Conditions: Blasts More Than 20 Percent of Bone Marrow Nucleated Cells Blasts More Than 20 Percent of Peripheral Blood White Cells Myelodysplastic/Myeloproliferative Neoplasm Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of ruxolitinib phosphate when given together with decitabine and to see how well they work in treating patients with acute myeloid leukemia that has come back or is not responding to treatment, or has developed from a type of bone marrow diseases called myeloproliferative neoplasms. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate together with decitabine may be an effective treatment for acute myeloid leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the tolerability of the combination of decitabine and ruxolitinib phosphate (ruxolitinib \[DI\]) in patients with leukemia. (Phase I) II. To determine the efficacy of ruxolitinib in increasing and prolonging response induced by decitabine alone in patients with post myeloproliferative neoplasm acute myeloid leukemia (AML) (post MPN-AML) alternatively referred to as (myeloproliferative neoplasm - blast phase; MPN-BP). (Compared to historical response rate with decitabine alone) (Phase II)

SECONDARY OBJECTIVES:

I. To compare whether there is a difference in response rate patients with post-MPN AML with janus kinase 2 (JAK2) mutations and patients without JAK2 mutations.

OUTLINE: This is a phase I, dose-escalation study of ruxolitinib phosphate followed by a phase II study.

Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on days 1-28 and decitabine intravenously (IV) over 1-2 hours on days 1-5. Treatment repeats every 4-6 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Patients receive ruxolitinib phosphate PO BID on days 1-28 and decitabine IV on days 1-5. Treatment repeats every 4-6 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive 50mg ruxolitinib phosphate PO BID on days 1-28 and decitabine IV on days 1-5. Treatment repeats every 4-6 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Decitabine intervention 2: Laboratory Biomarker Analysis intervention 3: Ruxolitinib Phosphate
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
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Protocol No.  2014-0344 
 
 
 
 
 
 
PHASE I/II STUDY OF RUXOLITINIB PLUS DECITABINE IN 
PATIENTS WITH POST MYELOPROLIFERATIVE 
NEOPLASM - ACUTE MYELOID LEUKEMIA  
 
Short title: Phase I/II study of RUXOLITINIB plus decitabine in  
patients with acute myeloid leukemia 
 
PI: Farhad Ravandi, MD 
Professor of Medicine, 
Department of Leukemia 
University of Texas – MD Anderson Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1.0
OBJECTIVES ............................................................................................................................ 4
1.1.
For phase I portion of study ................................................................................................... 4
1.2.
For phase II portion of study .................................................................................................. 4
1.3.
Endpoints ............................................................................................................................... 4
2.0
BACKGROUND AND RATIONALE ......................................................................................... 4
3.0
STUDY DESIGN ........................................................................................................................ 8
3.1
Design .................................................................................................................................... 8
3.2
Intervention ............................................................................................................................ 9
4.0
THERAPEUTIC AGENTS ..................................................................................................... 910
4.1
Ruxolitinib ............................................................................................................................ 10
4.1.1
Chemistry ......................................................................................................................... 10
4.1.2
Physical Properties ........................................................................................................... 10
4.1.3
Stability ............................................................................................................................. 10
4.1.4
Formulation ...................................................................................................................... 10
4.1.5
FDA approval status and IND issues ............................................................................... 11
4.1.6
Decitabine ........................................................................................................................ 11
4.1.7
Chemistry and Physical Properties .................................................................................. 11
4.1.8
Formulation and Stability .................................................................................................. 11
4.1.9
FDA approval status ......................................................................................................... 11
5.0
ELIGIBILITY CRITERIA .......................................................................................................... 12
5.1
Inclusion Criteria .................................................................................................................. 12
5.2
Exclusion Criteria ................................................................................................................. 12
6.0
RECRUITMENT PLAN ............................................................................................................ 13
7.0
PRETREATMENT EVALUATION ........................................................................................... 13
8.0
TREATMENT/INTERVENTION PLAN .................................................................................... 14
8.1
Treatment Schedule ............................................................................................................. 14
8.2 Dose escalation scheme for phase I ......................................................................................... 16
8.3 Definition of DLT and MTD: ...................................................................................................... 17
9.0
EVALUATION DURING TREATMENT/INTERVENTION ....................................................... 21
10.0
TOXICITIES/SIDE EFFECTS .................................................................................................. 23
11.0
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 24


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12.0
CRITERIA FOR REMOVAL FROM STUDY ........................................................................... 27
13.0
STATISTICAL DESIGN .......................................................................................................... 28
14.0
PROTECTION OF HUMAN SUBJECTS ................................................................................ 32
14.1
Serious Adverse Event (SAE) Reporting ............................................................................. 32
15.0 CORRELATIVE STUDIES ......................................................................................................... 33
16.0
REFERENCES ........................................................................................................................ 35
 
 
 


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1.0 
OBJECTIVES 
1.1. 
For phase I portion of study:  
To determine the tolerability of the combination of decitabine and RUXOLITINIB (DI) 
in patients with leukemia.  
1.2. 
For phase II portion of study:  
Primary objective - To determine the efficacy of RUXOLITINIB in increasing and 
prolonging response induced by decitabine alone in patients with post 
myeloproliferative neoplasm AML (post MPN-AML) alternatively referred to as 
(myeloproliferative neoplasm- Blast phase; MPN-BP).(Compared to historical 
response rate with decitabine alone) 
Secondary objective - To compare whether there is a difference in response rate  
patients with post-MPN AML with JAK2 mutations and patients without JAK2 
mutations. 
        1.3. 
Endpoints: 
 
1. Assessment of DLT and MTD 
2. Proportion of patients achieving overall response (CR + CRi). We will also assess 
response by the MPN criteria (including ALR-C and ALR-P, see section 11.00) 
3. Proportion of patients with post-MPN AML with JAK2 mutations and the proportion 
of patients without JAK2 mutations and any difference in response rate. 
 
 
2.0 
BACKGROUND AND RATIONALE 
RUXOLITINIB phosphate is an inhibitor of the Janus kinase family of protein tyrosine 
kinases (JAKs) that has been recently approved for the treatment of patient with 
myelofibrosis and is undergoing further evaluation for the treatment of other 
myeloproliferative disorders under IND No. 77,456.  Unless otherwise noted, 
RUXOLITINIB phosphate is referred to throughout this protocol as RUXOLITINIB.  
RUXOLITINIB 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 RUXOLITINIB may be found in the Clinical 
Investigators Brochure (CIB). 
We propose to investigate the combination of decitabine and RUXOLITINIB in 
patients with high-risk MDS/MPN and post-MPN AML.  In the phase I portion of the 
trial, the aim is to determine the tolerability of the combination.  In the phase II portion 
of the trial, the number and duration of responses in patients with post-MPN AML and 
high-risk MDS/MPN (> 20% blasts) will be determined. 


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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 SH2-containing proteins.1 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. 1 
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.2-4 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-JAK2.5 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.1  
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.  
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 


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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.1  
Abnormalities of the JAK-STAT pathways have been described in a variety of 
leukemias and their inhibition can be a goal for leukemia therapy. Myelofibrosis (MF) 
is a clonal stem cell disorder with the potential to transform to acute leukemia (AML), 
referred to as myelofibrosis in blast phase (MF-BP).6 The outcome of patients with 
MF-BP is grave with a median survival of only 2.7 months. MF-BP is largely refractory 
to conventional chemotherapy and intensive induction therapy fails to have a 
significant impact with a median survival of 3.9 months.7 
Decitabine (5-aza-2′deoxycytidine) is a deoxycytidine analog originally synthesized in 
the 1960s. The compound is phosphorylated by deoxycytidine kinase prior to 
incorporation into DNA, and it is an S-phase–specific agent. Decitabine also inhibits 
DNA methyltransferases (DNMTs) by forming irreversible covalent bonds with DNMTs 
at cytosine sites targeted for methylation. At low doses, hypomethylation of DNA with 
subsequent gene reactivation and induction of cellular differentiation occur. At higher 
doses, cellular cytotoxicity predominates. 
DNA hypermethylation of promoter-specific CpG islands is a well-known mechanism 
of epigenetic silencing, occurring frequently in cell cycle regulatory genes such as 
p15INK4B in a variety of hematologic malignancies, including MDS and AML. In MF, 
p15INK4B and p16INK4A hypermethylation has been reported to occur as the disease 
advances into accelerated and blast phases. Hypermethylation of the calcitonin gene 
(used as a marker of methylation at the 11p15 chromosome locus where several 
tumor-suppressor genes appear to cluster) has been reported in MF even in the 
chronic phase of the disease compared with other Philadelphia chromosome–
negative chronic myeloproliferative diseases. In addition, the retinoic acid receptor β 
(RARβ) gene has been found to be a target of epigenetic silencing in MF and has 
been proposed as a candidate tumor-suppressor gene in this disease. In clinical trials, 
decitabine has clinical activity in MDS at lower doses. Furthermore, a decrease in 
hypermethylation of the p15INK4B gene was observed in some patients with MDS 
following treatment with decitabine and correlated with clinical response.Significant 
evidence of clinical activity was also reported in a recent phase I study of decitabine at 
low doses in hematologic malignancies, but this study found no evidence of a 


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correlation of clinical responses with p15INK4B methylation, suggesting that the biologic 
effects of the drug may not be mediated solely through p15INK4B demethylation. 
Our group has previously conducted a phase-II study to evaluate the activity of DNA 
methyltransferase inhibitor, 5-azacitidine, in patients with MF.8 Thirty-four patients 
(76% previously treated) received 5-azacitidine at 75 mg/m(2) subcutaneously daily 
for 7 days, every 4 weeks. Twelve (35%) patients had abnormal cytogenetics and 19 
(70%) of 27 evaluable patients had JAK2(V617F) mutation. Responses occurred in 8 
(24%) patients after a median of 5 months (range, 3-10). Partial response occurred in 
1 (3%) patient (duration 22+ months) and clinical improvement in 7 (21%) patients 
(median duration 4 months; range, 2-8.5). Myelosuppression was the major adverse 
effect, with grade 3-4 neutropenia in 10 (29%) patients. Global DNA methylation 
assessed by the long interspersed nucleotide element (LINE) bisulfite/pyrosequencing 
assay decreased from 53% pretherapy to 44% on day 14 (P=0.0014) and returned to 
50% at the end of the first 28-day cycle (P=0.016). 5-azacitidine is relatively well 
tolerated and results in induction of global hypomethylation in patients with MF, but 
results in limited clinical activity.9 
In another recently published study, 54 patients with Philadelphia-negative 
myeloproliferative neoplasm (MPN, including 21 essential thrombocythemia [ET], 21 
polycythemia vera [PV], 7 primary myelofibrosis, and 5 unclassified MPN) who had 
progressed to AML (n = 26) or MDS (n = 28) were treated with azacitidine in a patient-
named program.10 Overall response rate was 52% (24% complete response [CR], 
11% partial response [PR], 8% marrow CR or CR with incomplete recovery of 
cytopenias, 9% hematologic improvement) and median response duration was 9 
months. Prognostic factors were for overall response the underlying MPN (71% vs 
33% responses in ET and PV, respectively; P = .016); prognostic factors for CR 
achievement were the underlying MPN (14% CR for PV vs 43% for ET; P = .040) and 
World Health Organization classification at transformation (36% vs 12% CR in MDS 
and AML, respectively, P = .038). Recurrence of chronic phase features of the initial 
MPN was observed in 39% of the responders. Median overall survival was 11 months. 
The authors concluded that azacitidine gives encouraging results in Ph-negative MPN 
having progressed to AML or MDS, but response duration is short, and consolidation 
treatments have to be evaluated.10 
We and others have also evaluated decitabine in the treatment of MF and have 
demonstrated significant activity.11 In a study from Mount Sinai School of Medicine, 
Four out of seven patients (57%) with MF-BP treated with decitabine reported 
subjective improvement in symptoms of fatigue/global weakness and left upper 
quadrant abdominal fullness/pain.7 All seven patients experienced an objective 
reduction in spleen size on physical examination with a mean 35% reduction of 
palpable splenomegaly (range 11–61%). Four out of seven patients (57%) had a 
decrease in RBC transfusion requirements and a single patient achieved transfusion 
independence after three cycles of therapy. The three patients who remain alive 
currently are in a morphologic complete response with incomplete platelet recovery 
(CRi) by IWG response criteria for AML 


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We have recently conducted a phase II study of RUXOLITINIB in patients with 
relapsed/refractory leukemias for which no standard therapies were anticipated to 
result in a durable remission. Patients with acceptable performance status (0-2) with 
adequate organ function and no active infection received RUXOLITINIB 25mg orally 
twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of 
treatment. Responding patients or patients with stable disease were allowed to 
continue until progression. Dose escalation to 50 mg twice daily was permitted in 
patients demonstrating a benefit. 38 patients with median age 69 (range 45-88) with 
relapsed and refractory leukemias were treated. The median number of prior 
therapies was 2 (range 1-6). 12 patients had JAK2V617F mutation. Patients who 
completed 2 cycles of INCB with clinical improvement were defined as having stable 
disease (SD). Patients received a median of 2 cycles of therapy (range 1-22). Three 
patients with AML developing after prior MF (MF-BP) showed remarkable response 
with 2 achieving complete remission (CR) and one remission with insufficient platelet 
count (CRi). 12 patients had SD. Responding patients have had a significant reduction 
in their spleen size. Overall INCB was tolerated very well.  
Rationale: 
There is no standard medical treatment for MF-BP or other post-MPN-AML. We 
believe that the combination of ruxolitinib and decitabine is a candidate approach to 
the treatment of MF-BP that is worthy of exploration based on the current 
understanding of the biology of disease. The molecular pathogenesis of MPN and 
progression to blast phase is almost certainly due to a complex combination of gene 
mutations (JAK2V617F, MPL) and epigenetic alterations (IDH1/2, IKZF1, EZH2, 
TET2) that culminate in the emergence of leukemic clones. Recent evidence 
indicates that the JAK2V617F protein can localize in the nucleus and influence global 
DNA methylation patterns which may lead to genomic instability and disease 
progression (40, 41). The inhibition of JAK-STAT mediated cell proliferation and 
survival in conjunction with the reversal of DNA hypermethylation of tumor 
suppressor genes would be predicted to have at least an additive if not synergistic 
effect in inducing apoptosis of cells belonging to the malignant myeloid clone. 
Correlative studies conducted within a trial of combination JAK2 inhibitor and DMNT1 
inhibitor in patients with MPN-BP would explore the effect on methylation status of 
various gene promoters as well as the influence on gene expression of chromatin 
related proteins and ultimately leukemic cell survival. The sequential administration of 
a JAK2 inhibitor followed by a DNMT inhibitor would also potentially serve to 
overcome the JAK2-independent effects of epigenetic lesions that lead to MPN-BP.  
 
3.0 
STUDY DESIGN 
3.1 
Design 


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In this non-randomized Phase I/II investigator-initiated, single center trial, cohorts of 
patients will be treated with increasing doses of ruxilitonib in combination with a 
decitibine at a dose of 20mg/m2 daily intravenously over 5 days. We will use an 
intitial dose of ruxolitinib of 10 mg orally twice daily. Patients will receive ruxolitinib for 
the first 28 days in addition to decitabine on days 1-5 of each cycle. Cycles will be 
repeated every 4-6 weeks depending on tolerance and  the recovery of the counts. 
Patients who become eligible for allogenic stem cell transplant may leave the study at 
any time after the first cycle.  
 
After the first cycle of therapy, modifications to the dose of Ruxolitinib felt to be in the 
best interest of the patient are allowed after discussion with the Principal Investigator 
of the study and with the documentation of the discussion in the patient’s medical 
records. 
 
For the purposes of assessing safety, DLTs will be defined as those adverse events 
occurring in the first cycle (i.e. 28 days) of therapy that are not clearly related to 
disease, intercurrent illness or concurrent medication. These events will be defined 
based on the NCI CTCAE version 4 as follows: 
 
x Any Grade 3 or higher non-hematologic toxicity (with the exceptions of Grade 3 or 
higher nausea, vomiting, or diarrhea, which will be considered DLTs only after optimal 
prophylactic measures have been prescribed; Grade 3 elevations of AST/ALT must 
be sustained for more than 4 days or reach Grade 4 to be considered a DLT. Grade 3 
elevations in bilirubin must occur in the setting of a direct bilirubin >1 to be 
considered a DLT. Fatigue must be Grade 4 to be considered a DLT) 
 
x Any Grade 4 hematologic toxicity lasting at least 42 days from the first day of the last 
cycle of therapy with a bone marrow cellularity of ≤5% and no evidence of leukemia.  
No dose modification will occur until any potential DLTs is fully assessed 

MTD is defined as the highest dose studied for which the incidence of DLT is less 
than or equal to 17% (1 out of 6). 
 
3.2 
Intervention 
Ruxolitinib will be administered as 5 mg (or if necessary, 25 mg) tablets taken orally 
at doses indicatedin table 1 on page 14, approximately every 12 hours for 28 days 
every cycle. Decitabine is administered intravenously at a dose of 20mg/m2 daily for 
5 days per cycle. Subsequent cycles may be administered at 4-6 week intervals as 
clinically tolerated with a provision to start early if in the best interest of the patient 
after discussion with the prinicipal investigator.  

4.0 
THERAPEUTIC AGENTS 


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4.1 
Ruxolitinib 
Ruxolitinib represents a novel, potent, and selective inhibitor of JAK1 (IC50 = 3.3 ± 
1.2 nM) and JAK2 (IC50 = 2.8 ± 1.2 nM) with modest to marked selectivity against 
TYK2 (IC50 = 19 ± 3.2 nM) and JAK3 (IC50 = 428 ± 243 nM), respectively. 
INCB018424 is inactive (ie, < 30% inhibition) against 28 additional kinases when 
tested at 200 nM.  
Ruxolitinib has high solubility and permeability, (ie, it is designated as a Class I 
molecule in the Biopharmaceutical Classification System (BCS)) and exhibits 
moderate- to-high clearance, volume of distribution and oral bioavailability in 
preclinical species. The apparent elimination half-life is short (< 5 hr) in all species. 
The primary clearance pathway is oxidative metabolism. The metabolism by human 
liver microsomes is catalyzed predominantly by CYP3A4. In a study using 14C-
Ruxolitinib in healthy volunteers, unchanged Ruxolitinib was the predominant 
circulating drug-related entity with 2 major circulating metabolites observed, both of 
which are mono-oxidation products. The metabolites of Ruxolitinib retain varying 
degrees of JAK-related pharmacological activity. Excretion was fairly rapid by both 
urinary and fecal routes with parent drug accounting for < 1% of the administered 
dose. Tissue distribution studies in rats indicate rapid and complete elimination of 
radioactivity in most tissues. Ruxolitinib exhibits high plasma protein binding in 
humans with an unbound fraction of 3.3%.  
4.1.1 Chemistry  
The chemical name of ruxolitinib, previously known as INCB018424 (also referred to 
as INC424) phosphate is (R)-3-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-
3-cyclopentylpropanenitrile phosphate. INCB018424 phosphate has a molecular 
formula of C17H21N6O4P and a molecular weight of 404.36.  
4.1.2 Physical Properties  
Ruxolitinib is a white to off-white powder.  
4.1.3 Stability  
Based on available stability data, the drug product should be stored in high density 
polyethylene (HDPE) bottles with induction sealing and child-resistant closure 
between 15°C and 30°C.  
4.1.4 Formulation 
Ruxolitinib is provided as 5 mg, 10 mg, 15 mg, 20 mg and 25 mg strength tablets. 
The tablet formulations contain the active ingredient and may include the following 
commonly used excipients: microcrystalline cellulose, lactose, stearic acid, 
magnesium stearate, colloidal silicone dioxide, sodium starch glycolate, Povidone 
and hydroxyl propyl cellulose. All excipients are of US and EuPh compendial grade. 


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4.1.5 FDA approval status and IND issues  
Ruxolitinib was approved by the FDA with the trade name, Jakafi, for the treatment of 
patients with intermediate or high-risk myelofibrosis.  
4.1.6 Decitabine 
Decitabine is a cytidine antimetabolite analogue that is believed to exert its 
antineoplastic effects after phosphorylation and direct incorporation into DNA and 
inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular 
differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is 
achieved at concentrations that do not cause major suppression of DNA synthesis. 
Decitabine-induced hypomethylation in neoplastic cells may restore normal function 
to genes that are critical for the control of cellular differentiation and proliferation. In 
rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the 
formation of covalent adducts between DNA methyltransferase and decitabine 
incorporated into DNA. Non-proliferating cells are relatively insensitive to 
decitabine.Decitabine is approved by the FDA for the treatment of patients with 
myelodysplastic syndromes. 
 
4.1.7 Chemistry and Physical Properties 
Decitabine  is also known as 5-aza-2’-deoxycytydine, an analogue of the 
natural nucleoside 2’-deoxycytidine. Decitabine is a fine, white to almost white 
powder with themolecular formula of C8H12N4O4 and a molecular weight of 228.21. 
Its chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-
2(1H)-one. Decitabine is slightly soluble in ethanol/water (50/50), methanol/water 
(50/50) and methanol; sparingly soluble in water and soluble in dimethylsulfoxide 
(DMSO). 
 
4.1.8 Formulation and Stability 
Decitabine for injection is supplied as Dacogen™, a sterile lyophilized white to almost 
white powder, in a single-dose vial, packaged in cartons of 1 vial. Dacogen™ 
(decitabine) for Injection is a sterile lyophilized powder supplied in a clear colorless 
glass vial. Each 20 mL, single dose, glass vial contains 50 mg decitabine, 68 mg 
monobasic potassium phosphate (potassium dihydrogen phosphate) and 11.6 mg 
sodium hydroxide (NDC 58063- 600-50). Vials are to be stored at 25°C (77°F) with 
excursions permitted to 15-30°C (59-86°F). Unless used within 15 minutes of 
reconstitution, the diluted solution must be prepared using cold (2°C - 8°C) infusion 
fluids and stored at 2°C - 8°C (36°F - 46°F) for up to a maximum of 7 hours until 
administration. 
4.1.9 FDA approval status 
Decitabine was approved as Dacogen™ by the FDA for treatment of patients 
with myelodysplastic syndromes (MDS) including previously treated and 
untreated, de novo and secondary MDS of all French-American-British 
subtypes (refractory anemia, refractory anemia with ringed sideroblasts, 


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refractory anemia with excess blasts, refractory anemia with excess blasts in 
transformation, and chronic myelomonocytic leukemia) and intermediate-1, 
intermediate-2, and high-risk International Prognostic Scoring System groups. 
The indication of refractory anemia with excess blasts in transformation has 
been included in the definition of acute myeloid leukemia according to the 
most recent WHO classification. As a result, decitabine is a common treatment 
of AML, and has been incorporated into standard treatment pathways for AML 
by the National Comprehensive Cancer Network, especially in patients who 
are unfit for standard therapies, such as those over age 60 years.  
 
5.0 
ELIGIBILITY CRITERIA 
5.1 
Inclusion Criteria 
1. Diagnosis of  AML (WHO classification definition of > 20% blasts). 
2. In the phase I portion of  the study all patients with relapsed or refractory AML are 
eligible.  For the Phase II portion of the study, patients must have AML progressing 
from prior MPN (MPN-BP) or have MDS/MPN with more than 20% blasts.. 
Temporary prior measures to control blood counts, such as apheresis or hydrea are 
allowed. Patients with newly diagnosed or previously treated disease are eligible as 
long as prior therapy does not include hypomethylating agents.Prior therapy for 
RUXOLITINIB for MPN is allowed. 
3. Serum biochemical values with the following limits unless considered due to 
leukemia: 
 
   - creatinine < 1.5 mg/dl 
- total bilirubin < 1.5 mg/dL, unless increase is due to hemolysis or congenital 
disorder 
- transaminases (SG PT) < 2.5x ULN 
4. Ability to take oral medication. 
5. Ability to understand and provide signed informed consent. 
6. Performance status ≤ 3, unless directly related to disease process as 
determined by the Principal Investigator   
 
7. Age ≥ 18 years 
 
5.2 
Exclusion Criteria 
1.  Any coexisting medical condition that in the judgment of the treating physician 


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is likely to interfere with study procedures or results including uncontrolled severe 
infections, as well as uncontrolled cardiac disease, or other organ dysfuction. 
Patients with history of tuberculosis, HIV or hepatitis B and C are excluded. 
 
2. Nursing women, women of childbearing potential with positive blood pregnancy 
test within 30 days of study start, or women of childbearing potential who are not 
willing to maintain adequate contraception (such as birth control pills, IUD, 
diaphragm, abstinence, or condoms by their partner) over the entire course of the 
study.. 
3. Incomplete recovery from any prior surgical procedures or had surgery within 4 
weeks prior to study entry, excluding the placement of vascular access.  
 
4. Active clinically serious and uncontrolled infection  
 
6.0 
RECRUITMENT PLAN 
Patients will be recruited among the patients referred to the Leukemia Department at 
the University of Texas – MD Anderson Cancer Center. There will be no direct 
advertising for this study. The study will be available to the public and the details of 
the inclusion criteria, exclusion criteria and study design will be posted at 
www.clinicaltrials.gov. A maximum of 36 patients (up to 12 patients in phase I and up 
to 24 patients in the phase II) will be enrolled in the study. Up to 6 patients can be 
replaced in the phase I portion of the study.   
 
7.0 
PRETREATMENT EVALUATION 
The following tests must be done within 30 days of entry: 
 
x A complete history and physical exam including ECOG performance status 
assessment and manual measurement (in cm) of the liver and spleen from the costal 
margin, if palpable. 
x CBC with differential, comprehensive metabolic panel, LDH, direct bilirubin, 
phosphorus, albumin, uric acid, coagulation profile (PT, aPTT, fibrinogen), and ßHCG 
(for pre-menopausal females),  
x HIV and Hepatitis B and C testing 
x Chest X-ray (PA and lateral) 
x Abdominal imaging (only if clinically indicated, e.g. organomegaly) 
x Bone marrow aspirate  
o Cytogenetics, and if necessary, FISH analysis (if insufficient aspirate, these 
tests can be performed in peripheral blood samples) 
o JAK2V617F and MPLW515L/K mutation analysis and allele burden (if insufficient 
aspirate, these tests can be performed in peripheral blood samples)  
x Bone marrow biopsy (including reticulin stain to assess the degree of fibrosis)  


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x ) 
x Peripheral blood sample for scientific correlative studies: one red top tube (10ml) and 
two purple top tubes (10ml each)  
x ECG, MUGA/Echo  
x CT/MRI abd/pelvis without contrast, if clinically indicated 
x 
Pregnancy test performHG only on women of child-bearing potential.  
 
8.0 
TREATMENT/INTERVENTION PLAN 
8.1 
Treatment Schedule 
Phase I 
Assuming MTD is not achieved, the first 9 patients on study will receive RUXOLITINIB for 
28 days during induction therapy at escalating doses per the table below, plus 
Decitabine 20 mg/m2 IV daily for 5 days 
 
Dose of RUXOLITINIB will be as follows: 
Table 1 – RUXOLITINIB dose 
Dose level 
RUXOLITINIB (mg PO) 
(x 28 days) 
No of evaluable 
patients 
0 
10 BID 
3 
1 
15 BID 
3 
2 
25 BID 
3 
3 
50 BID 
3 
 
We will utilize the above design format to determine the tolerable dose of 
RUXOLITINIB to be used in combination with decitabine, with 25 mg PO BID as the 
target dose. The enrollment of participants will be staggered; all the participants in 
each cohort will finish the first cycle of therapy followed by 7 days of observation (i.e. 
day 35 of therapy) before proceeding to the next cohort. Subsquence cycles will 
begin on the first day of decitabine therapy and, in the absence of toxicity, 
RUXOLITINIB administration will not be interrupted.Patients who come off the study 
during the first cycle for reasons other than development of dose limiting toxicity (e.g. 
disease progression) will be replaced in order to ensure adequate chance for the 
assessment of DLT. 
If grade 3-4 non-hematological RUXOLITINIB-related toxicities are observed in ≥ 2/6 
patients, this dose level would exceed the MTD.  


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If grade 3-4 RUXOLITINIB-related toxicities are observed in 0-1/6 patients, the study 
will continue at the RUXOLITINIB dose of 15, 25, and 50 mg P.O. BID x 28 days plus 
chemotherapy, as outlined above. We will examine the dose of 50 mg BID to assess 
its tolerability and if well tolerated, this will be the dose to move to phase II, However, 
the target dose for phase II is 25 mg po BID x 28 days. 
 
Cycles will be repeated approximately every 4 to 6 weeks, depending on the recovery 
of the blood counts and will continue until clinically significant progression, withdrawal 
of consent or unacceptable toxicity for a maximum of 24 cycles (see section 13.0). 
 
Toxicities to be monitored include any grade 3 or 4 non-hematological toxicity felt to 
be related to RUXOLITINIB and prolonged cytopenias (lasting for more than 42 days 
after the initiation of the treatment) felt to be related to the treatment and not the 
underlying disease. Patients with prolonged cytopenias should have a bone marrow 
exam around day 42 to establish whether this is due to the treatment or whether 
there is persistent disease. In the case of the former, treatment should be 
discontinued. 
Prior to advancing/changing dose levels, a cohort summary must be completed and 
submitted to the IND Medical Monitor for review. 
Each cohort will have up to 6 patients enrolled. 
Phase II 
Twenty four patients (not including any patients from the phase I portion of the study) 
will receive cycles of therapy according to the following starting schedule: 
RUXOLITINIB at dose defined by Phase I portion of the study, on days 1-28 of 
each cycle 
Decitabine 20 mg/m2 IV daily for 5 days 
Cycles will be repeated every 4 to 6 weeks depending on tolerance and  the recovery 
of counts. 
RUXOLITINIB will be provided by the sponsor (Incyte) free of charge to the 
participating patients for a maximum period of up to 24 months. Any used or expired 
study drug will be disposed of accordance to the MD Anderson policy. 
 
 
 
Dose modifications during induction therapy in phase I and II: 


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Patients who experience RUXOLITINIB-specific (defined as determined by the 
principal investigator) grade 3-4 extramedullary toxicities during induction cycle #1, 
and who are not in CR after cycle #1, may receive a second induction course at the   
next lower dose with respect to RUXOLITINIB (as defined in table1 on page 14).  
Other dose modification schedules felt to be in the best interest of the patient may be 
permitted, after discussion with the principal investigator with the documentation of 
the discussion in the patient’s medical records.  There will be no dose modifications 
of decitabine for either induction cycle #1, or second induction course, secondary to 
myelosuppression. 
Adjustment of dose of RUXOLITINIB to 15 mg BID or 10 mg BID are acceptable in 
patients who have toxicity but are having benefit from the treatment. If patients 
develop significant myelosuppression that is thought to be specifically related to 
RUXOLITINIB, it can be held for a week and then resumed at a lower dose (5-10 mg 
per day less than the prior dose). 
Toxicities to be monitored include any grade 3 or 4 non-hematological toxicity felt to 
be related to RUXOLITINIB and prolonged cytopenias (lasting for more than 42 days 
after the initiation of the treatment) felt to be related to the treatment and not the 
underlying disease. Patients with prolonged cytopenias should have a bone marrow 
exam around day 42 to establish whether this is due to the treatment or whether 
there is persistent disease. In the case of the former, treatment should be 
discontinued.  
Number of patients: 
A maximum of 36 patients (up to 12 patients in phase I and up to 24 patients in the 
phase II) will be enrolled in the study.   
Phase I study 
Nine to 12 patients will be treated.  Open study to phase II if first cycle RUXOLITINIB 
attributable toxicity in <2 of 6. If first cycle RUXOLITINIB-related DLTs are observed 
in more than 2/6 patients, this dose level would exceed the MTD, and 3 patients will 
be treated at the next lower dose level according to Table 1. 
Phase 2 study 
We will accrue a maximum of 24 patients at a rate of 2 patient per month. The 
primary outcome for this trial is overall response rate.   
8.2 Dose escalation scheme for phase I 
Cohorts of 3-6 patients each will be treated with increasing doses of ruxolitinib in a 
progression of 10mg, 15mg, 25 mg and 50 mg twice daily.  
At least 3 patients will be treated at each dose level.  All patients treated at the 
preceding dose level will be observed a minimum of 5 weeks before dose escalation 
occurs.  Dose escalation will proceed as follows: 
 


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x If none of the initial 3 evaluable patients in a cohort experiences first cycle dose 
limiting toxicity (DLT), then a new cohort of 3 patients will be treated at the next 
higher dose level. 
x If one of 3 evaluable patients in a cohort experiences DLT, then up to an 
additional 3 patients will be treated at the same dose level.  Escalation will 
continue if only one of the 6 patients experiences a DLT. 
x In the event that 2 of 3 evaluable patients, or 2 of 6 patients in the first cohort 
experiences a DLT, then the next cohort of patients will be treated at a lower dose 
level (dose level -1) and no further dose escalation with occur in this step.  Three 
patients will be enrolled at this dose level, if 0 or 1 patients experiences a DLT, a 
further 3 patients will be enrolled at this dose level.  If overall 0 or 1 patient 
experiences a DLT at this dose level, this dose will be established as the 
maximum tolerated dose (MTD). 
x If two or more evaluable patients in the cohort experience DLT, then the 
maximum tolerated dose (MTD) will have been exceeded, and no further dose 
escalation will occur.  The previous dose will be considered as the MTD. 
x If only three patients were treated at the dose level under consideration as the 
MTD, then up to an additional 3 patients will be accrued.  If no more than one 
patient at that dose level experiences DLT, then that dose level will be confirmed 
as the MTD.  If two or more patients in that cohort experience DLT, then the 
previous dose level will be studied in the same fashion. 
 
8.3 Definition of DLT and MTD: 
For the purposes of assessing safety, DLTs will be defined as those adverse events 
occurring in the first cycle (i.e. 28 days) of therapy that are not clearly related to 
disease, intercurrent illness or concurrent medication. These events will be defined 
based on the NCI CTCAE version 4 as follows: 
 
x Any Grade 3 or higher non-hematologic toxicity (with the exceptions of Grade 3 or 
higher nausea, vomiting, or diarrhea, which will be considered DLTs only after optimal 
prophylactic measures have been prescribed; Grade 3 elevations of AST/ALT must 
be sustained for more than 4 days or reach Grade 4 to be considered a DLT. Grade 3 
elevations in bilirubin must occur in the setting of a direct bilirubin >1 to be 
considered a DLT. Fatigue must be Grade 4 to be considered a DLT) 
 
x Any Grade 4 hematologic toxicity lasting at least 42 days from the first day of the last 
cycle of therapy with a bone marrow cellularity of ≤5% and no evidence of leukemia.  
No dose modification will occur until any potential DLTs is fully assessed 

MTD is defined as the highest dose studied for which the incidence of DLT is less 
than 17% (1 out of 6). 
 
 


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Table 2 -  Criteria for dose modifications of RUXOLITINIB due to study drug-related 
toxicity – These must be clearly related to ruxolitinib and not the underlying 
disease; to be determined by PI and treating physician  
Worst Toxicity 
CTCAE Grade* unless otherwise specified 
(Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended 
day of dosing) 
HEMATOLOGICAL TOXICITIES 
Thrombocytopenia 
< 20 x 109/L 
Interrupt study treatment dosing 
until resolved to ≥ 20 x 109/L, 
then restart study treatment at 
reduced level as per Table 5 
> 20 x 109/L + grade 3 
bleed 
Interrupt study treatment dosing 
until bleeding is resolved and 
platelet count is at level before 
bleed was noted, then resume 
study treatment at reduced level 
as per Table 5 
Neutropenia (ANC) 
Grade 4 (ANC < 0.5 x 
109/L) 
Interrupt study treatment dosing 
until resolved to ≤ grade 2, or 
baseline, then: 
x If resolved within 7 days 
restart study treatment at an 
unchanged dose level 
x If resolved in more than 7 
days then restart study 
treatment at reduced level as 
per Table 5 
Febrile neutropenia 
(ANC < 1.0 x 109/L, fever 
≥ 38.5°C) 
Interrupt study treatment dosing 
until fever resolved and ANC ≤ 
grade 2, then restart study 
treatment at reduced level as 
per Table 5 


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Worst Toxicity 
CTCAE Grade* unless otherwise specified 
(Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended 
day of dosing) 
Anemia#  
only requires dose 
reductions after cycle 
6  
Doubling of transfusion 
frequency from baseline 
or hemoglobin  
Hold Ruxolitinib only and 
continue Decitabine, if 
hemoglobin (or transfusion 
frequency) returns to baseline 
within 28 days restart Ruxolitnib 
at same dose, if this recurs 
again then reduce dose as pre 
Table 5 
NON-HEMATOLOGICAL TOXICITIES 
GASTROINTESTINAL 
Diarrhea 
Grade 2 (4-6 stools/day 
over baseline, etc) 
despite the use of optimal 
antidiarrheal medications 
Hold Ruxolitinib dosing until 
resolved to ≤ grade 1, or 
baseline, then restart at 
unchanged dose level 
Grade 3 (≥ 7 stools/day 
over baseline, etc) 
despite the use of optimal 
antidiarrheal medications 
Hold Ruxoltinib dosing until 
resolved to ≤ grade 1, or 
baseline, then restart study 
treatment at reduced level as 
per Table 5 
Grade 4 (life-threatening 
consequences, 
hemodynamic collapse, 
etc) despite the use of 
optimal antidiarrheal 
medications 
Permanently discontinue study 
treatment dosing 
Vomiting/Nausea*** 
Grade 1 & 2 not requiring 
treatment or controlled 
using standard anti-
emetics 
Maintain dose level 
Grade 3 or 4 vomiting or 
Grade 3 nausea that 
cannot be controlled 
despite the use of 
standard anti-emetics 
Interrupt study treatment dosing 
until resolved to ≤ grade 1, or 
baseline, then restart study 
treatment at reduced level as 
per Table 5 
HEPATIC 
Total Bilirubin 
Grade 3 or 4 
Interrupt study treatment dosing 
until resolved to ≤ grade 2, or 
baseline, then restart study 
treatment at reduced level as 
per Table 5 


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Worst Toxicity 
CTCAE Grade* unless otherwise specified 
(Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended 
day of dosing) 
Note: If Grade 3 or Grade 4 hyperbilirubinemia is due to the indirect component only, 
and hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., 
review of peripheral blood smear and haptoglobin determination), then reduction of 
one dose level and continuation of treatment is at the discretion of the Investigator. 
AST/SGOT, 
ALT/SGPT 
> 5-10 x ULN 
Interrupt study treatment dosing 
until resolved to ≤ grade 1 (or ≤ 
grade 2 if liver infiltration with 
tumor is present), or baseline, 
then: 
x If resolved within 7 days, 
then: 
x restart study treatment at 
unchanged dose level 
x If resolved in more than 7 
days, then restart study 
treatment at reduced level as 
per Table 5 
> 10 x ULN 
Interrupt study treatment dosing 
until resolved to ≤ grade 1, or 
baseline, then: 
x restart study treatment at 
reduced level as per Table 5 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) 
** It is critical that electrolyte abnormalities be followed closely and corrected prior to 
dosing 
*** See also concomitant medication section 
If Ruxoltinib is required to be held based on the dose holding and modification rules 
above, then it is permissible to use a prednisone taper starting at a dose of 20mg or 
more a day at the discretion of the investigator to reduce the rebound symptoms that 
have been well documented in previous studies with Ruxolitinib.  
 
 


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9.0 
EVALUATION DURING TREATMENT/INTERVENTION 
Response assessment 
Response assessment (RA) can be performed at the end of any cycle after cycle 1.  
Specific events that will prompt response assessment include of resolution of splenomegaly 
on exam and clearance of blasts from the peripheral blood, which will prompt bone marrow 
aspirate and biopsy. Patients continuing to maintain at least SD by the response criteria 
shown below should continue to receive ruxolitinib and decitabine until progression of 
disease, unacceptable toxicity or patient withdrawal. Patients may receive up to 24 cycles in 
this study. Patients may proceed to allogeneic stem cell transplant at any time after Cycle 1. 
Dose modification of ruxolitinib will be allowed after Cycle 1. RUXOLITINIB will be provided 
by the sponsor for a maximum of up to 2 years, after which it will be required to procure it 
from commercial sources. 
Adverse events will be captured as long as patients are on study and will be used to fully 
characterize the tolerability and toxcicity of this combination therapy.  These events will be 
defined based on the NCI CTCAE version 4. Patients who withdraw from the study for any 
reason will be followed and seen 28 days (+/- 5 days) for an end of study visit to capture all 
adverse events.  
Adverse events will only be captured after the first dose of RUXOLITINIB has been 
administered. 
Table 3 - Schedule of study procedures 
Evaluation 
Baseline 
screening 
Cycle 1 
Cycle 2 
and 
beyond 
Response 
assessment 
End of 
Study 
At 
least 
once 
weekly 
(+/- 3 
days) 
At least 
once 
every 2 
weeks 
(+/- 3 
days) 
 
(+/- 5 
days) 
History 
x 
 
 
 
 
physical exam 
X 
X 
X 
 
X 
Vital signs 
X 
X 
X 
 
X 
Concomitant 
medications 5 
X 
X 
X 
 
X 
Adverse event 
assessment 
 
X 
X 
 
X 
HIV, HBV, HCV 
serology 
X 
 
 
 
 
MUGA or Echo 
X 
 
 
 
 
ECG 
X 
 
 
 
X 
CT/MRI abd/pelvis 
without contrast, 
X 
 
 
X3 
 


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1. Preferentially performed on the marrow, but will be performed on the peripheral blood if a 
specimen cannot be obtained. Allele burden will not be repeated if neither Jak2 nor MPL is 
mutated. The sample will be obtained in 5 ml EDTA tube.  
2. After one cycle of therapy, after 3 cycles, and then every 3 cycles while on the study (in addition 
to base-line and end of the study samples), peripheral blood will be collected for measurements 
of inflammatory cytokine levels, expression of different proteins related to intracellular signaling, 
and methylation of genes. This will include collection of: one red top (10ml) and two purple top 
tubes (10ml each).  All samples will be submitted to the laboratory of Dr. Srdan Verstovsek at 
MD Anderson. 
3. There are 2 milestone events that will prompt response evaluation. Resolution of palpable 
splenomegaly will prompt imaging of the abdomen and pelvis.  Clearance of blasts from the 
peripheral blood will prompt bone marrow aspirate and biopsy. 
4. Direct Bilirubin, Phosphorus, Albumin, PT/PTT, Alk Phos, Total Bilirubin, Total Protein, Glucose, 
Calcium, Magnesium, Na, K, Cl, HCO3, BUN, creatinine, AST, ALT, LDH and uric acid 
5. Comcomitant medications will not be captured in CRF.  Available in Clinic Station. 
 
Testing in outside labs are allowed and the PI or treating physician must review lab results, 
determine clinical significance for abnormal labs and sign/date the report. 
 
End of Study Visit (Within 6 weeks of the last dose of decitabine) 
x 
An interval history and physical exam including ECOG PS assessment and manual 
measurement (in cm) of the liver and spleen from the costal margin, if 
palpable.Record concomitant medications 
x 
Record Adverse Events 
x 
Vitals (temperature, HR, BP and RR) 
x 
ECG 
x 
Bone marrow aspirate and biopsy (A peripheral blood sample may be substituted in 
patients with more than 10% blasts in the peripheral blood) 
x 
Laboratory Assessments 
o Hematology:  CBC with differential, platelets 
if clinically 
indicated 
Pregnancy test 
X 
 
 
 
 
CBC with 
differential 
X 
X 
X 
 
X 
Chemistry 4 
X 
X 
X 
 
X 
Bone marrow 
biopsy 
X 
 
 
X3 
X 
Bone marrow 
aspirate 
X 
 
 
X3 
X 
Jak2/MPL allele 
burden1 
X 
 
 
 
 
Correlative 
studies2 
X 
 
 
 
X 
Chest X-ray 
X 
 
 
 
 


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o Chemistry:  Na, K, Cl, Mg, CO2, BUN, Cr, CPK, glucose (random), Ca, 
Phosphorus, AST, ALT, Alk Phos, total bilirubin, LDH, total protein, albumin, 
uric acid 
o Peripheral blood sample for scientific correlative studies: one red top tube 
(10ml) and two purple top tubes (10ml each).  
Outside Physician Participation During Treatment 
x 
MDACC physician communication with the outside physician is required prior to the patient 
returning to the local physician.  This will be documented in the patient record. 
x 
A letter ot the local physician outlining the patient’s participation in a clinical trial will request 
local physician agreement to supervise the patient’s care (Appendix D) 
x 
Protocol required evaluation outside MDACC will be documented by telephone, fax or e-mail.  
Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that they 
have reviewed it. 
x 
Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in the 
patient record. 
x 
A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
x 
Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and 
documentation of any hosptializations.  
x 
The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
x 
Patients will return to MDACC every two to three months for evaluation. 
10.0 TOXICITIES/SIDE EFFECTS 
Adverse Event: An adverse event is any noxious, pathologic, or unintended change in 
anatomical, physiologic, or metabolic functions, as indicated by physical signs, symptoms, 
and/or laboratory changes occurring in any phase of the clinical trial, whether associated 
with drug or placebo and whether or not considered drug related. All of the following are to 
be considered adverse events: 
x An exacerbation of a pre-existing condition 
x An intercurrent illness 
x Any drug interaction 
x Any event related to a concomitant medication 
x Development of an abnormal laboratory value or a significant change from baseline 
in a laboratory value within the range of normal, considered by the investigator to be 
clinically important 
x An unexpected significant worsening of the cancer under treatment. Anticipated day-
to-day fluctuations in the activity of the cancer or the anticipated progression of the 
cancer (other than death) should not be considered an adverse event. 
 
Serious Adverse Event: A serious adverse event is one that is fatal or life-threatening (see 
below), is temporarily or permanently disabling, requires inpatient hospitalization (initial or 


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prolonged), or is associated with a congenital anomaly, a new cancer or a drug overdose 
(either accidental or intentional). In addition, any event suggesting a significant hazard, 
contraindication, side effect or precaution should also be considered serious. The MDACC 
criteria for adverse events in Leukemia will be used for reporting (Appendix E). 
 
Life-threatening: means an immediate risk of death from the reaction as it occurred. Life-
threatening does not include a reaction that, had it occurred in a more serious form, might 
have caused death. For example, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
The following potential adverse reactions may occur:  bone marrow suppression with risks 
of neutropenia, anemia, and thrombocytopenia.  It is anticipated that there will be a risk of 
infection both from myelosuppression and immunosuppression.  There is a risk for 
developing a secondary neoplasm such as acute leukemia or myelodysplastic syndrome 
(MDS).  Specific side effects of the drugs given during treatment are listed below: 
 
The main anticipated side effect of treatment with Decitabine is myelosuppression. This is 
both expected and acceptable in this clinical setting and will be managed with standard of 
care practice including appropriate anti-microbial prophyalxis for bacterial, fungal and viral 
infections. Red blood cell transfusions are acceptable for a hemoglobin <8g/dL or higher if 
the investigator believes the transfusion will ameliorate symptoms of anemia. Platelet 
transfusions are acceptable in cases of acute bleeding or routinely for a platelet count below 
20 x 109/L.  
Treatment with Ruxolitinib would also expect to induce myelosuppresion and the same 
standard practices listed above would apply. The clinical adverse event profile of Ruxolitinib 
as has been described in the published phase I/II would indicate minimal gastrointestinal 
and other non-hematological toxicity.  
11.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Response assessment will follow the standard response assessment for AML defined 
by Cheson et al 12: 
Complete Response (CR) 
x The subject must be free of all symptoms related to leukemia and have an absolute 
neutrophil count ≥ 1 x 109/L, no need for red blood cell transfusion, platelet count ≥ 
100 x 109/L, and normal marrow differential (≤ 5 % blasts) in a normo- or 
hypercellular marrow 
 
CRi 
x As per CR but incomplete count recovery. 
 


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Partial Response (PR) 
x CR with 6 – 25 % abnormal cells in the marrow or 50 % decrease in bone marrow 
blasts.  
 
In addition, we will also use the response criteria recently published by Mascarenhas, et al 13: 
 
Table 4 -  Response criteria for myeloproliferative neoplasm in blast phase (MPN-BP)13 
Complete Molecular Response (CMR) 
Description 
Complete remission of both leukemia and MPN  
Hematologic 
profile 
ANC>1000 
Hemoglobin>10g/dL  
Platelets >100 X109/L 
Absence of leukoerythroblastosis1 
Spleen 
Non-palpable 
Bone 
Marrow 
Celullarity appropriate for age 
Loss of abnormal morphology 
Blasts ≤5%2 
≤ grade 1 marrow fibrosis 
Cytogenetics Normal karyotype3 
Molecular 
markers 
Loss of any previously documented markers 
associated with either the leukemic or MPN 
clone 
 
Complete Cytogenetic Response (CCR) 
Description 
Complete remission of both leukemia and MPN  
Hematologic 
profile 
ANC>1000 
Hemoglobin>10g/dL  
Platelets >100 X109/L 
Absence of leukoerythroblastosis1 
Spleen 
Non-palpable 
Bone 
Marrow 
Celullarity appropriate for age 
Loss of abnormal morphology 
Blasts ≤5%2 
≤ grade 1 marrow fibrosis 
Cytogenetics Normal karyotype3 


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Molecular 
markers 
Residual expression of MPN mutation (e.g. 
Jak2V617F) 
 
 
Acute Leukemia Response- Complete  (ALR-C) 
Description 
Complete remission of leukemia with residual 
MPN features 
Hematologic 
profile 
Absence of blasts 1 
Spleen 
<25% increase in spleen size by palpation or 
imaging if baseline spleen <10cm or <50% if 
baseline spleen ≥ 10cm 
Bone 
Marrow 
Blasts ≤5%2 
 
Cytogenetics Loss of cytogenetic abnormality associated with 
leukemic clone, may have persistent abnormality 
associated with MPN 
Molecular 
markers 
Loss of previously identified markers in leukemic 
clone, may have persistent molecular markers 
associated with MPN 
 
Acute Leukemia Response-Partial (ALR-P) 
Description 
Decrease in leukemic burden but without 
resolution of peripheral blood or bone marrow 
blasts and residual MPN features 
Hematologic 
profile 
>50% reduction in blasts  
 
Spleen 
<25% increase in spleen size by palpation or 
imaging if baseline spleen <10cm or <50% if 
baseline spleen ≥ 10cm 
Bone 
Marrow 
>50% reduction in blasts  
 
Cytogenetics No new abnormalities 


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Molecular 
markers 
No new abnormalites 
 
Stable Disease (SD)  
Description 
Failure to achieve at least ALR-P, but no 
evidence of progression for at least 8 weeks. 
 
Progressive Disease (PD) 
Description 
Progression of leukemia and/or background 
MPN  
Hematologic 
profile 
For patients with 10-20% blasts: ≥50% increase 
to >20% blasts 
For patients with >20% blasts: ≥50% increase to 
> 30%  blasts  
Spleen 
>25% increase in spleen size by palpation or 
imaging if baseline spleen <10cm and >50% if 
baseline spleen ≥ 10cm 
Bone 
Marrow 
 For patients with 5-10% blasts: ≥50% increase 
to >10% blasts 
For patients with 10-20% blasts: ≥50% increase 
to >20% blasts 
For patients with >20% blasts: ≥50% increase to 
> 30%  blasts  
 
12.0 CRITERIA FOR REMOVAL FROM STUDY 
Patients may voluntarily withdraw from the study or be removed at the discretion of the 
investigator at any time. If such withdrawal occurs, or if the patient fails to return for visits, the 
investigator must determine the primary reason for a patient’s premature withdrawal from the 
study and record this information on the appropriate eCRF. Patients may be withdrawn from 
the study prematurely for one of the following reasons: 
x Adverse event(s) 
x Abnormal laboratory value(s) 
x Abnormal test procedure result(s) 
x Protocol deviation 
x Subject withdrew consent 
x Lost to follow-up 
x Administrative problems 


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x Death 
x Initiation of new cancer therapy 
x Disease progression 
x The investigator determines that further therapy is not in the patient’s best interest (e.g., 
due to non-compliance, toxicity etc.). 
Patients who experience disease progression, start of new anti-cancer therapy, or withdraw 
consent, must be permanently discontinued from the study. 
For patients who are lost to follow-up, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g., dates of 
telephone calls, registered letters, etc. 
 
13.0 STATISTICAL DESIGN 
Basis for sample size: 
Phase I 
 
First, a phase I study is performed to assess the safety of different dosing regimens for 
RUXOLITINIB combined with decitabine. Four combination dose levels are defined (table 1). A 3+3 
design will be used to for dose escalation. Detailed dose escalation rules are described in the 
following section. A maximum of 18 evaluable patients will enroll in the phase I study. 
 
Dose Escalation Procedures: 
The dose of treatment agent will be escalated in successive cohorts of patients. The starting dose is 
at dose 0 as shown in table 1. Enroll 3 patients at the dose level and proceed to the next higher 
dose level with a cohort of 3 patients until at least 1 patient experiences a dose-limiting toxicity 
(DLT). If only 1 of 3 patients experiences a DLT at a given dose level, enter 3 additional patients at 
the current dose level. If only 1 of 6 patients experiences a DLT at a given dose level, proceed to the 
next higher dose level with a cohort of 3 patients. If at least 2 of 3 or 2 of up to 6 patients experience 
a DLT at a given dose level, then the MTD has been exceeded (stopping dose).  Once the MTD has 
been exceeded, treat another 3 patients at the MTD if there were only 3 patients treated at that dose 
level. The MTD is defined as the highest dose level in which 6 patients were treated with at most 1 
experiencing a DLT during the 1st cycle. One cycle of therapy is defined 5 days of decitabine and 28 
days of RUXOLITINIB but treatment with RUXOLITINIB can be continued until the next cycle (start 
of decitabine) in the absence of toxicity, beyond the day 28 and without interruption. 
 
 
 
 
 
Table 5 - Dose levels of decitabine and RUXOLITINIB 


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Dose level 
Decitabine (mg/m2/d x 5 
days) 
RUXOLITINIB (mg PO) 
(x 28 days) 
0 (starting dose) 
20 
10 BID 
1 
20 
15 BID 
2 
20 
25 BID 
3 
20 
50 BID 
 
Phase II 
 
Phase II part is a single arm study using the dosage level recommended from phase I. The patients 
treated at the MTD in phase I will not be included in phase II part, and the sample size for phase II is 
a maximum of 24 patients. The trial will be continuously monitored for efficacy and toxicity (non-
hematological ≥grade 3 and hematological ≥grade 4). The method of Thall, Simon, and Estey will be 
used to perform interim efficacy and safety monitoring.  
 
Efficacy and Toxicity Monitoring 
The primary endpoint is the overall response (CR+CRi) after three cycles of treatment. Overall 
response (OR) and toxicity will be monitored simultaneously using the Bayesian approach of Thall, 
Simon, Estey (1995, 1996) and the extension by Thall and Sung (1998. The historical data 
suggested the overall response rate is 10% and the target overall response rate with the 
experimental treatment is 30%. This regimen of the combination treatment will be considered 
worthy of further investigation if it elicits an increase in OR to 20% with acceptable toxicity.  A 
>20% toxicity rate is considered unacceptable.  Thus, interim monitoring rules, assuming the prior 
distributions above, were constructed that meet the following two conditions, 
Pr(0.2 < θE, Toxicity | data) > 0.80 and 
Pr(θE, OR  > 0.3| data) < 0.025. 
where TE, Toxicity and TE, OR  are the true toxicity and overall response for the combination treatment, 
respectively.  The first rule provides for stopping the study if excessive toxicity is highly probable 
(i.e., probability >80.0%) for the combination treatment.  The second condition will stop the study 
early if the data suggest that it is unlikely (i.e., probability < 2.5%) that OR rate of the combination 
treatment is 30%.  Monitoring for toxicity and futility will not begin until 4 patients have been 
evaluated, and cohort size for future evaluations is 2. 
  


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The monitoring rule for the toxicity rate, based on these assumptions and monitoring conditions 
above is found in Table 7.  For example, accrual will cease if 3 or more patients experience 
toxicities among the first 6 patients. 
 
Table 7. Stop accrual if the number of toxicities is greater than or equal to indicated (i.e., # 
patients with toxicities) among the number of patients evaluated 
# patients evaluated  
2-4 
6-8 
10-12 
14-16 
18-20 
22 
24 
# patients with 
toxicities 
2-4 
3-8 
4-12 
5-16 
6-20 
7-22 
Always stop 
with this 
many patients 
 
Monitoring the OR rate, based on the above assumptions and monitoring conditions is found in 
Table 8.  For example, accrual will cease if 0 or fewer patients experience a response in the first 8 
patients treated. 
 
Table 8. Stop accrual if the number with OR is less than or equal to indicated (i.e., # patients 
with OR) among the number of patients evaluated 
# patients evaluated  
2-6 
8-12 
14-18 
20-22 
24 
# patients  
with OR 
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0 
0-1 
0-2 
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Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the OC table (Table 9). In order to utilize the software for the design, a 30% 
response rate and beta (0.6, 1.4) priors were assumed for the standard treatment response 
distribution and experimental treatment response prior distribution, respectively. In addition, a 30% 
toxicity constant rate and beta (0.6, 1.4) priors were assumed for the standard treatment toxicity 
constant rate and experimental treatment toxicity prior distribution, respectively. 
 
The probability of stopping the study early if the true response rate of the combination treatment 
was not better than 30% and the true toxicity rate is 20% was 44%.  Probabilities of stopping early 
for high true toxicity rates (i.e., 40%) were 10% when the true OR rate was 10% and 39% when 
true OR rate was 20%. 
 


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Table 9.  Operating characteristics for simultaneous monitoring response and toxicity rates for 
patients treated with combination treatment 
True OR 
True 
Toxicity 
Rate 
True Probability Vector 
(OR/Tox, OR/NoTox, 
NoOR/Tox, NoOR/NoTox) 
Probability of 
Stopping 
Average 
number of 
patients 
treated 
10% 
10% 
(0.01, 0.09, 0.09, 0.81) 
0.7689 
14 
10% 
20% 
(0.02, 0.08, 0.18, 0.72) 
0.8437 
12 
10% 
30% 
(0.03, 0.07, 0.27, 0.63) 
0.9325 
9 
10% 
40% 
(0.04, 0.06, 0.36, 0.54) 
0.9827 
7 
20% 
10% 
(0.02, 0.18, 0.08, 0.72) 
0.3679 
19 
20% 
20% 
(0.04, 0.16, 0.16, 0.64) 
0.5724 
15 
20% 
30% 
(0.06, 0.14, 0.24, 0.56) 
0.8153 
11 
20% 
40% 
(0.08, 0.12, 0.32, 0.48) 
0.9526 
7 
30% 
10% 
(0.03, 0.27, 0.07, 0.63) 
0.1676 
21 
30% 
20% 
(0.06, 0.24, 0.14, 0.56) 
0.4369 
17 
30% 
30% 
(0.09, 0.21, 0.21, 0.49) 
0.7568 
12 
30% 
40% 
(0.12, 0.18, 0.28, 0.42) 
0.9379 
8 
40% 
10% 
(0.04, 0.36, 0.06, 0.54) 
0.1036 
22 
40% 
20% 
(0.08, 0.32, 0.12, 0.48) 
0.3936 
18 
40% 
30% 
(0.12, 0.28, 0.18, 0.42) 
0.7381 
12 
40% 
40% 
(0.16, 0.24, 0.24, 0.36) 
0.9328 
8 
 
Analysis method 
Data analysis will be performed using SAS or S-plus, as appropriate. All patients who 
received at least 1 dose of the combined agents will be included in the intent-to-treat 
analysis for efficacy.  Demographic and disease characteristics of the patients at registration 
will be summarized using descriptive statistics such as mean, standard deviation (SD), 
median and range. Overall response rates will be presented with 95% confidence intervals. 


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The association between response and patient and disease characteristics will be examined 
by two-sample t-test (or Wilcoxon rank-sum test) or Chi-square test.  
 
The data from all patients who received the combined therapy during the study will be 
included for safety analysis.  Safety data will include laboratory, physical exam, and adverse 
event reports on study patients.  These descriptive summaries will be provided for all 
patients for each safety parameter by cycle, grade, and relationship to treatment.   
 
14.0 
PROTECTION OF HUMAN SUBJECTS 
14.1 Serious Adverse Event (SAE) Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
x 
Death 
x 
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. 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
x 
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). 
x 
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 the IND Sponsor, IND Office. 
x 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting  Unanticipated Adverse Events for Drugs and Devices”.  Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the 
IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
x 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office.   
 
x 
Unless otherwise noted, the electronic SAE application (eSAE) will be Utilized for safety 
reporting to the IND Office and MDACC IRB.  
 


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x 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent.  Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
x 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND office.  This may include the 
development of a secondary malignancy. 
 
Reporting to FDA: 
x 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
Investigator Communication with Supporting Companies: 
Serious adverse events (SAE) will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug.  The investigator will inform Incyte of any SAE 
or pregnancy within 24 hours of being aware of the event via email and/or fax. Respective 
companies will to be informed based on the attribution of a given event: 
 
1. 
Due to RUXOLITINIB alone – These SAEs will only to be reported to INCYTE. 
2. 
Due to both the RUXOLITINIB and decitabine – These SAEs will be reported to INCYTE 
3. 
All pregnancies will be reported to INCYTE If the investigator can’t associate causality 
with one or the other alone then causality needs to be associated with the combination of 
the products.  These SAEs will go to INCYTE. 
 
Adverse events will be documented in the Leukemia-specific AE Recording and Reporting 
Guidelines attached in Appendix E. medical record and entered into the case report form. PDMS/ 
CORE will be used as the electronic case report form for this protocol. All adverse events will be 
captured in CRF during Phase I portion of the study.  In Phase II, only Grade 3 and higher 
related will be captured in the CRF. Investigator or physician designee is responsible for 
verifying and providing source documentation for all adverse events and assigning the attribution 
for each event for all subjects enrolled on the trial. SAEs must be documented using the MDACC 
IND eSAE electronic form.This form must be completed and supplied to Incyte within 24-hours/1-
business day at the latest on the following working day.  The initial report must be as complete as 
possible, including details of the current illness and (serious) adverse event, and an assessment of 
the causal relationship between the event and the investigational product(s).  Information not 
available at the time of the initial report (e.g., an end date for the adverse event or laboratory 
values received after the report) must be documented on a follow-up MDACC IND eSAE reporting 
form. 
 
15.0 CORRELATIVE STUDIES 


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After one cycle of therapy, after 3 cycles, and then every 3 cycles while on the study (in addition to 
baseline and end of study samples), peripheral blood will be collected for measurements of 
inflammatory cytokine levels, (including but not limited to IL6, TNF-alpha, CRP and IL10), expression 
of different proteins related to intracellular signaling, (including but not limted to STAT3, STAT5, and 
JAK2), and methylation of genes (including but not limited to p15, ER, and ECAD). This will include 
collection of: one red top (10ml) and two purple top tubes (10ml each).  All samples will be submitted 
to the laboratory of Dr. Srdan Verstovsek at MD Anderson. 
All research samples may not be drawn at all times, missed samples will not be considered a 
deviation. 
16.0 CONCOMITANT MEDICATIONS 
The use of standard agents deemed necessary for patient supportive care are permitted (antibiotics, 
allopurinol, GCSF). Only other chemotherapy agents or investigational agents are prohibited. 
Temporary prior measures to control blood counts, such as apheresis or hydrea are allowed.   
 
 
 
 


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16.0 REFERENCES 
 
1. 
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. 
2. 
Lacronique V, Boureux A, Valle VD, et al. A TEL-JAK2 fusion protein with constitutive 
kinase activity in human leukemia. Science. 1997;278:1309-1312. 
3. 
Lacronique V, Boureux A, Monni R, et al. Transforming properties of chimeric TEL-
JAK proteins in Ba/F3 cells. Blood. 2000;95:2076-2083. 
4. 
Carron C, Cormier F, Janin A, et al. TEL-JAK2 transgenic mice develop T-cell 
leukemia. Blood. 2000;95:3891-3899. 
5. 
Peeters P, Raynaud SD, Cools J, et al. Fusion of TEL, the ETS-variant gene 6 
(ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and 
t(9;15;12) in a myeloid leukemia. Blood. 1997;90:2535-2540. 
6. 
Odenike O, Tefferi A. Conventional and new treatment options for myelofibrosis with 
myeloid metaplasia. Semin Oncol. 2005;32:422-431. 
7. 
Mascarenhas J, Navada S, Malone A, Rodriguez A, Najfeld V, Hoffman R. 
Therapeutic options for patients with myelofibrosis in blast phase. Leuk Res. 2010;34:1246-
1249. 
8. 
Quintas-Cardama A, Tong W, Kantarjian H, et al. A phase II study of 5-azacitidine for 
patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis. 
Leukemia. 2008;22:965-970. 
9. 
Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged 
exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in 
hematopoietic malignancies. Blood. 2004;103:1635-1640. 
10. 
Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-
negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid 
leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des 
Myelodysplasies (GFM). Blood. 2010;116:3735-3742. 
11. 
Danilov AV, Relias V, Feeney DM, Miller KB. Decitabine is an effective treatment of 
idiopathic myelofibrosis. Br J Haematol. 2009;145:131-132. 
12.  
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the international 
working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting 
standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642-9 
 


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13.  
Mascarenhas J, Heaney ML, Najfeld V, et al. Proposed criteria for response 
assessment in patients treated in clinical trials for myeloproliferative neoplasms in blast 
phase (MPN-BP): formal recommendations from the post-myeloproliferative neoplasm acute 
myeloid leukemia consortium. Leuk Res. 2012 Dec;36(12):1500-4