelet count 
less than 100 x 109/L, an absolute increase of 30 x 109/L or 
more; for platelet transfusion-dependent patients, stabilization of 
platelet transfusion independence. 
Minor response: For patients with a pretreatment platelet count 
less than 100x109/L a 50% or more increase in platelet count 
with a net increase greater than 10 x 109/L but less than 30 
x109/L 
 
 
6.1.4.3 
Neutrophil response (HI-N)  
Major response: For absolute neutrophil count (ANC) less than 
1.5 x 109/L before therapy, at least a 100% increase, or an 


Protocol Number 2007-0925 
October 13, 2008 
Page 24 of 36 
 
absolute increase of more than 0.5 x 109/L, whichever is 
greater.  
Minor response: For ANC less than 1.5 x 109/L before therapy, 
ANC increase of at least 100%, but absolute increase less than 
0.5 x 109/L. 
 
 
6.1.4.4 
Progression/relapse after HI 
 
One or more of the following: a 50% or greater decrement from 
maximum response levels in granulocytes or platelets, a 
reduction in hemoglobin concentration by at least 2 g/dL, or 
transfusion  
 
6.2 
CML response criteria 
 
6.2.1 Hematologic Response (HR) 
 
1. Complete Hematologic Response (CHR):  
a. WBC ≤ institutional upper limit of normal (ULN) 
b. Platelets ≤ 450,000 x109/L 
c. No blasts or promyelocytes in peripheral blood. 
d. < 5% myelocytes plus metamyelocytes in peripheral blood 
e. Peripheral blood basophils < 2% 
f. No extra-medullary involvement including no splenomegaly or hepatomegaly 
g. <5% blasts in bone marrow 
2. No Evidence of Leukemia (NEL) - meet the same criteria as CHR except for: 
a. Platelets ≥ 20,000/mm3 and < 100,000 mm3, and/or 
b. ANC > 500/mm3 and < 1,000/mm3 
3. Minor Hematologic Response (MiHR) - meet all of the following: 
c. < 15% blasts in BM and in PB 
d. < 30% blasts + promyelocytes in BM and PB 
e. < 20% basophils in PB 
f. No extra-medullary disease other than spleen and liver 
4. Major Hematologic Response (MHR) is defined as CHR or NEL 
5. Overall Hematologic Response (OHR) is defined as CHR, NEL or MiHR 
 
A confirmed HR is obtained when all above criteria are fulfilled at least 28 days after 
they are first met. 
 
6.2.2 Cytogenetic Response (CyR):  
Classified according to suppression of the Philadelphia chromosome (Ph) by 
cytogenetics (FISH if cytogenetic analysis not informative, e.g., insufficient metaphases) 
1. No cytogenetic response - Ph positive >95%  
2. Minimal cytogenetic response - Ph positive 66-95%  
3. Minor cytogenetic response - Ph positive 36-65%  


Protocol Number 2007-0925 
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4. Partial cytogenetic response - Ph positive 1-35%  
5. Complete cytogenetic response - Ph positive 0% 
* Major cytogenetic response = complete + partial (Ph positive ≤35%) 
 
6.2.3 Molecular response  
1. Major (MMR): BCR-ABL/ABL ratio < 0.02% 
2. Complete: Undetectable BCR-ABL 
 
7. 
Pharmacokinetic and Pharmacodynamic Methods 
 
7.1 
Pharmacokinetic Methods 
 
7.1.1 Blood Collection 
 
On Days 1 of Cycle 1, PK blood samples will be obtained pre-dose, 0.5, 1, 
1.5, 2, 4, 6 and if possible, 8 hours after administration of the morning 
dose of the study medication. PK samples will also be obtained pre-dose 
on Day 1 of Cycles 2 and 3.  The exact date and time of the PK blood 
draws will be recorded along with the date and time of the last dose of 
study medication preceding the blood draw.   
 
See Appendix F for specific information regarding the procedures for PK 
blood sample collection, processing and shipment. 
 
7.1.2 Bioanalytical Methodology 
 
The plasma samples will be analyzed for INCB018424 by a validated 
LC/MS/MS assay, carried out by Incyte Corporation (Wilmington, DE) or 
Incyte’s designee. 
 
7.1.3 Population Pharmacokinetic Analysis 
 
The limited amount of plasma concentration data from this study, will be 
pooled with the results of a Phase 1 study in healthy volunteers to perform 
the population PK analysis. If there is sufficient demographic diversity in 
the population, an attempt will be made to evaluate the effect of 
demographic characteristics and baseline characteristics (e.g., age, 
weight, sex, race, renal function, smoking history, etc.) on the population 
PK profile. 
 
7.2 
Pharmacodynamic Method 
 
7.2.1 Blood Collection  
 
On Day 1 of Cycle 1 (at pre-dose and 2 hours after dose), and on Day 1 of 
Cycles 2 and 3 (pre-dose sample only) venous whole blood samples will be 
obtained for both whole blood and plasma PD markers according to the Study 


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calendar.  Collection of a plasma PD sample will be done on Day 1 of 
subsequent cycles as described in Section 5.2. The exact date and time of the 
blood draws will be recorded along with the date and time of the last dose of 
study medication preceding the blood draw.   
 
See Appendix F for specific information regarding the procedures for PD blood 
sample collection, processing and shipment. 
 
7.2.2 Pharmacodynamic Analysis 
 
The whole blood PD samples will be evaluated both unstimulated and following 
stimulation with a cytokine (e.g., IL-6) to activate the JAK/STAT pathways and 
then analyzed for both basal and activated levels of JAKs and STATs, including 
phosphorylated STAT3 and STAT5.  Phosphorylated STAT3 and STAT5 will be 
measured using phospho-specific STAT3 and STAT5 ELISAs.  For each patient, 
the percent inhibition of phosphorylated STAT3 and/or STAT5 will be calculated 
by comparing predose values with values obtained at different times after dosing.  
Additional PD markers (e.g., monitoring other cell signaling pathways, measuring 
specific cell populations or measuring cell surface markers that can be measured 
by flow cytometry, Western blot or ELISA) may be evaluated utilizing excess 
whole blood PD samples. 
 
In addition, using the plasma PD sample, changes in plasma cytokine levels and 
markers of disease activity will be monitored over time using specific ELISAs.  
For each patient, the percent change in level will be calculated by comparing 
predose values with values obtained at different times after dosing.  Additional 
PD markers (e.g., other cytokine levels, chemokine levels or other non-genomic 
protein markers that can be measured by Western blot or ELISA) may be 
evaluated utilizing excess PD or PK samples.  These analyses will be carried out 
by Incyte Corporation (Wilmington, DE) or Incyte’s designee. 
 
7.3 
Bone Marrow Aspiration, Biopsy and Cytogenetics 
 
Bone marrow aspiration or biopsy will be taken pre-dose during the screening 
phase and at Day 1 ± 7 days of Cycle 4, Day 1 of Cycle 7 ± 7 days and thereafter 
on Day 1 ± 7 days of each 6th subsequent cycle.  This includes staining and 
determination of cytogenetics if abnormal prior to therapy.  
 
7.3.1 Bone Marrow Assessment  
 
The bone marrow biopsy or aspirate should be assessed by an 
experienced hematopathologist using his/her standard examination.  Bone 
marrow evaluation will include staining, cytogenetics if abnormal prior to 
therapy and mutation analysis if present prior to therapy.   
 
 


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7.3.2 Cytogenetics 
 
Cytogenetic studies will be repeated only in patients with abnormalities at 
baseline on Day 1 of Cycle 4, Day 1 of Cycle 7 and thereafter on Day 1 of 
each 6th subsequent cycle. This will be generally done on the bone 
marrow samples provided at the defined time points but may also be done 
on peripheral blood collected at these time points in the event bone 
marrow aspirate could not be obtained.  The cytogenetic testing laboratory 
will provide specific instructions to the Investigators. 
 
8.  
REGULATORY AND REPORTING REQUIREMENTS 
Adverse event reporting will be as per the current NCI criteria and the MDACC 
Adverse Event Reporting Policy for Leukemia Phase I and early Phase II studies. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for adverse event 
reporting. (http://ctep.cancer.gov/reporting/ctc.html).   
 
Serious Adverse Event Reporting (SAE) 
 
A serious adverse event is – any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity – a substantial disruption of a 
person’s ability to conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 


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• Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
Sponsor. 
 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must by reported to the IRB in accordance with the timeframes and 
procedures outlined in  “University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy ”. SAEs must be reported to the IRB and the 
Sponsor (Safety Project Manager) regardless of attribution. 
 
• All life-threatening or fatal events with possible, probable or definite attribution 
to the study drug must have a written report faxed within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the Office of 
Research Education and Regulatory Management (ORE&RM) (fax 713-792-
9631). The sponsor representative should be notified by phone at 713-563-0379 
to confirm receipt of the fax.  
 
• The MDACC Internal Adverse Event Reporting Form will be used for 
reporting to the IRB and the Sponsor (Safety Project Manager ORE&RM).  
 
• Serious adverse events will be captured from the time the patient signs 
consent until 30 days after the last dose of drug. Serious adverse events 
must be followed until clinical recovery is complete and laboratory test 
have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IRB 
and the Sponsor (Safety Project Manager ORE&RM). This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the Sponsor (Safety Project 
Manager ORE&RM) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
 
 
 
 


Protocol Number 2007-0925 
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8.1  Expedited Adverse Event Reporting 
 
Leukemia associated symptoms are not to be reported as adverse events on this 
protocol. Myelosuppression and associated complication are expected events during 
leukemia therapy and are part of the treatment success (marrow emptying of 
leukemia cells).  Therefore, myelosuppression and associated complications such as 
fever, infections, bleeding, and related hospitalization will be reported in the study 
summary.  Only prolonged myelosuppression, as defined by the NCI criteria specific 
for leukemia, i.e. marrow cellularity <5% on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia, will be reported as an SAE and considered in 
defining the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT).  
Admission to the hospital for administration of a new cycle of treatment does not 
require expedited reporting. SAEs occurring in patients registered to the trial but not 
receiving any protocol agents (ie occurring before protocol treatment) do not require 
expedited reporting.  
 
For this protocol, the following adverse events are specifically excluded from 
expedited AE reporting: 
 
 
CTCAE Category 
 
Adverse Event 
 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
 
Comments 
 
Blood/Bone marrow/ 
Infection 
 ↓Hemoglobin, leukocytes (total 
WBC), lymphopenia, ↓neutrophils/ 
granulocytes (ANC/AGC), 
↓ platelets, fever, sepsis 
 
1-4 
  
Yes 
Do 
not 
require 
expedited reporting 
 
Gastrointestinal 
 
Diarrhea, nausea, vomiting, 
stomatitis 
 
1-3 
 
Yes 
Hospitalization for grade 
3 AEs does not require 
expedited reporting 
 
Metabolic/laboratory 
 
↓K,↓Mg, ↓Na, ↓glucose, ↑K, 
↑Mg, ↑glucose, ↑uric acid,↑LDH 
Or other metoablic indeces 
 
1-4 
 
Yes 
Do 
not 
require 
expedited 
reporting 
unless 
hospitalized 
for management 
 
9. STATISTICS 
 
9.1 
Study Population 
 
All patients who received at least one dose of study medication will be included in 
the safety analyses.  
 
9.1.1 
Selection of Sample Size 
 
This phase II study will use a Gehen’s design. Assuming a null response rate 
of 0%, targeting a 15% response rate and power=80%, the trial will initially 
enroll 10 patients in each disease category:  1) AML; 2) ALL; 3) MDS; and 4) 
CML. If at least one response is achieved in the 10 patients in a disease  
 


Protocol Number 2007-0925 
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Category, then a total of 30 patients will be enrolled in this disease category. 
Thirty patients will provide a confidence interval for response rate with half-
width=0.13, assuming the true response rate is 15%. The total sample size is 
120. 
 
 
For toxicity evaluation, patients enrolled in the study will be considered in 2 
cohorts (I) those with relapsed/refractory AML, ALL, and MDS (including CMML), 
and blast phase CML, and (II) those with chronic phase CML. At any time after 6 
patients are enrolled in cohort I (including AML, ALL, MDS, blast phase CML 
patients), if 30% or more patients experience grade 3 or 4 toxicity thought to be 
directly related to INCB018424 and lasting longer than 2 weeks, then we will stop 
that cohort of the trial. At any time after 6 patients are enrolled in cohort II 
(including chronic phase CML patients), if 15% or more patients experience 
grade 3 or 4 toxicity thought to be directly related to INCB018424 and lasting 
longer than 2 weeks, then we will stop that cohort of the trial. 
 
 
9.2  
Efficacy and PK/PD Variables 
 
The efficacy variables include  
 Clinical response 
 Cytogenetic response 
 The PK and PD variables will include: 
o Determination of the PK of INCB018424 by measuring plasma 
concentration time profiles.  
o Determination of PD markers including % inhibition of STAT3/5 protein 
phosphorylation 
 
9.2.1 
Efficacy and PK/PD Analysis 
 
Efficacy analyses will be exploratory in nature.  All efficacy measures will be 
estimated with 95% confidence intervals at the dose used in the expanded 
cohort.  The clinical response and the hematological response will be 
estimated with 95% confidence intervals at each time point.  The response 
rates over time may be analyzed graphically or using a statistical model. 
 
The PK parameters of INB018424 will be summarized using descriptive 
statistics, and the log-transformed INCB018424 PK parameters will be 
compared using a 1-factor analysis of variance.  The mean values of the PK 
parameters may be compared to historical data in healthy volunteers to 
determine if the INCB018424 PK profile is different between patients with 
hematological malignancies and healthy patients. 
 
For each patient who has taken study medication, the PD parameters will be 
calculated to explore preliminary evidence of PD activity by assessing the 


Protocol Number 2007-0925 
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effect of INCB018424 on pre- and post-dose.  If the p-STAT3/5 signaling data 
are sufficiently robust, an exploratory PK/PD analysis will be performed. 
 
9.3  
Safety Analysis 
 
The clinical safety data (vital signs, ECGs, routine laboratory tests and adverse 
events) will be analyzed using summary statistics (e.g., mean, frequency) and no 
formal statistical comparisons among the treatment groups are planned. 
 
9.3.1 
Adverse Events 
 
Severity of adverse events will be based on the NCI–CTCAE v3.0 (NCI 
Common Terminology Criteria for Adverse Events, Publ. Aug 9, 2006). The 
subset of adverse events that are considered by the Investigator to have a 
possible or probable relationship to study medication will be considered to be 
treatment-related adverse events.  If the Investigator does not specify the 
relationship of the adverse event to study medication, the adverse event will 
be considered to be treatment-related.  The incidence of adverse events and 
treatment-related adverse events will be tabulated.  
 
9.3.2 
Clinical Laboratory Tests 
 
Laboratory test values outside the normal range will be assessed for drug 
association based on screening and baseline values and for severity based on 
the normal ranges for the clinical reference laboratory.  The incidence of 
abnormal laboratory values and shift tables relative to baseline will be 
tabulated.   
 
9.3.3 
Vital Signs 
 
Descriptive statistics and mean change from baseline will be determined for 
vital signs (blood pressure, heart rate, respiratory rate and body temperature) 
at each assessment time.  Vital sign results will be reviewed for clinically 
notable abnormalities and patients exhibiting clinically notable vital sign 
abnormalities that were not present at screening or baseline will be listed. 
 
9.4  
Study Definitions 
 
Survival, time to progression, time to treatment failure, and duration of response 
will be presented using Kaplan-Meier curves for each patient group 
 
 
9.4.1    Survival 
 
"Survival" is defined as the period of time from date of first study drug  
administration to the date of death or date patient withdrawn from 
study. 


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 9.4.2    Time to Progression 
 
"Time to Progression" is defined as the period of time from the date of  
first study drug administration to the date that the patient is withdrawn  
because of clinical or radiographic progressive disease or death from  
any cause.   
 
9.4.3    Time to Treatment Failure 
 
"Time to Treatment Failure " is defined as the period of time from the  
date of first study drug administration to the date of withdrawal from the 
study for any reason other than study closure. 
 
  9.4.4     Duration of Response 
 
"Duration of Response " is defined as the period of time from the date 
of first objective response to the date of progression. "Duration of 
Response" is defined for patients with an objective response only. 
 
 9.4.5 
Time to Response 
 
"Time of Response " is defined as the period of time from the date of 
first study drug administration until the first objective documentation of 
response.    
 
  9.4.6 
Intent-to-Treat Data Set 
 
The Intent-to-Treat Data Set will include all patients who receive at 
least one dose (full or partial dose) of study drug.   
 
9.5  
Reporting and Exclusions 
 
9.5.1  
Evaluation of toxicity.   
 
 
 
All patients will be evaluable for toxicity from the time of their first 
treatment with INCB018424. 
 
9.5.2 
Evaluation of response.   
 
 
All patients included in the study must be assessed for response to 
treatment, unless there are major protocol treatment deviations or they 
are ineligible.  Each patient will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable 
disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other 


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cause, or 8) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” 
status of any type of data in a clinical database.]  
 
10.0 ETHICS 
 
10.1 Institutional Review Board or Ethics Review Committee 
 
It is the responsibility of the Investigator to assure that all aspects of the ethics 
review are conducted in accordance with the current Declaration of Helsinki as 
described in the International Conference on Harmonisation (ICH) E6: Guideline 
for Good Clinical Practice (GCP), and/or local laws, whichever provides the 
greatest level of protection for the study participants.  The protocol and any 
information supplied to the patient to obtain informed consent, including written 
informed consent form(s), patient recruitment procedures (e.g., advertisements), 
and written information to be provided to patients (information leaflets), must be 
reviewed and approved by a qualified IRB/ERC prior to enrollment of participants 
in the study. 
 
Amendments to the protocol and revisions to the informed consent must also be 
submitted to and, if required, approved by the IRB/ERC. 
 
At intervals required by the IRB/ERC, but not less than annually, the Investigator 
must submit to the IRB/ERC a progress report with a request for re-evaluation 
and re-approval of the study.   
 
After completion or termination of the study, the Investigator must submit a final 
report to the IRB/ERC.  This report should include:  deviations from the protocol, 
the number and types of participants evaluated, the number of participants who 
discontinued (with reasons), results of the study, if known, and significant 
adverse events, including deaths that occurred during the conduct of the study. 
 
The Investigator, as part of the records retention requirements for the study, must 
maintain documentation of all submissions, correspondence, and approvals to 
and from the IRB/ERC. 
 
Each clinical Investigator is responsible to conduct the study in accordance with 
the protocol, all applicable laws, regulations, and GCP according to ICH 
guidelines. 
 
10.2 Informed Consent 
 
Before being enrolled in the clinical study, patients must consent to participate 
after the nature, scope, and possible consequences of the study have been 
explained in a form understandable to them.  
  


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An informed consent document that includes both information about the study 
and the consent form will be prepared and given to the patient.  This document 
will include all elements required by the ICH, GCP, and applicable regulatory 
requirements, and must adhere to GCP and to the ethical principles that have 
their origin in the Declaration of Helsinki.  Prior to the beginning of the study, the 
Investigator must have the IRB/ERC’s written approval/favorable opinion of the 
written informed consent form and any other information to be provided to the 
patients. 
 
The document must be in a language understandable to the patient and must 
specify who informed the patient.  Where required by local law, the person who 
informs the patient must be a physician. 
 
After reading the informed consent document, the patient must give consent in 
writing.  The patient’s consent must be confirmed at the time of consent by the 
personally dated signature of the patient and by the personally dated signature of 
the person conducting the informed consent discussions. 
 
If the patient is unable to read, oral presentation and explanation of the written 
informed consent form and information to be supplied to patients must take place 
in the presence of an impartial witness.  Consent must be confirmed at the time 
of consent orally and by the personally dated signature of the patient or by a local 
legally recognized alternative (e.g., the patient’s thumbprint or mark).  The 
witness and the person conducting the informed consent discussions must also 
sign and personally date the consent document. 
 
A copy of the signed consent document must be given to the patient.  The 
original signed consent document will be retained by the Investigator. 
 
The Investigator will not undertake any measures specifically required only for 
the clinical study until valid consent has been obtained. 
 
The Investigator must inform the patient’s primary physician about the patient’s 
participation in the trial if the patient has a primary physician and if the patient 
agrees to the primary physician being informed. 
 
10.2.1 Update of Informed Consent 
 
The informed consent and any other information provided to patients or 
the patient’s legally acceptable representative, should be revised 
whenever important new information becomes available that is relevant to 
the patient’s consent, and should receive IRB/ERC approval/favorable 
opinion prior to use.  The Investigator, or a person designated by the 
Investigator should fully inform the patient or the patient’s legally 
acceptable representative of all pertinent aspects of the study and of any 
new information relevant to the patient’s willingness to continue 


Protocol Number 2007-0925 
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participation in the study.  This communication should be documented.  
During a patient’s participation in the trial, any updates to the consent form 
and any updates to the written information will be provided to the patient. 
 
 


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REFERENCES 
 
1. 
Ravandi F, Kantarjian H, Giles F, Cortes J. New agents in acute myeloid leukemia and 
other myeloid disorders. Cancer. 2004;100:441-454. 
2. 
Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic 
leukemia. Cancer. 2003;98:1337-1354. 
3. 
Garcia-Manero G, Faderl S, O'Brien S, Cortes J, Talpaz M, Kantarjian HM. Chronic 
myelogenous leukemia: a review and update of therapeutic strategies. Cancer. 2003;98:437-457. 
4. 
Ravandi F, Talpaz M, Estrov Z. Modulation of cellular signaling pathways: prospects for 
targeted therapy in hematological malignancies. Clin Cancer Res. 2003;9:535-550.