Clinical trial NCT03041636
Conditions: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Untreated Chronic Lymphocytic Leukemia
Sponsor: M.D. Anderson Cancer Center
Start date: 2017-03-08; Completion date: 2020-04-29
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well ruxolitinib phosphate works in treating patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the effect of ruxolitinib phosphate (ruxolitinib) in patients with high-risk chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who do not require anti-neoplastic therapy according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 recommendations and were either previously untreated or treated with Ibrutinib for less than 3 months and were deemed Ibrutinib intolerant:

Ia. On disease burden. Ib. The rate of complete response (CR) and partial response (PR) as assessed by the IWCLL 2008 response criteria.

SECONDARY OBJECTIVES:

I. To evaluate the time to next treatment of high-risk CLL/SLL who do not require anti-neoplastic therapy according to the IWCLL 2008 recommendations.

OUTLINE:

Patients receive ruxolitinib phosphate orally (PO) twice daily (BID). Treatment continues for up to 3 years in the absence of disease progression or unacceptable toxicity. Treatment beyond 3 years may be permitted after discussion with the principal investigator.

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

Arms: arm 1: Patients receive ruxolitinib phosphate PO BID. Treatment continues for up to 3 years in the absence of disease progression or unacceptable toxicity. Treatment beyond 3 years may be permitted after discussion with the principal investigator.
Interventions: intervention 1: Ruxolitinib intervention 2: Ruxolitinib Phosphate
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
Administration of Jakafi (Ruxolitinib) to Patients with Previously Untreated High-
Risk Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): 
A Phase II Clinical Trial
2015-0570
Core Protocol Information
Short Title 
Administration of Jakafi (Ruxolitinib) to Patients with Previously 
Untreated High-Risk CLL: A Phase II Clinical Trial
Study Chair: 
Zeev Estrov
Additional Contact:
Carol L. Ancelet
Sarah K. Renner
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-794-1675
Unit:
0428
Study Manager:
Mary Beth Rios
Full Title: 
Administration of Jakafi (Ruxolitinib) to Patients with Previously 
Untreated High-Risk Chronic Lymphocytic Leukemia (CLL)/Small 
Lymphocytic Lymphoma (SLL): A Phase II Clinical Trial
Public Description:
BACKGROUND: 
Disease-related symptoms impair the quality of life of patients 
with chronic lymphocytic leukaemia (CLL) who do not require 
systemic therapy. Available therapies are not specifically aimed at 
symptom control. Because stimulation of the B-cell receptor 
activates JAK2 in CLL cells and the JAK2 inhibitor ruxolitinib 
improves symptoms in patients with myelofibrosis, we postulated 
that ruxolitinib would improve disease-related symptoms in 
patients with CLL. We did a phase 2 trial of ruxolitinib to test this 
hypothesis.
METHODS: 
Symptomatic patients with CLL who did not require systemic 
therapy were enrolled at MD Anderson Cancer Center (Houston, 
TX, USA) between Sept 15, 2014, and Sept 20, 2015. 
Participants were given 10 mg ruxolitinib orally twice a day. 
Scores on the Brief Fatigue Inventory (BFI), CLL module of the 
MD Anderson Symptom Inventory (MDASI) and symptom-
associated interference in daily activities, were assessed before 
treatment and after 3 months. This trial is ongoing and is 
registered at ClinicalTrials.gov (NCT02131584).
FINDINGS: 
41 patients (25 previously untreated for CLL and 16 previously 
treated) were enrolled. At 3 months, the mean percentage change 
from baseline in BFI score was 44·3% (SD 35·0, p<0·0001), in 
symptom interference score was 43·4% (51·5, p<0·0001), and in 
MDASI score was 42·1% (37·4, p<0·0001). 32 (78%) of the 
patients experienced 20% or greater reduction in the mean BFI, 
and 24 (59%) had a reduction of two units or more in worst fatigue 
score in past 24 hours as assessed by the BFI. The most 
comment grade 3-4 adverse events were neutropenia (n=2 [5%]), 
hypertension (n=2 [5%]), insomnia (n=1 [2%]), tinnitus and 
dizziness (n=1 [2%]), and thrombocytopenia (n=1 [2%]).
INTERPRETATION: 
In patients with CLL, ruxolitinib was associated with significant 
improvements in disease-related symptoms as measured by BFI, 
MDASI, and symptom interference scores. As of now, 60 patients 
have been enrolled. Analysis of these patients’ outcome is 
pending.
Protocol Type:
Standard Protocol


Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 06/07/2019
Version:
11
Document Status:
Saved as "Final"
Submitted by:
Carol L. Ancelet--9/13/2018 10:37:04 AM
OPR Action:
Accepted by:  Inar Y. Graur -- 9/17/2018 3:40:21 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
  


 
 
 
ADMINISTRATION OF JAKAFI (RUXOLITINIB) TO PATIENTS WITH PREVIOUSLY 
UNTREATED HIGH-RISK CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/SMALL 
LYMPHOCYTIC LYMPHOMA (SLL): A PHASE II CLINICAL TRIAL 
 
 
 
 
 
 
 
 
 
 
PI: Zeev Estrov, MD 
Department of Leukemia  
Unit 428 
MD Anderson Cancer Center 
1515 Holcombe Blvd. 
Houston, TX 77030  
 


 
 
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TABLE OF CONTENTS 
 
Contents 
1.0 OBJECTIVES ....................................................................................................................................... 4 
1.1 
Primary Objectives ..................................................................................................................... 4 
1.2 
Secondary Objective .................................................................................................................. 4 
2.0 BACKGROUND ................................................................................................................................... 4 
2.1 Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lyphoma (SLL) ........................... 4 
2.2 Ruxolitinib (Jakafi) ........................................................................................................................... 7 
3.0 PATIENT SELECTION ..................................................................................................................... 24 
3.1 Eligibility .......................................................................................................................................... 24 
4.0 TREATMENT PLAN .......................................................................................................................... 27 
4.1 Administration of Study Drug ....................................................................................................... 27 
4.2 Treatment Compliance ................................................................................................................. 27 
4.3 Duration of Treatment and Subject Participation ...................................................................... 28 
4.4 Patient Assessments ..................................................................................................................... 28 
5.0 DOSING DELAYS/ DOSE MODIFICATIONS ............................................................................... 29 
5.1 Concomitant Use with Strong CYP3A4 Inhibitors or Fluconazole .......................................... 29 
5.2 Dosing Delays ................................................................................................................................ 29 
5.3 Dose Modification of Ruxolitinib in Different Clinical Scenarios ............................................. 29 
Table 5. Dose modification for drug interactions ......................................................................... 29 
5.4 Renal Function Impairment .......................................................................................................... 30 
Table 6. Dosing for renal function impairment ............................................................................. 30 
5.5 Hepatic Impairment ....................................................................................................................... 30 
Table 7. Dosing for hepatic impairment ........................................................................................ 30 
6.0 AGENT FORMULATION AND PROCUREMENT ........................................................................ 31 
7.0 CORRELATIVE/ SPECIAL STUDIES ............................................................................................ 32 
8.0 PATIENT EVALUATION ................................................................................................................... 32 
8.1 Outside Physician Participation during Treatment ................................................................... 32 


 
 
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8.2 Symptom Score Assessment ....................................................................................................... 33 
8.3 Disease Response Assessment .................................................................................................. 33 
9.0 RESPONSE CRITERIA .................................................................................................................... 34 
9.1 Disease Response Criteria .......................................................................................................... 35 
10.0 CRITERIA FOR REMOVAL FROM THE STUDY ...................................................................... 35 
11.0 STATISTICAL CONSIDERATIONS ............................................................................................. 35 
11.1 Toxicity monitoring Rule ............................................................................................................. 37 
11.2 Trial Conduct ................................................................................................................................ 39 
12.0 REPORTING REQUIREMENTS ................................................................................................... 39 
12.1 Adverse Events ............................................................................................................................ 40 
12.2 Serious Adverse Event Reporting (SAE) ................................................................................. 41 
13.0 REFERENCES ................................................................................................................................ 43 
 
 
 


 
 
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1.0 OBJECTIVES 
 
1.1 Primary Objectives  
 
To determine the effect of ruxolitinib in patients with high-risk CLL/SLL who do not 
require anti-neoplastic therapy according to the IWCLL 2008 recommendations and 
were either previously untreated or treated with Ibrutinib for less than 3 months and 
were deemed Ibrutinib intolerant: a.) On disease burden, and b.) The rate of 
complete response (CR) and partial response (PR) as assessed by the IWCLL 2008 
response criteria. 
 
1.2 Secondary Objective  
 
To evaluate the time to next treatment in high-risk CLL/SLL who do not require anti-
neoplastic therapy according to the IWCLL 2008 recommendations.  
 
 
2.0 BACKGROUND 
 
2.1 Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lyphoma (SLL) 
 
B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in the Western 
hemisphere, is characterized by a dynamic imbalance between the proliferation and 
apoptosis of neoplastic B-lymphocytes co-expressing CD19, CD5 and CD23 antigens.  
The clinical course of the disease is variable. At the time of diagnosis, most patients 
have an indolent disease that might require therapy several years thereafter or no 
treatment at all. The life expectancy of the latter group is similar to that of age-matched 
healthy individuals. However, a significant number of patients present with a rapidly 
progressive disease that requires immediate therapeutic intervention.  
 
Recently, oral agents that inhibit the B cell receptor (BCR) of CLLSLL cells became 
available. The currently available BCR inhibitors have a variety of side effects that will 
make a significant number of elderly patients with CLL/SLL ineligible for treatment with 
these agents. In a phase III clinical trial of the Bruton tyrosine kinase (BTK) inhibitor 
Ibrutinib Vs. chlorambucil (Burger JA., et al. N Engl J Med 2015; 373:2425-37), that 
ultimately led to the approval of Ibrutinib for untreated patients with CLL/SLL, the side 
effects of Ibrutinib included diarrhea in 42% of the patients (including grade 3 diarrhea in 
4%), and fatigue, nausea, and cough in 20% or more of the patients. In addition, 
hypertension was observed in14% of the patients with grade 3 hypertension occurring in 
4%,atrial fibrillation occurred in 6%, major hemorrhage (defined as any serious or grade 
3 or higher hemorrhage or central nervous system hemorrhage of any grade) occurred 
in 4% of the patients. Furthermore, Ibrutinib-resistant clones were found in a significant 
number of Ibrutinib-treated patients and the clinical outcome of these patients is dire 
(Furman RR et al. N Engl J Med. 2014; 370:2352-4; Woyach JA et al. N Engl J Med. 
2014; 370:2286-94; Burger JA et al. Nat Commun. 2016; May 20; 7:11589).  


 
 
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Another BCR ibhibitor Idelalisib, an oral inhibitor of PI3Kδ that has substantial activity in 
patients with relapsed/refractory CLL induces transaminase elevation that led to 
discontinuation of the drug in 45.3%, diarrhea in 12.5%, and colitis in 6.3% of the 
patients. In addition, Idelalisib induced in dyspnea in 4.7%, pneumonia in 17.2%, and 
rash in 4.7% of the patients (O’Brien SM et al., Blood 2016; 126:2686-2694). 
Remarkably, The European Medicines Agency (EMA) Committee for Medicinal 
Products for Human studies apprehended the Idelalisib study in Europe because of 
deaths in 3 patients. Eventually, the study re-opened with specific strict precautions 
(www.gilead.com). 
 
Although other BTK and PI3K inhibitors are currently investigated in clinical trials, the 
activity of Ruxolitinib, an agent that targets a different pathway and has a different side 
effect profile is warranted as it addresses an unmet need. 
 
Although approximately 20% of CLL patients are diagnosed as a result of routine blood 
tests, most patients present with a wide range of symptoms typically witnessed in 
chronic inflammatory diseases (Hallek et al., 2008).  
 
The role of cytokines and chemokines in the pathogenesis, maintenance, and 
progression of CLL has been the subject of intense research over the past two decades. 
In culture, CLL cells undergo spontaneous apoptosis (Collins et al., 1989). However, co-
culture with T lymphocytes, mesenchymal stromal cells (MSC), nurse-like cells (NLCs), 
or endothelial cells, significantly reduces apoptosis rates of CLL cells (Badoux et al. 
2011; Burger JA, 2011), suggesting that soluble factors and cell-to-cell interactions 
provide CLL cells with survival signals. Various cytokines whose levels are not 
increased in CLL also play a role in this process. For example, IL-4 activates the Janus 
kinase (JAK)/signal transducer and activator of transcription (STAT) pathway that 
protects CLL cells from chemotherapy-induced apoptosis (Dietrich et al., 2012). 
Although IL-4 levels are not elevated in the serum of patients with CLL (Yan et al. 
2011), IL-4 receptor levels are constitutively high in CLL cells (Douglas et all., 1997). 
Similarly, BAFF, a member of the TNF superfamily, is thought to provide CLL cells with 
a survival advantage (Kern et al., 2004). As found in our laboratory, activation of the B-
cell receptor activates JAK2 in CLL cells and, like in other inflammatory conditions 
(Ivanenkov et al., 2008; Vijayakrishnan et al., 2011) inhibition of JAK2 induces 
apoptosis of CLL cells.   
 
Two large-scale DNA deep-sequencing studies detected somatic mutations in CLL 
cells. In one study, deep sequencing of 105 CLL samples detected 1246 mutations 
affecting 1100 protein-coding genes (Quesada et al., 2012).  In another study, parallel 
exome and whole genome sequencing of 91 CLL samples detected 1838 non-
synonymous mutations in 1608 protein coding genes (Wang et al., 2012). Surprisingly, 
only 186 recurrent and non-recurrent mutations were identified simultaneously in both 
data sets. In spite of the limited overlap in mutation detection, the mutated genes were 
clustered in similar pathways in the two data sets with an overwhelming representation 
of pro-inflammatory pathways.   


 
 
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In a comprehensive analysis of 23 cytokines in the sera of 84 patients with CLL and 49 
age-matched healthy individuals, the levels of 17 cytokines, mostly inflammatory 
cytokines, were significantly higher in the serum of patients with CLL (Yan et al. 2011). 
More than 14-fold increase in INF-γ was found in the serum of untreated CLL patients 
(Mahadevan et al., 2009). Similarly, plasma levels of IL-1, IL-6, IL-10 (Fayad et al., 
2001), IL-8, and TNF-α (Yoon et al., 2012) were also typically increased. The majority of 
those inflammatory cytokines are produced as a result of activation of the transcription 
factor κB, known to be constitutively activated in CLL cells (Liu et al., 2010) and several 
of them (such as IL-6) bind to their corresponding receptors and activate JAK1. Most of 
those cytokines are known to be responsible for signs and symptoms of inflammatory 
diseases. Whether produced by CLL or other cells, these cytokines contribute both 
directly and indirectly, to the survival of CLL cells and to the signs and debilitating 
symptoms of patients with CLL.  
 
In various neoplastic cells activation of the JAK/STAT pathway provides cells with 
survival advantage. In a recent study (Rozovski et al., 2014) we investigated whether 
activation of the B-cell receptor (BCR) activates the JAK/STAT pathway. To stimulate 
the BCR we incubated CLL cells with anti-IgM antibodies. We found that activation of 
the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL 
cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation 
and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and 
time-dependent manner. Therefore we sought to determine whether treatment with 
ruxolitinib would benefit patients with CLL. If ruxolitinib is found be effective we intend to 
further develop it for the treatment of CLL. 
 
2.1.1 Effect of Ruxolitinib in patients with CLL/SLL 
 
Because no standard therapeutic intervention is available to control CLL/SLL patients’ 
symptoms and because stimulation of the BCR activates the JAK/STAT3 pathway, 
known to induce the production of inflammatory cytokines (Rozovski et al., 2014), we 
conducted a clinical trial (protocol 2013-0044) to assess the effect of ruxolitinib on 
symptoms in CLL/SLLpatients. After the enrollment of 40 patients onto this study we 
found that: 1.) Ruxolitinib is well tolerated in patients with CLL/SLL. Very few patients 
had to be removed from the study because of adverse events. 2.) The vast majority of 
the patients (78 %) responded to therapy, their symptoms improved, often dramatically, 
and the clinical improvement in the patients correlated with a significant reduction in 
plasma inflammatory cytokine levels. 3.) In several patients, the number of peripheral 
blood lymphocyte counts increased and then decreased to or below baseline level, as 
observed in CLL/SLL patients treated with the Bruton tyrosine kinase (BTK) inhibitor 
Ibrutinib, suggesting that, like Ibrutinib, ruxolitinib induces mobilization and then 
apoptosis of CLL/SLL cells. Therefore we intend to explore whether ruxolitinib would 
reduce disease burden in patients with high-risk CLL/SLL. 
 
 
 


 
 
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2.1.2 Previously untreated patients with high-risk CLL/SLL 
 
The clinical course of patients with CLL/SLL is diverse; some patients have indolent 
disease, never needing treatment, whereas others have aggressive disease requiring 
early intervention. We currently use clinical criteria to initiate therapy. Hoewever several 
investigators suggested that early intervention in patients with high-risk disease might 
be beneficial. To determine which patients are at high risk of disease progression, a 
multivariable analysis was performed to identify prognostic factors independently 
associated with time to first treatment for patients with CLL (Wierda et al., 2011). This 
multivariable model was used to develop a nomogram-a weighted tool to calculate 2- 
and 4-year probability of treatment and estimate median time to first treatment.  
 
The factors independently associated with shorter time to first treatment included: a.) 
three involved lymph node sites, b.) increased size of cervical lymph nodes, c.) 
presence of 17p deletion or 11q deletion assessed by fluorescence in situ hybridization 
(FISH), increased serum lactate dehydrogenase (LDH), and unmutated IgHV (Wierda et 
al., 2011).  
 
Given that ruxolitinib is well tolerated and efficiently alleviates the symptoms of patients 
with CLL/SLL and given that, similar to Ibrutinib, treatment with ruxolitinib increased and 
then reduced the number of circulating lymphocytes, we sought to investigate the 
clinical benefits of ruxolitinib in patients with previously untreated high-risk CLL/SLL. In 
particular, we intend to study the effect of ruxolitinib on disease burden and determine 
whether treatment with ruxolitinib will delay the time to next treatment of previously 
untreated patients with high-risk CLL/SLL who are expected to require therapy for 
CLL/SLL within 4 years according to the above described nomogram (Wierda et al., 
2011). 
 
2.2 Ruxolitinib (Jakafi)  
 
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H-
pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate 
and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural 
formula:  
 
 
 


 
 
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Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in 
aqueous buffers across a pH range of 1 to 8. Jakafi (ruxolitinib) Tablets are for oral 
administration. Each tablet contains ruxolitinib phosphate equivalent to 5 mg, 10 mg, 
15 mg, 20 mg and 25 mg of ruxolitinib free base together with microcrystalline 
cellulose, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, sodium 
starch glycolate, povidone and hydroxypropyl cellulose. 
 
2.2.1 Mechanism of Action   
 
Ruxolitinib is a kinase inhibitor that inhibits the Janus kinases (JAKs) JAK1 and JAK2 
which mediate the signaling of a number of cytokines and growth factors that are 
important for hematopoiesis and immune function. JAK signaling involves recruitment 
of signal transducers and activators of transcription (STATs) to cytokine receptors, 
activation and subsequent localization of STATs to the nucleus leading to modulation 
of gene expression. Myelofibrosis (MF) and polycythemia vera (PV) are 
myeloproliferative neoplasms (MPN) known to be associated with dysregulated JAK1 
and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral 
administration of ruxolitinib prevented splenomegaly, preferentially decreased 
JAK2V617F mutant cells in the spleen and decreased circulating inflammatory 
cytokines (e.g., TNF-α, IL-6).  
 
2.2.2 Pharmacodynamics   
 
Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy 
subjects and patients with MF and PV. Ruxolitinib administration resulted in maximal 
inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near 
baseline by 10 hours in both healthy subjects and patients with MF and PV.  
 
2.2.3 Pharmacokinetics  
 
Absorption.  In clinical studies, ruxolitinib is rapidly absorbed after oral ruxolitinib 
(Jakafi) administration with maximal plasma concentration (Cmax) achieved within 1 
to 2 hours post-dose. Based on a mass balance study in humans, oral absorption of 
ruxolitinib was estimated to be at least 95%. Mean ruxolitinib Cmax and total 
exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. 
There were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon 
administration of Jakafi with a high-fat meal, with the mean Cmax moderately 
decreased (24%) and the mean AUC nearly unchanged (4% increase). 
 
Distribution.  The mean volume of distribution at steady-state is 72 L in patients with MF 
with an associated inter-subject variability of 29% and 75 L in patients with PV with an 
associated inter-subject variability of 23%. Binding to plasma proteins in vitro is 
approximately 97%, mostly to albumin.  
 
Metabolism.  In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a 
lesser extent by CYP2C9.  


 
 
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Elimination.  Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult 
subjects, elimination was predominately through metabolism with 74% of radioactivity 
excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 
1% of the excreted total radioactivity. The mean elimination half-life of ruxolitinib is 
approximately 3 hours and the mean half-life of ruxolitinib + metabolites is 
approximately 5.8 hours. 
 
Effects of Age, Gender, or Race.  In healthy subjects, no significant differences in 
ruxolitinib pharmacokinetics were observed with regard to gender and race. In a 
population pharmacokinetic evaluation in patients with MF, no relationship was 
apparent between oral clearance and patient age or race, and in women, clearance 
was 17.7 L/h and in men, 22.1 L/h with 39% inter-subject variability. Clearance was 
12.7 L/h in patients with PV, with a 42% inter-subject variability, and no relationship 
was apparent between oral clearance and gender, patient age or race in this patient 
population. 
 
2.2.4 Drug Interactions 
Strong CYP3A4 inhibitors: In a trial of 16 healthy volunteers, a single dose of 10 mg of 
Jakafi was administered alone on Day 1 and a single dose of 10 mg of Jakafi was 
administered on Day 5 in combination with 200 mg of ketoconazole (a strong CYP3A4 
inhibitor, given twice daily on Days 2 to 5). Ketoconazole increased ruxolitinib Cmax and 
AUC by 33% and 91%, respectively. Ketoconazole also prolonged ruxolitinib half-life 
from 3.7 to 6.0 hours. 
 
Fluconazole: Simulations using physiologically-based pharmacokinetic (PBPK) models 
suggested that fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increases steady 
state ruxolitinib AUC by approximately 100% to 300% following concomitant 
administration of 10 mg of Jakafi twice daily with 100 mg to 400 mg of fluconazole once 
daily, respectively.  
 
Mild or moderate CYP3A4 inhibitors: In a trial of 15 healthy volunteers, a single 
dose of 10 mg of Jakafi was administered alone on Day 1 and a single dose of 10 
mg of Jakafi was administered on Day 5 in combination with 500 mg of 
erythromycin (a moderate CYP3A4 Inhibitor, given twice daily on Days 2 to 5). 
Erythromycin increased ruxolitinib Cmax and AUC by 8% and 27%, respectively.  
 
CYP3A4 inducers: In a trial of 12 healthy volunteers, a single dose of 50 mg of Jakafi 
was administered alone on Day 1 and a single dose of 50 mg of Jakafi was 
administered on Day 13 in combination with 600 mg of rifampin (a strong CYP3A4 
inducer, given once daily on Days 3 to 13). Rifampin decreased ruxolitinib Cmax and 
AUC by 32% and 61%, respectively. In addition, the relative exposure to ruxolitinib 
active metabolites increased approximately 100%. 
 


 
 
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In vitro studies: In vitro, ruxolitinib and its M18 metabolite do not inhibit CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib is not an 
inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations. In vitro, 
ruxolitinib and its M18 metabolite do not inhibit the P-gp, BCRP, OATP1B1, OATP1B3, 
OCT1, OCT2, OAT1 or OAT3 transport systems at clinically relevant concentrations. 
Ruxolitinib is not a substrate for the P-gp transporter. 
 
Thorough QT interval Study:  The effect of single dose ruxolitinib 25 mg and 200 mg 
on QTc interval was evaluated in a randomized, placebo-, and active-controlled 
(moxifloxacin 400 mg) four-period crossover thorough QT study in 47 healthy 
subjects. The study demonstrated the ability to detect small effects, the upper bound 
of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-
corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the 
threshold for regulatory concern. The dose of 200 mg is adequate to represent the 
high exposure in a clinical scenario. 
 
2.2.5 Nonclinical toxicity 
Carcinogenesis, Mutagenesis, Impairment of Fertility:  Ruxolitinib was not carcinogenic 
in the 6-month Tg.rasH2 transgenic mouse model or in a 2-year carcinogenicity study 
in the rat. Ruxolitinib was not mutagenic in a bacterial mutagenicity assay (Ames test) 
or clastogenic in in vitro chromosomal aberration assay (cultured human peripheral 
blood lymphocytes) or in vivo in a rat bone marrow micronucleus assay. In a fertility 
study, ruxolitinib was administered to male rats prior to and throughout mating and to 
female rats prior to mating and up to the implantation day (gestation day 7). Ruxolitinib 
had no effect on fertility or reproductive function in male or female rats at doses of 10, 
30 or 60 mg/kg/day. However, in female rats doses of greater than or equal to 30 
mg/kg/day resulted in    increased post-implantation loss.The exposure (AUC) at the 
dose of 30 mg/kg/day is approximately 34% the clinical exposure at the maximum 
recommended dose of 25 mg twice daily. 
 
2.2.6 Drug product 
Formulation: Ruxolitinib (Jakafi®) is commercially available in the US in 5, 10, 15, 20, 
and 25 mg strength tablets. The tablet contains 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. 
 
The 5 mg (free base equivalent) and 25 mg (free base equivalent) tablets are packaged 
in HDPE bottles. All bottles of Incyte investigational product contain the following 
language: “Caution: New Drug-Limited by Federal Law to Investigational Use.” The 
clinical supply for investigational use is the 5 mg tablet.   
 
Storage and stability: Ruxolitinib has been shown to be stable for up to 6 months at 
40°C and up to 24 months when stored at 25°C.  
 


 
 
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Compatibility: Ruxolitinib may be taken either with food or without food 
 
Handling: Qualified personnel, familiar with procedures that minimize undue exposure 
to themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 
 
Availability: Ruxolitinib will be supplied free-of-charge from Incyte in 5 mg tablets. 
 
 
 


 
 
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2.2.7 Human pharmacokinetics 
Ruxolitinib exhibits near complete oral absorption, achieving maximal plasma 
concentration at approximately 1-2 h post-dose with linear PK over a dose range of 5-
200 mg. Ruxolitinib is mainly eliminated by metabolism via CYP3A4 with minor 
contributions of CYP2C9 with a terminal elimination half-life of approximately 3 h. 
Administration with food did not affect ruxolitinib overall exposure. Ruxolitinib may be 
administered without regard to meals. 
 
When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily dose of 
ruxolitinib should be decreased by approximately 50% based on the platelet counts (or 
as specified in country-specific product labels). No dose adjustment is necessary when 
a mild or moderate CYP3A4 inhibitor is used as concomitant medication (although 
patients should be monitored closely for cytopenias when starting a mild or moderate 
CYP3A4 inhibitor). Upon initiation of a CYP3A4 inducer, no dose adjustment is 
recommended. Gradual dose increases of ruxolitinib may be considered if the 
effectiveness of therapy is diminished during chronic treatment with a CYP3A4 inducer. 
 
In patients with moderate (CrCl 30-50 mL/min) and severe renal impairment (CrCl <30 
mL/min), the recommended starting dose should be based on platelet count and 
reduced by approximately 50% (or as specified in country specific product labels). 
Available data in patients with end stage renal disease suggests that patients on 
hemodialysis should initiate dosing with a single dose of 15 mg or 20 mg following each 
hemodialysis, based on platelet counts, with subsequent doses following each 
hemodialysis session and administered only on dialysis days with careful monitoring of 
safety and efficacy. Doses in patients with renal impairment should be subsequently 
adjusted based on individual safety and efficacy. 
 
Although ruxolitinib exposure was increased in subjects with hepatic impairment, there 
was no relationship between ruxolitinib exposure and the degree of hepatic impairment 
as determined by the Child-Pugh score. Conservatively, in patients with any degree of 
hepatic impairment, the recommended starting ruxolitinib dose should be based on 
platelet count and reduced by approximately 50% (or as specified in country specific 
product labels). Patients developing any hepatic impairment during treatment should be 
carefully monitored and may have their doses reduced to avoid toxicity. Further dose 
modifications should be based on the safety and efficacy. 
 
2.2.8 Safety and efficacy 
The safety profile for ruxolitinib in the Phase I development program was assessed in 
over 145 healthy subjects for single doses from 5 mg to 200 mg, and in 53 healthy 
subjects for repeat doses from 15 mg to 50 mg b.i.d. and 50 to 100 mg q.d. Ruxolitinib 
has also been administered to 32 subjects with various degrees of renal impairment, 24 
subjects with various degrees of hepatic impairment, and 50 subjects with rheumatoid 
arthritis (RA). Adverse events (AEs) were, in general, mild and resolved without 
interventions. In the first in human study one subject had hyponatremia after receiving 5 


 
 
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mg ruxolitinib. The hyponatremia was assessed as severe in intensity, unrelated to 
study medication, reversed within 5 days, and was reported as a serious adverse event 
(SAE). 
 
In the repeat-dose study in healthy subjects, the intensity of an AE was graded 
according to the protocol-defined toxicity criteria based on Rheumatology Common 
Toxicity Criteria V 1.0. The dose-limiting AE was neutropenia, which occurred at a dose 
of 50 mg b.i.d. Neutropenia as an AE was noted in three subjects, all receiving the 
highest dose of ruxolitinib, 50 mg b.i.d. Neutropenia at the Grade 4 level, assessed as 
severe, led to study drug discontinuation on Day 5 in one subject, and was reported as 
a SAE. Neutrophil count returned to a normal level 12 days after the final dose of study 
medication. In two other subjects, neutropenia was Grade 1 or 2, and resolved with 
dose interruption or during continued dosing. The AE profile was similar for single- and 
multiple-dose studies, and no differences were observed between males and females. 
The most frequent (≥2subjects) treatment-emergent AEs (TEAEs) occurring in the 
Phase I multiple-dose study were: neutropenia (4.2%), dizziness (2.8%), headache 
(2.8%) and nausea (2.8%). Overall, in healthy volunteer studies where frequent 
sampling of the neutrophil count was performed, a transient, reversible decrease in 
neutrophil count was frequently seen following dosing, which reversed after 12-24 h off 
drug. 
 
2.2.8.1 Studies in myelofibrosis (MF) 
Three studies enrolled patients with MF for which data has been reported as per 
planned analyses. Phase I/II study enrolled 158 patients in the target disease population 
of PMF, PPV-MF, and PET-MF to establish safety, efficacy, MTD, dose limiting 
toxicities, and appropriate dose regimens for the Phase III studies. The Phase III clinical 
program consists of two studies: study, conducted in the USA, Canada and Australia, 
which is a placebo controlled study that enrolled 309 patients and study conducted in 
Europe, which compares ruxolitinib with BAT in 219 patients. Those phase III trials 
(COMFORT I and II) confirmed the findings observed in the phase I/II studies. 
 
In general, in the phase I/II studies the proportions of patients showing improvement 
were similar across dose cohorts. At Week 24, nine patients (42.9%) who started at 10 
mg b.i.d., 16 patients (51.6%) who started at 15 mg b.i.d., 15 patients (37.5%) who 
started at 25 mg b.i.d., three patients (75.0%) who started at 50 mg b.i.d., and 11 
(37.9%) patients who started with a q.d. dose regimen showed clinical improvement. 
Among the b.i.d. treatment arms, patients who initiated dosing at 15 mg b.i.d. and had 
subsequent optimization of treatment showed the highest consistent response rate over 
time through Cycle 16 (Week 60).  
 
Reduction in spleen size: At the first assessment (Week 4), 37.7% of patients had a 
≥50% reduction from baseline in spleen length assessed by palpation. At Week 24 (6 
months of treatment), 43.8% of patients had a ≥50% reduction from baseline in spleen 
length. The median percent reduction from baseline in spleen length assessed by 
palpation was approximately 52% at Week 24 and 63% at Week 60 (Verstovsek et al., 
2010, Verstovsek et al., 2012). 


 
 
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Improvement in symptom scores: In this study a modified MFSAF questionnaire was 
used (questionnaire consisting of 15 common signs and symptoms experienced by 
patients in MF), which was a predecessor of the one utilized in the Phase III MF studies. 
This improvement was generally maintained over time; at Week 60, the median percent 
reduction from baseline was 65%. (Verstovsek et al., 2010; Mesa et al., 2011; 
Verstovsek et al., 2012). 
 
Increase in body weight: Patients showed a gradual increase in body weight over the 
course of the study. It is important to note that weight gain in this population may be a 
positive response, as splenomegaly causes early satiety and constitutional symptoms of 
anorexia are common. When examined by baseline body mass index (BMI) quartile, the 
four groups generally gained weight consistently over time. Further, assessment of the 
percent change from baseline showed that the lowest BMI group gained the most 
weight and the highest BMI group gained the least weight (Verstovsek et al., 2010; 
Mesa et al., 2011; Verstovsek et al., 2012). 
 
Improvement in overall survival: A Kaplan-Meier estimate of overall survival (OS) 
showed that the probability of survival was 96% at 1 year and 90% at 2 years. 
(Verstovsek et al., 2012). 
 
Improvement in symptoms and QoL: Symptoms of MF were assessed using a symptom 
diary (modified MFSAF v2.0 diary, electronic device). Improvement in MF symptoms 
and QoL correlated with a reduction in inflammatory cytokine levels (Verstovsek et al., 
2010; Mesa et al., 2011; Verstovsek et al., 2012). 
 
2.2.9 Adverse events 
A summary of most frequently (≥5%) reported AEs in the Phase III population 
regardless of study drug relationship by preferred term is presented in Table 1. The 
comparison of the control groups to the ruxolitinib patients showed that headache was 
more frequent in ruxolitinib-treated patients (13.6% vs. 6.0% on placebo and 5.5% on 
BAT). Most AEs of headache were Grade 1 or 2. Similarly, dizziness (12.0% vs. 6.6% 
on placebo and 6.8% on BAT) was more frequent in ruxolitinib-treated patients, again 
mostly Grade 1 or 2. When adjusted for patient-year exposure, the differences are still 
present for headache and dizziness. 
 
Weight increase was also more frequent in ruxolitinib-treated patients than in the control 
groups (9.6% vs. 1.3% on placebo and 1.4% on BAT). Although some of these patients 
had co-reported AEs of edema, many had a past medical history of weight loss and the 
weight gain usually gradually accumulated over the course of one year of treatment. 
The majority of weight gain AEs were Grade 1 and 2. It is worth noting that weight gain 
may be a beneficial effect in patients with MF, given the catabolic nature of the disease 
and the frequency of weight loss reported as a constitutional symptom. 
 
Other preferred terms with increased frequency in the ruxolitinib arms included bruising 


 
 
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(2.6% vs. 1.3% on placebo in, contusion (8.6% vs. 5.3% on placebo herpes zoster 
(4.0% vs. 0.7% on placebo and 0% on BAT) and flatulence (3.3% vs. 1.3% on placebo 
and 0% on BAT). Abdominal pain was more frequent in the control groups than in the 
ruxolitinib group (43% on placebo and 13.7% on BAT vs. 12% on ruxolitinib), as were 
weight decrease (8.6% on placebo and 8.2% on BAT vs. 1% on ruxolitinib), early satiety 
(8.6% on placebo and 0% on BAT vs. 0.3% on ruxolitinib) and splenic infarction (6.0% 
on placebo and 0% on BAT vs. 1.0% on ruxolitinib). 
 
 
Table 1. Most frequently reported adverse events (AEs) in a Phase III clinical trial 
 
                                                                  Study INCB 18424-351             Study CINC424A2352             Total 
 
 
 
Ruxolitinib 
N=155 
n (%) 
Placebo 
N=151 
n (%) 
Ruxolitinib 
N=146 
n (%) 
BAT 
N=73 
n (%) 
Ruxolitinib 
N=301 
n (%) 
Any 
152 (98.1) 
149 (98.7) 
145 (99.3) 
67 (91.8) 
297 (98.7) 
Thrombocytopenia 
58 (37.4) 
14 (9.3) 
65 (44.5) 
9 (12.3) 
123 (40.9) 
Anemia 
49 (31.6) 
22 (14.6) 
61 (41.8) 
10 (13.7) 
110 (36.5) 
Diarrhea 
37 (23.9) 
35 (23.2) 
38 (26.0) 
11 (15.1) 
75 (24.9) 
Edema peripheral 
31 (20.0) 
36 (23.8) 
34 (23.3) 
19 (26.0) 
65 (21.6) 
Fatigue 
43 (27.7) 
54 (35.8) 
19 (13.0) 
8 (11.0) 
62 (20.6) 
Dyspnea 
28 (18.1) 
28 (18.5) 
24 (16.4) 
13 (17.8) 
52 (17.3) 
Nausea 
23 (14.8) 
29 (19.2) 
21 (14.4) 
5 (6.8) 
44 (14.6) 
Headache 
24 (15.5) 
9 (6.0) 
17 (11.6) 
4 (5.5) 
41 (13.6) 
Pyrexia 
19 (12.3) 
12 (7.9) 
22 (15.1) 
7 (9.6) 
41 (13.6) 
Cough 
18 (11.6) 
13 (8.6) 
22 (15.1) 
12 (16.4) 
40 (13.3) 
Pain in extremity 
22 (14.2) 
16 (10.6) 
17 (11.6) 
3 (4.1) 
39 (13.0) 
Arthralgia 
18 (11.6) 
14 (9.3) 
19 (13.0) 
7 (9.6) 
37 (12.3) 
Abdominal pain 
19 (12.3) 
65 (43.0) 
17 (11.6) 
10 (13.7) 
36 (12.0) 
Dizziness 
25 (16.1) 
10 (6.6) 
11 (7.5) 
5 (6.8) 
36 (12.0) 
Vomiting 
20 (12.9) 
17 (11.3) 
16 (11.0) 
1 (1.4) 
36 (12.0) 
Asthenia 
8 (5.2) 
12 (7.9) 
26 (17.8) 
7 (9.6) 
34 (11.3) 
Nasopharyngitis 
7 (4.5) 
9 (6.0) 
27 (18.5) 
10 (13.7) 
34 (11.3) 
Constipation 
21 (13.5) 
19 (12.6) 
11 (7.5) 
4 (5.5) 
32 (10.6) 
Weight increased 
13 (8.4) 
2 (1.3) 
16 (11.0) 
1 (1.4) 
29 (9.6) 
Hemoglobin decreased 
23 (14.8) 
6 (4.0) 
4 (2.7) 
3 (4.1) 
27 (9.0) 
Insomnia 
18 (11.6) 
15 (9.9) 
9 (6.2) 
5 (6.8) 
27 (9.0) 
Back pain 
11 (7.1) 
13 (8.6) 
15 (10.3) 
9 (12.3) 
26 (8.6) 
Contusion 
23 (14.8) 
8 (5.3) 
3 (2.1) 
1 (1.4) 
26 (8.6) 
Platelet count decreased 
15 (9.7) 
4 (2.6) 
11 (7.5) 
2 (2.7) 
26 (8.6) 
Muscle spasms 
11 (7.1) 
11 (7.3) 
14 (9.6) 
5 (6.8) 
25 (8.3) 
Night sweats 
12 (7.7) 
18 (11.9) 
13 (8.9) 
6 (8.2) 
25 (8.3) 
Abdominal pain upper 
10 (6.5) 
13 (8.6) 
12 (8.2) 
4 (5.5) 
22 (7.3) 
Bronchitis 
4 (2.6) 
2 (1.3) 
18 (12.3) 
5 (6.8) 
22 (7.3) 
Urinary tract infection 
12 (7.7) 
7 (4.6) 
10 (6.8) 
2 (2.7) 
22 (7.3) 
Epistaxis 
9 (5.8) 
8 (5.3) 
12 (8.2) 
5 (6.8) 
21 (7.0) 
Abdominal distension 
13 (8.4) 
17 (11.3) 
5 (3.4) 
1 (1.4) 
18 (6.0) 
Cardiac murmur 
12 (7.7) 
5 (3.3) 
6 (4.1) 
3 (4.1) 
18 (6.0) 


 
 
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Hematoma 
4 (2.6) 
0 
14 (9.6) 
3 (4.1) 
18 (6.0) 
Pneumonia 
13 (8.4) 
11 (7.3) 
4 (2.7) 
5 (6.8) 
17 (5.6) 
Rash 
9 (5.8) 
8 (5.3) 
8 (5.5) 
1 (1.4) 
17 (5.6) 
Dyspnea exceptional 
6 (3.9) 
5 (3.3) 
10 (6.8) 
2 (2.7) 
16 (5.3) 
Paraesthesia 
6 (3.9) 
4 (2.6) 
10 (6.8) 
4 (5.5) 
16 (5.3) 
Dyspepsia 
9 (5.8) 
8 (5.3) 
6 (4.1) 
4 (5.5) 
15 (5.0) 
 
The most frequently occurring Grade 3 and 4 AEs regardless of study drug relationship 
were hematologic including anemia (14%) and thrombocytopenia (8%). Non-
hematologic Grade 3-4 AEs were infrequent and rarely reported more frequently than in 
the control arms. Two patients (0.7%) had febrile neutropenia. In general, the pattern of 
AEs was similar between the two ruxolitinib arms in both studies, although there were 
some differences in frequency for specific AEs. 
 
In the clinical study program the severity of adverse drug reactions was assessed based 
on the CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe and 
grade 4=life threatening. 
 
Adverse drug reactions from clinical studies (Table 2) are listed by MedDRA system 
organ class. Within each system organ class, the adverse drug reactions are ranked by 
frequency, with the most frequent reactions first. In addition, the corresponding 
frequency category for each adverse drug reaction is based on the following convention: 
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare 
(≥1/10,000 to <1/1,000); very rare (<1/10,000). 
 
 
Table 2. Percent of patients with adverse drug reactions 
 
 
ADRs and CTCAE 
Grade 
INCB 18424-351 
CINC424A2352 
Total 
Ruxolitinib 
N=301 
Frequency 
category 
Ruxolitinib 
N=155 
Placebo 
N=151 
Ruxolitinib 
N=146 
BAT 
N=73 
 
% 
% 
% 
% 
% 
 
Infections and infestations 
 
 
Urinary Tract infections1 
 
9.0 
 
5.3 
 
14.4 
 
6.8 
 
11.6 
Very 
common 
Herpes zoster1 
1.9 
0.7 
4.8 
0 
3.3 
Common 
Blood and lymphatic system disorders 
 
Anemia2 
 
 
 
 
 
 
CTCAE 3 Grade 4 
(<6.5g/dL) 
 
11.0 
 
2.6 
 
8.2 
 
9.6 
 
9.6 
Common 
CTCAE Grade 3 
(<8.0 – 6.5g/dL) 
 
31.6 
 
12.6 
 
30.1 
 
11.0 
 
30.9 
Very 
common 
 
Any CTCAE Grade 
 
81.9 
 
41.7 
 
81.5 
 
49.3 
 
81.7 
Very 
common 


 
 
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Thrombocytopenia2 
 
 
 
 
 
 
CTCAE Grade 4 
(<25,000/mm3) 
 
3.9 
 
0 
 
2.1 
 
2.7 
 
3.0 
Common 
CTCAE Grade 3 
(50,000 – 25,000/mm3) 
 
9.0 
 
1.3 
 
6.2 
 
4.1 
 
7.6 
Common 
 
Any CTCAE Grade 
 
68.4 
 
19.2 
 
66.4 
 
26.0 
 
67.4 
Very 
common 
Neutropenia2 
 
 
 
 
 
 
CTCAE Grade 4 
(<500/mm3) 
 
1.9 
 
1.3 
 
2.7 
 
1.4 
 
2.3 
Common 
CTCAE Grade 3 
(<1000 – 500/mm3) 
 
4.5 
 
0.7 
 
3.4 
 
0 
 
4.0 
Common 
 
Any CTCAE Grade 
 
18.1 
 
4.0 
 
12.3 
 
8.2 
 
15.3 
Very 
Common 
Metabolism and nutrition disorders 
 
Weight gain1 
7.1 
1.3 
9.6 
0 
8.3 
Common 
Hypercholesterolemia 2,4 
Any CTCAE Grade 
 
17.4 
 
0.7 
 
15.8 
 
6.8 
 
16.6 
Very 
common 
Nervous system disorders 
 
 
Dizziness1 
 
18.1 
 
7.3 
 
9.6 
 
8.2 
 
14.0 
Very 
common 
 
Headache1 
 
14.8 
 
5.3 
 
10.3 
 
4.1 
 
12.6 
Very 
common 
Gastrointestinal disorders 
 
Flatulence1 
5.2 
0.7 
1.4 
0 
3.3 
Common 
ADRs and CTCAE 
Grade 
INCB 18424-351 
CINC424A2352 
Total 
Ruxolitinib 
N=301 
Frequency 
category 
Ruxolitinib 
N=155 
Placebo 
N=151 
Ruxolitinib 
N=146 
BAT 
N=73 
 
% 
% 
% 
% 
% 
 
Hepatobiliary disorders 
 
Raised alanine 
aminotransferase2, 5 
 
 
 
 
 
  Common 
CTCAE Grade 3 
(>5x – 20 x ULN) 
 
1.3 
 
0 
 
1.4 
 
0 
 
1.3 
Common 
 
Any CTCAE Grade 
 
27.1 
 
7.9 
 
25.3 
 
6.8 
 
26.2 
Very 
common 
Raised aspartate 
aminotransferase2,5 
 
 
 
 
 
Very 
common 
Any CTCAE Grade 
18.1 
6.6 
19.2 
2.7 
18.6 
 
Skin and subcutaneous tissue disorders 
 


 
 
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Bruising1 
 
23.2 
 
14.6 
 
13.7 
 
5.5 
 
18.6 
Very 
common 
1 Frequency is based on adverse event data. 
2 Frequency is based on laboratory values. 
-A subject with multiple occurrences of an ADR is counted only once in that ADR category. 
-ADRs reported are on treatment or up to 28 days post treatment end date. 
3 CTCAE Version 3.0; 
Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening or disabling. 
4 In Phase III clinical studies no CTCAE Grade 3 or 4 hypercholesterolemia was observed. 
5 In Phase III clinical studies no CTCAE Grade 4 raised ALT was observed and no CTCAE Grade 3 or 4 raised 
AST was observed. 
ULN=upper limit of normal 
-A subject with multiple occurrences of an ADR is counted only once in that ADR category. 
-ADRs reported are on treatment or up to 28 days post treatment end date. 
 
Infectious complications 
 
Serious bacterial, mycobacterial, fungal and viral infections may occur. Therefore active 
serious infections should have resolved before starting therapy with ruxolitinib. Patients 
receiving ruxolitinib should be observed for signs and symptoms of infection and 
treatment should be initiated promptly. Few anecdotal reports have reported infectious 
complications including, reactivation of latent virus infections, Progressive multifocal 
leukoencephalopathy in a patient with myelofibrosis, Herpes Zoster (see also section 
6.1).  
 
Deaths and other serious adverse events in the MF clinical trials 
 
In the Phase III population, there were 34 deaths in total, 27 of which were on-treatment 
deaths: 20 deaths in study Comfort I (9 in the ruxolitinib group, 11 in the placebo group) 
and 7 deaths in study Comfort II (4 in the ruxolitinib group, 3 in the BAT group). The 
reasons for death (infections, intestinal perforation, disease progression and events 
probably due to disease progression, bleedings events) were similar in the ruxolitinib 
and the placebo groups. In the ruxolitinib-treated Phase III population, the overall 
frequency of SAEs was 28.9%. This frequency was similar across both studies. The 
most frequently reported SAEs in ruxolitinib-treated patients were anemia (4.0%) and 
pneumonia (3.7%). Pneumonia was the only SAE that was reported in more than 5% in 
any treatment group (ruxolitinib group with 6.5% and BAT group with 5.5%). When 
evaluating all lower respiratory tract infection AEs grouped by MedDRA higher level 
group term (MedDRA: Medical Dictionary for Regulatory Activities), there was no 
appreciable difference across the arms of the studies: ruxolitinib 10.3% vs. placebo 
7.3%; ruxolitinib 13.1% vs. BAT 18%). Most other SAEs were reported in three patients 
or fewer in any group, with the following exceptions: in the placebo group, abdominal 
pain was reported as an SAE in six patients (4.0%), and splenic infarction in four 
patients (2.6%); in the ruxolitinib-treated patients, fatigue, gastrointestinal hemorrhage 
and pyrexia were reported in four patients (1.3%) each. 
 
 


 
 
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2.2.10 Warnings and precautions 
Thrombocytopenia, Anemia and Neutropenia 
 
Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia.. Manage 
thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet 
transfusions may be necessary  
Patients developing anemia may require blood transfusions and/or dose modifications 
of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by 
withholding Jakafi until recovery.  Perform a pre-treatment complete blood count 
(CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as 
clinically indicated.   
 
Risk of Infection  
 
Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay 
starting therapy with Jakafi until active serious infections have resolved. Observe 
patients receiving Jakafi for signs and symptoms of infection and manage promptly. 
 
Tuberculosis  
 
Tuberculosis infection has been reported in patients receiving Jakafi.  Observe patients 
receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. 
Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and 
those at higher risk should be tested for latent infection. Risk factors include, but are not 
limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, 
close contact with a person with active tuberculosis, and a history of active or latent 
tuberculosis where an adequate course of treatment cannot be confirmed. 
 
For patients with evidence of active or latent tuberculosis, consult a physician with 
expertise in the treatment of tuberculosis before starting Jakafi. The decision to 
continue Jakafi during treatment of active tuberculosis should be based on the overall 
risk-benefit determination. 
 
PML 
 
Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib 
treatment for myelofibrosis.  If PML is suspected, stop Jakafi and evaluate. 
 
Herpes Zoster 
 
Advice patients about early signs and symptoms of herpes zoster and to seek 
treatment as early as possible if suspected. 
 
Hepatitis B 
 


 
 
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Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations 
in alanine aminotransferase and aspartate aminotransferase, have been reported in 
patients with chronic HBV infections taking Jakafi.  The effect of Jakafi on viral 
replication in patients with chronic HBV infection is unknown.  Patients with chronic 
HBV infection should be treated and monitored according to clinical guidelines. 
 
Symptom exacerbation following interruption or discontinuation of treatment with Jakafi 
 
Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may 
return to pretreatment levels over a period of approximately one week.  Some patients 
with myelofibrosis have experienced one or more of the following adverse events after 
discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ 
failure.  If one or more of these occur after discontinuation of, or while tapering the 
dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or 
increasing the dose of Jakafi.  Instruct patients not to interrupt or discontinue Jakafi 
therapy without consulting their physician. When discontinuing or interrupting therapy 
with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and 
Administration (2.5)], consider tapering the dose of Jakafi gradually rather than 
discontinuing abruptly. 
 
Non-Melanoma Skin Cancer 
 
Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell 
carcinoma have occurred in patients treated with Jakafi.  Perform periodic skin 
examinations. 
 
Lipid Elevations 
 
Treatment with Jakafi has been associated with increases in lipid parameters including 
total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. The effect 
of these lipid parameter elevations on cardiovascular morbidity and mortality has not 
been determined in patients treated with Jakafi.  Assess lipid parameters 
approximately 8-12 weeks following initiation of Jakafi therapy.  Monitor and treat 
according to clinical guidelines for the management of hyperlipidemia. 
 
2.2.11 Contraindications 
Hypersensitivity to the active substance or any of the excipients. 
 
2.2.12 Combination with other drugs 
No information exists for combining ruxolitinib with other standard MF-therapies and this 
is discouraged outside a clinical trial. No data are available regarding interactions of 
ruxolitinib with hematopoietic stimulatory drugs such as erythropoietin and 
thrombopoietin agents. However potential interactions with these agents are possible 
based on their signaling through the JAK/STAT pathway. 
 


 
 
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2.2.13 Dosage and administration  
The recommended starting dose of ruxolitinib is 15 mg given orally twice daily for MF 
patients with a platelet count between 100 x 109/L and 200 x 109/L and 20 mg twice 
daily for MF patients with a platelet count of >200 x 109/L. There is limited information to 
recommend a starting dose for patients with platelet counts between 50 x 109/L and 100 
x 109/L. The maximum recommended starting dose in these patients is 5 mg twice daily 
and the patients should be titrated cautiously. Doses may be titrated based on safety 
and efficacy. Treatment should be interrupted for platelet counts less than 50 x 109/L or 
ANC less than 0.5 x 109/L. After recovery of platelet and neutrophil counts above these 
levels, dosing may be restarted at 5 mg twice daily and gradually increased based on 
careful monitoring of blood cell counts. 
 
Dose reductions should be considered if the platelet counts decreases below 100 x 
109/L with the goal of avoiding dose interruptions for thrombocytopenia. 
If efficacy is considered insufficient and platelet and neutrophil counts are adequate, 
doses may be increased by a maximum of 5 mg twice daily. 
 
The starting dose should not be increased within the first four weeks of treatment and 
thereafter no more frequently than at 2-week intervals. 
 
The maximum dose of ruxolitinib is 25 mg twice daily. If a dose is missed, the patient 
should not take an additional dose, but should take the next usual prescribed dose. 
Treatment may be continued as long as the benefit: risk remains positive. 
 
2.2.14 Special populations 
Pregnancy 
 
Risk Summary:  There are no adequate and well-controlled studies of Jakafi in pregnant 
women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase 
in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be 
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
 
Animal Data:  Ruxolitinib was administered orally to pregnant rats or rabbits during the 
period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 
mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of 
approximately 9% in fetal weights were noted in rats at the highest and maternally toxic 
dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 
times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In 
rabbits, lower fetal weights of approximately 8% and increased late resorptions were 
noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is 
approximately 7% the clinical exposure at the maximum recommended dose. In a pre- 
and post-natal development study in rats, pregnant animals were dosed with ruxolitinib 
from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-
related adverse findings in pups for fertility indices or for maternal or embryofetal 


 
 
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survival, growth and development parameters at the highest dose evaluated (34% the 
clinical exposure at the maximum recommended dose of 25 mg twice daily). 
 
Nursing mothers  
 
It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its 
metabolites were excreted in the milk of lactating rats with a concentration that was 13-
fold the maternal plasma. Because many drugs are excreted in human milk and 
because of the potential for serious adverse reactions in nursing infants from Jakafi, a 
decision should be made to discontinue nursing or to discontinue the drug, taking into 
account the importance of the drug to the mother. 
 
Pediatric use  
 
The safety and effectiveness of Jakafi in pediatric patients have not been established. 
 
Geriatric Use  
 
Of the total number of patients with myelofibrosis in clinical studies with Jakafi, 52% 
were 65 years and older, while 15% were 75 years and older. No overall differences in 
safety or effectiveness of Jakafi were observed between these patients and younger 
patients.Renal Impairment - The safety and pharmacokinetics of single dose Jakafi (25 
mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in 
subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or 
severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with 
end stage renal disease requiring hemodialysis were also enrolled. The 
pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal 
impairment and in those with normal renal function. However, plasma AUC values of 
ruxolitinib metabolites increased with increasing severity of renal impairment. This was 
most marked in the subjects with end stage renal disease requiring hemodialysis. The 
change in the pharmacodynamics marker, pSTAT3 inhibition, was consistent with the 
corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; 
however, the removal of some active metabolites by dialysis cannot be ruled out. When 
administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or 
severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L 
and 150 X 109/L, a dose reduction is recommended. A dose reduction is also 
recommended for patients with polycythemia Vera and moderate (CrCl 30-59 mL/min) 
or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal 
disease on dialysis, a dose reduction is recommended. 
 
Hepatic Impairment  
The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a 
study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], 
moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The 
mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients 
with mild, moderate and severe hepatic impairment compared to patients with normal 


 
 
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hepatic function. The terminal elimination half-life was prolonged in patients with hepatic 
impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change 
in the pharmacodynamics marker, pSTAT3 inhibition, was consistent with the 
corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) 
hepatic impairment cohort where the pharmacodynamic activity was more prolonged in 
some subjects than expected based on plasma concentrations of ruxolitinib. When 
administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment 
and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is 
recommended. A dose reduction is also recommended for patients with polycythemia 
Vera and hepatic impairment. 
 
2.2.15 Drug Interactions 
Drugs that inhibit or induce cytochrome P450 enzymes: Ruxolitinib is metabolized by 
CYP3A4 and to a lesser extent by CYP2C9.  
 
CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, 
respectively following concomitant administration with the strong CYP3A4 inhibitor 
ketoconazole in healthy subjects. Concomitant administration with mild or moderate 
CYP3A4 inhibitors did not result in an exposure change requiring intervention. When 
administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction. 
 
Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% 
to 300% following concomitant administration with the combined CYP3A4 and 
CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively. 
Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg 
daily.  
 
CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, 
respectively, following concomitant administration with the strong CYP3A4 inducer 
rifampin in healthy subjects. No dose adjustment is recommended; however, monitor 
patients frequently and adjust the Jakafi dose based on safety and efficacy. 
 
2.2.16 Over-dosage 
There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have 
been given with acceptable acute tolerability. Higher than recommended repeat doses 
are associated with increased myelosuppression including leukopenia, anemia and 
thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is 
not expected to enhance the elimination of ruxolitinib. 
 
2.2.17 Post-marketing experience 
Ruxolitinib has been granted Marketing Authorization Approval in the USA for PV not 
responding to hydroxyurea, intermediate or high-risk myelofibrosis, including PMF, 
post– polycythemia vera myelofibrosis and post–essential thrombocythemia 
myelofibrosis, and in Canada marketing authorization was granted in June 2012 for the 


 
 
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indication of splenomegaly and/or its associated symptoms in adult patients with 
primary myelofibrosis (also known as chronic idiopathic myelofibrosis), 
postpolycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. 
In the EU, the CHMP has granted a positive opinion in April 2012, and granted approval 
for the treatment of disease related splenomegaly or symptoms in adult patients with 
primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-
polycythemia vera myelofibrosis, or post essential thrombocythemia myelofibrosis in 
August 2012. Regulatory review is ongoing in other countries. The product is currently 
marketed in the USA, Canada, and the European Union under the brand name 
JAKAFI® (USA) and JAKAVI® (Canada and EU). 
 
 
3.0 PATIENT SELECTION 
 
3.1 Eligibility 
 
Patients with high-risk (Figure 1), previously untreated CLL/SLL that do not require 
therapeutic intervention according to the IWCLL guidelines, based on the Rai and Binet 
staging systems(Table 3), but are likely to require treatment within ≤ 4 years if remain 
untreated, according to the below nomogram (Figure 1) will be eligible to enroll onto the 
study.  
 
Figure 1. Nomogram for time to first treatment (Wierda et al., 2011) 
 
 


 
 
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Nomogram used by totaling points identified at top scale for each of four independent 
variables. Point score for lactate dehydrogenase (LDH) identified based on IGHV 
mutation status. This summed point score then identified on total point scale to identify 
2- and 4-year treatment-free probability (prob) and estimate treatment-free survival. 
Fluorescent in situ hybridization (FISH) was categorized by Dohner hierarchic 
categorization. LN, lymph node.  
 
This nomogram provides a visual depiction of the relative contribution of each 
prognostic factor to the total point score and, thus, the weight of factors regarding risk 
for requiring first treatment. The formula for calculating the total point score is as 
follows: [I(No. of lymph node sites involved = 3) × 7.370 + I(FISH = 11q del) × 9.312 + 
I(FISH = 17p del) × 11.285 + (diameter of largest cervical lymph node in cm) × 4.172 + 
(LDH/100) × I([IGHV gene = mutated] × 5.000 + (LDH ÷ 100) × I(IGHV gene = 
unmutated) × 1.065] + 35.467. The indicator function (I) is equal to 1 if the statement in 
the parentheses is true and is equal to 0 otherwise. The total point scores ranged from 0 
to 87.4 points, with a median of 21.0.  
 
Table 3. IWCLL recommendations for the treatment of CLL/SLL (Hallek et al., 2008) 
 
General practice /Clinical trial
Treat with Rai stage 0 
NGI 
RQ 
Treat with Binet stage A 
NGI 
RQ 
Treat with Binet stage B or Rai stage I or Rai stage II 
Possible 
Possible 
Treat with Binet stage C or Rai stage III or Rai stage IV
Yes 
Yes 
Treatment of active/progressive disease 
Yes 
Yes 
Treat without active/progressive disease 
NGI 
RQ 
______________________________________________________________________ 
NGI, indicates not generally indicated unless the patients shows features of disease 
progression or disease transformation; and RQ, research question. 
 
3.1.1 Inclusion criteria 
1) Subjects who are able to understand and sign an informed consent document. 
2) Subjects 18 years of age or older. 
3) Subjects must be diagnosed with CLL/SLL and do not meet the IWCLL criteria for 
treatment (Hallek et al., 2008).  
4) Patients should be previously untreated or have only been treated with single agent 
ibrutinib therapy for a period of < 3 months and were deemed ibrutinib intolerant. 
5) Patients whose expected time to CLL/SLL treatment, according to our nomogram 
(Figure 1), is four years of less.  
6) Subjects with hemoglobin values at the screening visit equal to or greater than 12.0 
g/dL. 
7) Subjects with a platelet count of at least 100 x109/L at the screening visit. 
8) Subjects with an absolute neutrophil count (ANC) of equal to or higher than 0.5 
x109/L at the screening visit. 


 
 
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9) Subject who are willing to undergo a bone marrow aspiration and biopsy and CT 
scan for disease burden assessment. 
10) Patient who are capable to return to MDACC for follow-up. 
11) Subjects with an Eastern Cooperative Oncology Group (ECOG) performance status  
 of 0, 1 or 2. 
12) Patient must be capable of swallowing the Ruxolotinib capsules (tablets). 
 
 
3.1.2  Exclusion criteria 
1) Females who are pregnant or are currently breastfeeding. 
2) Subjects of childbearing potential who are unwilling to take appropriate precautions  
(Throughout the study from screening, including 30 days after discontinuation of the 
study drug) to avoid becoming pregnant or fathering a child. 
 Females of non-childbearing potential are defined as women who (a) are equal to 
or greater than 55 years of age with history of amenorrhea for 1 year, OR (b) are 
surgically sterile for at least 3 months.  
 For females of childbearing potential, or for males, appropriate precautions are 
those that are at least 99% effective in preventing the occurrence of pregnancy. 
These methods should be communicated to the subjects and their understanding 
confirmed:  
 Double barrier methods  
 Condom with spermicide in conjunction with use of an intrauterine device 
(IUD)      
 condom with spermicide in conjunction with use of a diaphragm  
 Oral, injectable, or implanted contraceptives   
 Tubal ligation or vasectomy (surgical sterilization) 
3) Subjects with recent history of inadequate bone marrow reserve as demonstrated by    
previous transfusions except for acute blood loss (e.g. surgery) in the month prior to 
screening. 
4) Subjects with inadequate liver or renal function at screening and baseline visits:  
 Alanine aminotransferase (ALT) > 2.5x ULN. 
 Modification of Diet in Renal Disease (MDRD) calculated GFR < 30 mL/min 
 
5) Subjects with active uncontrolled infection or who are HIV positive (Subjects with      
acute infections requiring treatment should delay screening/enrollment until the      
course of therapy has been completed and the event is considered controlled). 
6) Subjects with history of or a current invasive malignancy over the past 5 years 
except for treated ba+ 
7) sal or squamous carcinomas of the skin completely resected.  Other completely 
resected cancers less than 5 years may be considered after PI review. 
7)  Subjects with clinically significant uncontrolled cardiac disease. 
8)  Subjects being treated concurrently with any prohibited medications, including 
     investigational medication, rifampin, St. John’s wort, and potent CYP3A4 inhibitors, 
     Excluding ketoconazole) unless continuation of such medications are determined by  
     the investigator to be in the best interest of the patient (as detailed in protocol section  
     2.2.15 and Table 3). 


 
 
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9)  Subjects who have previously received JAK inhibitor therapy. ++ 
10) Subjects with active alcohol or drug addiction that would interfere with their ability to  
      Comply with the study requirements. 
11) Subjects with any concurrent condition that, in the Investigator’s opinion, would     
jeopardize the safety of the subject or compliance with the protocol. 
12) Subjects who have unknown transfusion history.  
13) Patients who cannot comply with the study requirements. 
 
 
4.0 TREATMENT PLAN 
 
4.1 Administration of Study Drug 
 
Ruxolitinib will be administered twice daily (bid), approximately 12 hours apart. The 
starting dose will be 20 mg bid for patients with a platelet count of ≥ 200 x109/L (dose 
level 1) and 15 mg bid for patients with a platelet count of ≥ 100 x109/L and ≤ 200 x109/L 
(dose level -1). The starting dose for patients a hemoglobin level of 12 -13 g/dL will be 
10 mg bid (dose level -2). Dose adjustment (de-escalation) will be done in accordance 
with the scheme outlined in Table 4. Tablets will be taken without regard to food on an 
outpatient basis. Vomited doses can be made up, if the person vomits within 30 minutes 
after taking ruxolitinib. If the person vomits after 30 minutes upon taking ruxolitinib, the 
person may wait to take it when it is time to take the next dose. 
 
Dose adjustments are required for protocol-specified clinically significant ruxolitinib-
related adverse events (AEs) of Grade 3 or Grade 4 severity, declining platelet counts, 
declining absolute neutrophil counts (ANC) and declining hemoglobin  levels (Table 4 
and Section 5).  Discontinuation of Ruxolitinib should be gradual to avoid “ruxolitinib 
withdrawal syndrome”. 
 
 
Table 4.  Dose (mg) adjustment schema 
 
 
 
 
 
 
 
4.2 Treatment Compliance 
 
 b.i.d 
 
Dose (b.i.d.)
 ‐1                       15
  1                        20
‐2                       10 
-3                         5 


 
 
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Subjects will return all bottles of unopened, empty, and opened/partially used study drug 
at study visits. Investigative site staff will perform a count of returned pills to assess 
compliance, and this information will be reported on the Case Report Form (CRF). 
Study drug which is returned will be destroyed in accordance with the site’s drug 
destruction policy. A standard institutionally approved diary may be issued to subjects. 
 
4.3 Duration of Treatment and Subject Participation 
 
Subjects will continue treatment as long as clinically indicated as judged by the Principal 
Investigator (PI) of the study or the attending physician for up to 3 years. Treatment 
beyond 3 years may be permitted after discussion with the PI.  The discussion should 
be documented in the subject’s medical record.   
 
4.4 Patient Assessments 
 
Patients will be presented with the informed consent at screening. They will fill out the 
Brief Fatigue Inventory (BFI) and the MD Anderson Symptom Inventory (MDSI) at 
each visit to MDA starting on Day 1.  Patients will be seen at MDA during the 
screening period (-15-1 day), Day 1, Day 15 + 7 days, Month 2 + 7days, Month 3 + 7 
days, Month  6 + 2 months and Month 8 + 2 months, 10, 12, and so on.  Every clinic 
visit to MDACC will include a routine physical examination, Brief Fatigue Inventory 
(BFI) and MD Anderson Symptom Inventory (MDSI) questionnaires and standard 
laboratory tests including CBC with differential and, plts, chemistries to include 
creatinine and ALT, Immunoglobulin levels (IgG, IgA and IgM), T cell counts and 
Beta-2 microglobulin (b2M).   
 
If you can become pregnant, blood (about 1 teaspoon) and/or urine will be collected 
for a pregnancy test. 
 
Correlative studies will be conducted to understand changes in the immunological and 
cytokine/chemokine pathways in CLL in response to ruxolitinib.  Correlative studies 
will only be performed at MDACC visits: Day 1 (pre-dose), Month 3 + 7 days, and 
Month 6 + 2 mos. or as requested by the PI for specific patients with unusual 
response or unusual clinical presentation. Complete blood counts should be 
monitored every 2-4 weeks at MDACC or by the patient’s local physician until counts 
are stabilized.  
 
After month 8 + 2 mos the patient is required to have a physical exam, hematology 
and chemistry every 2 months + 2 mos. (Month 10, 12, and so on.)  Every other visit 
may be conducted by the patient‘s local physician if more convenient for the patient. 
 
Follow-Up 
 
About 30 days after your last dose of ruxolotinib, blood (about 2 teaspoons) will be 
drawn for routine tests. 
 


 
 
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5.0 DOSING DELAYS/ DOSE MODIFICATIONS 
 
5.1 Concomitant Use with Strong CYP3A4 Inhibitors or Fluconazole 
 
Modify the dose of Jakafi when given concomitantly with strong CYP3A4 inhibitors 
(such as but not limited to boceprevir, clarithromycin, conivaptan, grapefruit juice, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole) and fluconazole doses of less than or equal to 200 mg as follows . 
 
5.2 Dosing Delays 
 
Up to a one month delay in the next dosing of Ruxolitinib, elected to be changed due to 
clinical side effects or laboratory abnormalities, is allowed.  
 
5.3 Dose Modification of Ruxolitinib in Different Clinical Scenarios 
 
Table 5. Dose modification for drug interactions 
 
 
Patients on concomitant strong CYP3A4 
inhibitors or fluconazole doses of less than 
or equal to 200 mg 
 
 
Recommended Dose Modification 
Starting Dose for Patients with Myelofibrosis 
with a platelet count: 
 
• 
Greater than or equal to 100 X 109/L 
10 mg twice daily 
• 
50 X 109/L to less than 100 X 109/L 
5 mg once daily 
Starting Dose for Patients with 
Polycythemia Vera 
5 mg twice daily 
All Patients on a Stable Dose of: 
 
• 
Greater than or equal to 10 mg twice daily 
Decrease dose by 50% 
(round up to the closest available tablet strength) 
• 
5 mg twice daily 
5 mg once daily 
• 
5 mg once daily 
Avoid strong CYP3A4 inhibitor or fluconazole 
treatment or interrupt Jakafi treatment for the 
duration of strong CYP3A4 inhibitor or fluconazole 
use 
 


 
 
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Avoid the use of fluconazole doses of greater than 200 mg daily concomitantly with 
Jakafi. Additional dose modifications should be made with careful monitoring of safety 
and efficacy. 
 
5.4 Renal Function Impairment  
 
Modify the dose of Jakafi accordingly in patients with moderate or severe renal function 
impairment. 
 
Table 6. Dosing for renal function impairment 
 
Renal Impairment Status 
Platelet Count 
Recommended Starting Dosage 
Patients with Myelofibrosis 
Moderate (CrCl 30–59 mL/min) 
or Severe (CrCl 15–29 mL/min) 
Greater than 150 X 109/L No dose modification needed 
100 X 109/L - 150 X 109/L 10 mg twice daily 
50 - less than 100 X 109/L 5 mg daily 
Less than 50 X 109/L 
Avoid use [see Use in 
Specific Populations (8.6)] 
Patients with Polycythemia Vera 
Moderate (CrCl 30-59 mL/min) 
or Severe (CrCl 15-29 mL/min) 
 
 
Any 
 
 
5 mg twice daily 
 
 
5.4.1 Patients on dialysis  
The recommended starting dose for patients with myelofibrosis with end stage renal 
disease on dialysis is 15 mg once after a dialysis session for patients with a platelet 
count between 100 X 109/L and 200 X 109/L or 20 mg for patients with a platelet count 
of greater than 200 X 109/L. The recommended starting dose for patients with 
polycythemia Vera with end stage renal disease on dialysis is 10 mg. Additional dose 
modifications should be made with frequent monitoring of safety and efficacy. Avoid use 
of Jakafi in patients with end stage renal disease (CrCl less than 15 mL/min) not 
requiring dialysis. 
 
5.5 Hepatic Impairment 
 
The dose of Jakafi should be reduced in patients with hepatic impairment. 
 
Table 7. Dosing for hepatic impairment 
 
Hepatic Impairment Status 
Platelet Count 
Recommended Starting Dosage 


 
 
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Patients with Myelofibrosis 
Mild, Moderate, or Severe 
(Child- Pugh categories A, B, 
C) 
Greater than 150 X 109/L No dose modification needed 
100 X 109/L - 150 X  
9
10 mg twice daily 
50 - less than 100 X 109/L 5 mg daily 
Less than 50 X 109/L 
Avoid use [see Use in 
Specific Populations (8.6)] 
Patients with Polycythemia 
Vera Mild, Moderate, or Severe 
(Child- Pugh categories A, B, 
C) 
 
Any 
 
5 mg twice daily 
 
 
6.0 AGENT FORMULATION AND PROCUREMENT 
 
Formulation: Ruxolitinib (Jakafi®) is commercially available in the US in 5, 10, 15, 20, 
and 25 mg strength tablets. The tablet contains 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. 
 
The 5 mg (free base equivalent) and 25 mg (free base equivalent) tablets are packaged 
in HDPE bottles. All bottles of Incyte investigational product contain the following 
language: “Caution: New Drug-Limited by Federal Law to Investigational Use.” The 
clinical supply for investigational use is the 5 mg tablet.   
 
Storage and Stability: Ruxolitinib has been shown to be stable for up to 6 months at 40 
degrees C and up to 24 months when stored at 25 degrees C.  
 
Compatibility: Ruxolitinib may be taken either with food or without food 
 
Handling: Qualified personnel, familiar with procedures that minimize undue exposure 
to themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 
 
Availability: Ruxolitinib will be supplied free-of-charge by Incyte Corp.  
 
 
 
 


 
 
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7.0 CORRELATIVE/ SPECIAL STUDIES 
 
Patients’ plasma samples and peripheral blood cells will be obtained prior to and 
approximately 3 and 6 months of treatment, or as requested by PI for specific patients 
with unusual response or unusual clinical presentation.  
 
Those samples will be stored at -20°C in the P.I.’s laboratory, using appropriate de-
identifiers, and plasma cytokine levels (such as IL-1, IL-6, and IFNs (Verstovsek et al., 
2008-0874) will be measured and changes in B-cell receptor signaling pathways will be 
assessed using standard technology. 
 
 
8.0 PATIENT EVALUATION 
 
Patients will be evaluated in accordance with our standard of care. Every clinic visit to 
MDACC will include a routine physical examination and standard laboratory tests 
including CBC with differential and, plts,  chemestries to include creatinine and ALT, 
Immunoglobulin levels (IgG, IgA and IgM), T cell counts and Beta-2 microglobulin 
(b2M).  Correlative studies will be conducted to understand changes in the 
immunological and cytokine/chemokine pathways in CLL in response to ruxolitinib.  
Correlative studies will only be performed at MDACC at visits: Day 1 (pre-dose), Month 
3 + 7 days, and Month 6 + 2 mos., or as requested by the PI for specific patients with 
unusual response or unusual clinical presentation. Complete blood counts should be 
monitored every 2-4 weeks at MDACC or by the patients local physician until counts are 
stabilized. After month 8 + 2 mos., the patient is required to have a physical exam, 
hematology and chemistry every 2 months + 2 mos, every other visit may be conducted 
by the patient‘s local physician if more convenient for the patient. A bone marrow 
aspiration and biopsy and whole body CT scan will be completed at screening (-15-1 
day) and at 6 months + 2 months of treatments (as per standard of care for CLL/SLL) 
will be performed at MDACC. We will use the CLL/SLL module of the MD Anderson 
Symptom Inventory and Brief Fatigue Inventory (measuring symptoms “at their worst”) 
of common symptoms associated with CLL/SLL at every visit to MDACC.  
 
8.1 Outside Physician Participation during Treatment 
 
1. MDACC Physician communication with the outside physician is required prior to the 
patient returning to the local physician. This will be documented in the patient record 
2. A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to supervise the patient's care (Appendix H) 
3. Protocol required evaluations outside MDACC will be documented by telephone, fax 
or e-mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, 
indicating that they have reviewed it. 
4. Changes in drug dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator, or their representative prior to initiation, and will be 
documented in the patient record. 


 
 
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5. A copy of the informed consent, protocol abstract, treatment schema and evaluation 
during treatment will be provided to the local physician. 
6. Documentation to be provided by the local physician will include drug administration 
records, progress notes, reports of protocol required laboratory and diagnostic 
studies and documentation of any hospitalizations. 
7. The home physician will be requested to report to the MDACC physician 
investigator all life threatening events within 24 hours of documented occurrence. 
8. Patient will have a physical exam every 1-2 months. 
 
Patients are allowed to have hematology and biochemistry tests performed in outside 
laboratory facilities.  Laboratory results will be obtained by the research staff assigned 
to this study.  The PI or treating physician listed on the delegation of authority log will 
review outside labs and determined the clinical significance of these labs.  The 
physician will sign and date the outside lab result. 
 
Follow-ups and disease burden assessments will only be performed by the MD 
Anderson Cancer Center team. Patients must be followed for SAE/AEs until at least 30 
days after the last dose of study drug.  SAE/AE will be assessed on their next visit to the 
leukemia clinic at MDACC.  Participant will be removed from the protocol study after the 
30-day post-treatment visit/assessment.   
 
All protocol specific data will be entered into PDMS/CORe. 
 
8.2 Symptom Score Assessment 
 
After signing the informed consent, patients will fill out the Brief Fatigue Inventory (BFI) 
(Appendix E) and the MD Anderson Symptom Inventory (MDSI) (Appendix F). The 
patients will fill out the BFI and MDSI forms at Day 1 and every visit to MDACC. These 
time points were chosen based on our symptom control study of patents with CLL 
(protocol 2013-0044).  
 
8.3 Disease Response Assessment  
 
Assessment of clinical response will be conducted in accordance with our standard of 
care (physical examination, CBC, a bone marrow aspiration, and a whole body CT scan 
to be done at screening and 6 + 2 months into treatment).  
 
The IWCLL response criteria (Hallek et al., 2008) (Table 8) will be used to assess 
disease response. A bone marrow aspiration, a whole body CT scan is to be done at 
screening and 6 + 2 months into treatment to further assess response. If a 20% 
reduction in tumor burden is observed at 6 + 2 months, Treatment will be continued. 
 
Table 8. Response definition after treatment for patients with CLL/’SLL, using the 
parameters of Tables 1 and 3 
 


 
 
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Parameter 
CR* 
PR* 
PD* 
 
Group A 
 
 
 
Lymphadenopathy† None > 1.5 cm 
Decrease ≥ 50% 
Increase ≥ 50% 
 
Hepatomegaly 
None 
Decrease ≥ 50% 
Increase ≥ 50% 
 
Splenomegaly 
None 
Decrease ≥ 50% 
Increase ≥ 50% 
 
Blood lymphocytes < 4000/μL 
Decrease ≥ 50% 
from baseline 
Increase ≥ 50% 
over baseline 
Marrow‡ 
Normocellular, < 30% 
lymphocytes, no B-lymphoid 
nodules. Hypocellular 
marrow defines CRi (5.1.6). 
50% reduction in 
marrow infiltrate, or 
B-lymphoid nodules 
 
Group B 
 
 
 
Platelet count 
> 100 000/μL 
> 100 000/μL or 
increase ≥ 50% 
over baseline 
Decrease of ≥ 
50% from 
baseline 
secondary to 
CLL/SLL 
Hemoglobin 
> 11.0 g/dL 
> 11 g/dL or 
increase ≥ 50% 
over baseline 
Decrease of > 2 
g/dL from 
baseline 
secondary to 
CLL/SLL 
Neutrophils‡ 
> 1500/μL 
> 1500/μL or > 50% 
improvement over 
baseline 
 
______________________________________________________________________ 
Group A criteria define the tumor load, group B criteria define the function of the hematopoietic 
system (or marrow). 
↵* CR (complete remission): all of the criteria have to be met, and patients have to lack disease-
related constitutional symptoms; PR (partial remission): at least two of the criteria of group A plus 
one of the criteria of group B have to be met; SD is absence of progressive disease (PD) and failure 
to achieve at least a PR; PD: at least one of the above criteria of group A or group B has to be met.  
 
 
9.0 RESPONSE CRITERIA 
 
Response criteria including tumor mass reduction will be assessed at approximately six 
to eight months by using physical examination, laboratory data, bone marrow analysis 
(including cytogenetic and, if indicated, molecular analysis), and CT scan analysis. 
 


 
 
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9.1 Disease Response Criteria 
 
Clinical response will be assessed based on physical examination, CBC, a bone 
marrow aspiration, a whole body CT scan to be done at screening and 6 + 2 months in 
accordance with the IWCLL guidelines (Hallek et al., 2008) as outlined in Table 8. If a 
20% reduction in tumor burden is observed at 6 + 2 months, Treatment will be 
continued as long as a CR, PR or at least a 20% reduction in tumor mass is achieved 
and sustained. 
 
10.0 CRITERIA FOR REMOVAL FROM THE STUDY 
Patients will be removed from the study for the following reasons: 
 
1. Pattern of noncompliance.  
2. Toxicity (grade 3 or 4) inducing clinical symptoms necessitating red blood cell or 
platelet transfusions and not alleviated after dose adjustment.  
3. Disease progression that require another therapeutic intervention (an increase in 
peripheral blood lymphocyte count is expected. If needed anti-CD20 antibody treatment 
(Rituximab or Ofatumumab) or leukopheresis are allowed). 
4. Lack of response (a reduction of 20% of tumor mass or PR) at 6 ± 2 months. 
5. Unexpected events (medical or other) that would prevent the patient from staying on 
study. 
6. Patient’s or physician’s choice. Compliance will be assessed by the P.I. based on    
the drug accountability documented by the site staff and monitored by the designee. 
The objective is 100% compliance and the P.I. and his staff will evaluate compliance at 
each visit, and take appropriate steps to optimize compliance. For the purpose of 
subgroup analyses, subjects with at least 80% compliance over the total duration of 
dosing from the first day of dosing to the analysis of the study will be considered to be 
compliant. 
 
 
11.0 STATISTICAL CONSIDERATIONS 
 
The study will be conducted at MDACC only. The primary endpoint will assess the 
clinical response (CR, PR, and a 20% reduction in tumor mass as assessed by a body 
scan and bone marrow aspiration/biopsy) at 6 ± 2 months after initiation of therapy.  
 
We will incorporate an informal futility analysis when half of the total patients have 
reached 6 ± 2 months after initiation to assess whether the average change in the tumor 
mass score is less than zero (calculated as the score at enrollment minus the score at 
six months). If the average at this time is less than zero, the trial will be stopped early. 
 


 
 
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Because no treatment is the standard of care for these patients, we will routinely 
analyze the outcome of our Ruxolitinib-treated patients at a 6 +2 month interval and 
compare their clinical outcome to that of patient who elected to receive no treatment. 
 
Table 9 shows the probability of stopping early under several different scenarios, as well 
as how the overall power is for the primary analysis is affected by early stopping. The 
operating characteristics were produced in R version 2.13.0 by simulating 5000 trials with 
17 patients at the interim and 34 patients at the end of the trial, accounting for a 15% 
drop out rate. The simulations stop early if the average change at 6 months is less than 
zero, and formally tests whether the change is not equal to zero at the final analysis 
using a paired t-test.  
 
Table 9. Operating characteristics 
 
True tumor burden 
difference (baseline 
score minus score at 
6 months) 
True SD of the 
Difference 
Prob(Stop Early) 
Power for Final 
Analysis 
-1 
2 
0.9818 
0.0026 
0 
2 
0.5068 
0.0218 
1 
2 
0.0202 
0.8064 
2 
2 
0.0000 
0.9998 
-1 
4 
0.8398 
0.0014 
0 
4 
0.4958 
0.0274 
1 
4 
0.1584 
0.2876 
2 
4 
0.0198 
0.8074 
 
For primary analysis, the paired t test will be used to evaluate the changes of tumor 
burden from baseline to 6 + 2 months after initiation of therapy. Response rate will be 
estimated with 95% confidence interval. Patients who drop out early will be counted as 
non-responders.  The Kaplan-Meier method will be used to estimate time to next 
treatment, and will compared to our historical data (Wierda et al., 2011) using Cox 
proportional hazards model, adjusting for effects of covariates. If necessary and 
applicable, appropriate methods such as propensity score matching will be used to 
match the patients of this study with the historical data to reduce comparison bias. 
 
Continuous variables will be summarized using descriptive statistics such as mean, 
standard deviation, median and range. Categorical variables will be tabulated by 


 
 
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frequencies and the corresponding percentages.  The Fisher’s exact test or logistic 
regression analysis will be used for any binary outcomes. Statistical t-tests or Wilcoxon 
rank sum tests will be used to compare continuous variables. Longitudinal analysis may 
be used to model the change in tumor burden.  
 
A Toxicity/Efficacy Summary will be submitted to the IND Office Medical Affairs and 
Safety Group, after the first five evaluable subjects complete 6 to 8 months from 
treatment initiation, and every five evaluable subjects thereafter.  
   
11.1 Toxicity monitoring Rule 
 
Bayesian sequential monitoring (1995) will be employed to perform interim safety 
monitoring targeting a grade 3 and 4 toxicity rate due to the drug of not more than 30% 
by 3 months. Patients will be monitored in cohorts of 5. Accrual will be stopped early if 
Pr [prob(toxicity) > 0.30 | data] > 0.96. That is, if we determine that there is a greater 
than 96% chance that the toxicity rate is greater than 30%, then the study will be 
stopped. We assume a beta (0.6, 1.4) prior distribution for the toxicity rate, which has a 
mean of 0.3 corresponding to the 30% target toxicity rate. The historical prior is based 
on a sample of (300, 700). Table 11 depicts stopping criteria. Stopping conditions 
corresponding to this probability criterion are to terminate accrual if: 
 
Table 10. Toxicity monitoring rules and stopping conditions 
 
If there are this many (or more) patients 
with 
ruxolitinib-related, grade 3 or 4 clinically 
significant toxicity 
Stop the study if this many (or fewer) 
patients  
4 
5 
6 
10 
9 
15 
11 
20 
12 
25 
14 
30 
16 
35 
18 
40 
 


 
 
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This stopping rule was chosen to assure that the probability that this portion of the study 
will stop early would be approximately 11% if the true rate of toxicity was no more than 
30%. The operating characteristics of this rule were generated by the Biostatistics 
Department’s Multc Lean Desktop program (version 1.2.0) and are shown in Table 11.  
 
 
 
 


 
 
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Table 11. Operating characteristics for toxicity stopping rule  
 
If the true grade 
toxicity 
rate is… 
Early Stopping 
Probability 
Achieved Sample Size 
25th, 50th, 75th percentiles 
0.1 
0.0006 
40 
40 
40 
0.2 
0.0127 
40 
40 
40 
0.3 
0.1073 
40 
40 
40 
0.4 
0.4311 
20 
40 
40 
0.5 
0.8225 
5 
20 
30 
0.6 
0.9808 
5 
10 
15 
 
 
11.2 Trial Conduct  
 
The PI or designee will be responsible for assessing the toxicity monitoring and early 
stopping rules. The biostatistical collaborators will be available for any assistance.  
 
Protocol specific data and adverse events will be entered into PDMS/CORe.  
PDMS/CORe will be used as the electronic case report form for this protocol. 
 
The 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. 
 
 
12.0 REPORTING REQUIREMENTS 
 
Adverse events will be reported in accordance with the Leukemia-specific 
Adverse Event Recording and Reporting Guidelines (Appendix G). 
Adverse events will only be collected up to 30 days after the last dose of 
ruxolitinib. Adverse event reporting will be as per the NCI version 4 criteria and 
the MDACC Leukemia Specific Adverse Event Recording and Reporting 
Guidelines.   
 
Adverse events will be recorded on the Adverse Event Record (AER) for each 
patient after every protocol visit.  The Principal Investigator will sign and date the 
Adverse Event record for every patient after every protocol visit.  Following 
signature, the Adverse Event Record will be used as source documentation for 
the adverse events for attribution.   
 
Concomitant medications will be captured in the electronic medical record and not 
needed in the data capture. 
 


 
 
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12.1 Adverse Events 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting protocol intervention, up to 30 days after the 
last dose of ruxolitinib, even if the event is not considered to be related to study drug. 
Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or 
test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy. 
 
As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant medication 
taken; non-drug therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
Information about common side effects already known about the investigational drug 
can be found in the [Investigators’ Brochure] (Appendix C).. 
Adverse events will be reported in accordance with the Leukemia-specific 
Adverse Event Recording and Reporting Guidelines (Appendix G), and as per 
the NCI CTCAE criteria version 4. 
Only unexpected AEs will be recorded in the Case Report Form (CRF).  The PI or 
designee will be responsible for assigning attribution of adverse events to the study 
agent.  
The Principal Investigator will sign and date the PDMS Case Report Form toxicity 
pages per each patient approximately every 3 months.  Following signature, the 
Case Report Form will be used as source documentation for the adverse events 
for attribution. 
Appendix G encloses the guidelines dated 06/24/16. 
 
 
 


 
 
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12.2 Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that, 
had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to     
 conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-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). 
 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. 
 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 Serious Unanticipated Adverse 
Events for Drugs and Devices”.  Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is 
complete and laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 


 
 
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 Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
 
Investigator Communication with Supporting Companies: 
 
 Incyte Corporation:  IncytePhVOpsIST@incyte.com for e-mail transmission of 
individual SAE reports. 
 Safety Contacts: 
Kathy Lenard Roberts, Exec. Dir, Incyte Pharmacovigilance 
                                      Phone: 302-498-6727, Fax:302-425-2780 
 Safety Contacts: 
Kathy Lenard Roberts, Exec. Dir, Incyte Pharmacovigilance 
                                 Phone: 302-498-6727, Fax:302-425-2780 
 Pharmacovigilance & Drug Safety: Robert Livingston, MD, Vice President, 
Incyte, Phone: 302-498-7098, Fax: 302-425-2780 
 
 


 
 
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