Clinical trial NCT01776723
Conditions: Myelomonocytic Leukemia
Keywords: Chronic Myelomonocytic Leukemia CMML Leukemia
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2013-02-20; Completion date: 2022-05-10
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if treating Chronic Myelomonocytic Leukemia (CMML) with a study drug \[ruxolitinib\] can improve outcomes of patients with CMML. The first step of the study is to learn the dose of ruxolitinib that is tolerable (bearable). It has already been studied in a number of patients with different bone marrow diseases and is approved for the treatment of a disease called Myelofibrosis; however, it is not approved for treatment of CMML. It is given orally (by mouth). Most people tolerate it well but the tolerability has not been determined in patients with CMML. We will be testing different doses to determine how much of the medication people can tolerate (bear) before they develop side effects.

Detailed description:
This is a phase 1/2, two-stage, sequential cohort dose escalation study. If dose escalation is completed as planned, no more than 53 subjects are expected to enroll onto this study at a rate of approximately 3 subjects every month. For the Phase 2 study the Simon's optimal two-stage design will be employed to test the null hypothesis that response rate (RR) equals to 10% versus the alternative that RR equals to 30%.

Demographic and clinical variables for the study patients will be summarized using descriptive statistics (mean, standard deviation, median, inter-quartile range, range, and frequency counts and percentages). Safety and efficacy data will be analyzed overall as well as separately for each dose cohort when appropriate.

Arms: arm 1: Phase I: Dose Escalation. In Phase I, participants will be allocated to dose levels starting at 10 mg/d (twice a day \[BID\] dosing) according to the "rolling six" Phase I design. arm 2: Phase II: Treatment at Maximum Tolerated Dose (MTD).
Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.

Protocol documents:
Prot_SAP_000.pdf: 
 
A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and 
Efficacy of Ruxolitinib for the Treatment of Chronic Myelomonocytic Leukemia 
(CMML) and Cataloging the Molecular Consequences of JAK2 Inhibition in 
Chronic Myelomonocytic Leukemia: A Correlative Study Identifying Targetable 
CMML Sub-Clones by Leveraging GM-CSF Dependent pSTAT Hypersensitivity 
 
  
NCT01776723 
 
Version 15 
October 28, 2016 


 
 
1
TITLE:   A Sequential Two-Stage Dose Escalation Study to Evaluate the 
Safety and Efficacy of Ruxolitinib for the treatment of Chronic 
Myelomonocytic Leukemia (CMML) and Cataloging the Molecular 
Consequences of JAK2 Inhibition in Chronic Myelomonocytic Leukemia: A 
Correlative Study Identifying Targetable CMML Sub-Clones by Leveraging 
GM-CSF Dependent pSTAT Hypersensitivity 
 
 
Sponsor: 
 
 
H. Lee Moffitt Cancer Center & Research Institute 
 
Funding: 
 
 
INCYTE 
 
*Principal Investigator: 
 
 
Eric Padron, MD 
 
 
H. Lee Moffitt Cancer Center & Research Institute 
 
 
12902 Magnolia Drive 
 
 
Tampa, FL  33612  
 
 
Telephone: 813-745-8264 
 
 
e-mail address: Eric.Padron@moffitt.org 
 
Co-Investigators:                              Rami Komrokji, MD 
                                                            Alan F List, MD 
                                                            Jeffrey E Lancet, MD 
                                                            Kendra Sweet, MD 
                                                            Bijal Shah, MD 
                                                             
                                                            Maria Balasis, BS 
                                                            Qing Zhang 
 
 
Statistician:  
 
 
Jae K. Lee, PhD 
 
Version: 
 
 
15 
Date: 
 
 
10/28/2016 
 
 
 


 
 
2
Table of Contents 
 
 
 
1 
OBJECTIVES ....................................................................................................................7 
2 
BACKGROUND ...............................................................................................................8 
3 
STUDY ENDPOINTS ....................................................................................................... 14 
4 
PATIENT SELECTION ..................................................................................................... 15 
5 
STUDY DESIGN ............................................................................................................. 17 
6 
TREATMENT PLAN ........................................................................................................ 17 
7 
DURATION OF THERAPY ............................................................................................... 22 
8 
DURATION OF FOLLOW-UP .......................................................................................... 23 
9 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 23 
10 
DOSING DELAYS/MODIFICATIONS ................................................................................ 24 
11 
ADVERSE EVENTS:  REPORTING REQUIREMENTS ........................................................... 27 
12 
PHARMACEUTICAL INFORMATION ............................................................................... 32 
13 
STUDY CALENDAR ........................................................................................................ 32 
14 
MEASUREMENT OF EFFECT ........................................................................................... 37 
15 
STATISTICAL CONSIDERATIONS..................................................................................... 38 
16 
LABORATORY CORRELATES .......................................................................................... 39 
17 
REGULATORY CONSIDERATIONS ................................................................................... 43 
18 
REFERENCES ................................................................................................................ 46 
19 
APPENDIX A ................................................................................................................. 49 
20 
APPENDIX B ................................................................................................................. 50 
21 
APPENDIX C: CYP3A4 STRONG INHIBITORS ................................................................... 52 
22 
APPENDIX D: SYMPTOM SCORE SCALES ........................................................................ 53 
23 
APPENDIX E: WHO CLASSIFICATION FOR CMML ............................................................ 55 
 
 
 
 
 
 
 
 
 
 


 
 
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Protocol Synopsis 
 
Title: A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and 
Efficacy of Ruxolitinib for the treatment of Chronic Myelomonocytic Leukemia 
(CMML) 
Study 
Objectives 
UPrimary Objectives: 
1. To determine the safety and tolerability of ruxolitinib in CMML subjects at diagnosis or 
relapse. (phase I) 
2. To determine overall best response rates as measured by the international working group 
criteria (2006). (phase II) 
USecondary Objectives: 
1. To determine the time to AML transformation of subjects on Ruxolitinib. 
2. To determine the median overall survival.  
3. To determine the duration of response.  
4. To determine the change in symptom score from baseline to best response.  
5. To determine the change in spleen length at 16 weeks 
6. To determine the change in downstream targets of JAK2 on ruxolitinib. 
7. To determine if the in vitro activity of ruxolitinib correlates to response rates. 
8. To determine if a correlation exist between the presence of the known recurrent 
mutations (JAK2, c-CBL, N-RAS, K-RAS, RUNX-1, TET2, SRSF2, EZH2, ASXL1, 
and DNMT3a) and response to ruxolitinib. . 
9. To determine non-V617F JAK2 mutations at end of study or progression and their 
clinical relevance in the context of ruxolitinib. 
. 
 
 
Study 
Endpoints      
UPrimary 
1. The maximum tolerated dose (MTD) of ruxolitinib for the treatment of CMML. 
The MTD is defined as the highest dose where less than 33% of subjects 
experience a drug related predefined dose limited toxicity (DLT). 
2. Proportion of subject achieving a hematological response, partial response,  
complete response, or stable disease by the IWG 2006 criteria (see appendix B) 
USecondary 
3. Acute myeloid leukemia (AML) transformation according to WHO criteria. 
4. Overall survival (OS). 
5. Duration of response. 
6. The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) at 
baseline and at best response. 
7. 
>50% decrease in splenic length as measured by physical exam if applicable 
8. The suppression of pSTAT5 intracellular signaling after ruxolitinib in CMML 
subjects (pretreatment, at 1-2hr post treatment, cycle 2, cycle 4, and 
progression.)  
9. Determine number of colonies formed in the presence of GM-CSF and/or 
ruxolitinib (pretreatment and progression) as a future predictor of response. 
10. Mutational status in our CMML subjects by sanger sequencing of JAK2, c-
CBL, N-RAS, K-RAS,RUNX-1, TET2, SRSF2, EZH2, ASXL1, and DNMT3a 
(pretreatment and progression). 
11. Mutational status of JAK2 tyrosine kinase at time of progression by deep 
sequencing of JAK2 to include M929I, Y931C, G935R, R938L, I960V, E985K. 
(pretreatment and at progression) 
 
 
Eligibility 
Criteria 
Inclusion Criteria: 
1. Confirmed diagnosis of CMML using the World Health Organization (WHO) 


 
 
4
classification (appendix E). 
2. Age >18 years at the time of obtaining informed consent. 
3. Must be able to adhere to the study visit schedule and other protocol requirements.  
4. Subjects must be able to provide adequate BM aspirate and biopsy specimens for 
histopathological analysis and standard cytogenetic analysis during the screening 
procedure.  
5. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 is 
required.  
6. Women of childbearing potential must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse 1) for at 
least 28 days before starting study drug; 2) while participating in the study; and 3) for at 
least 28 days after discontinuation from the study. The two methods of reliable 
contraception must include one highly effective method (i.e. intrauterine device [IUD], 
hormonal [birth control pills, injections, or implants], tubal ligation, partner’s vasectomy) 
and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap).  
7. Must understand and voluntarily sign an informed consent form. 
8. Must have a life expectancy of greater than 3 months at time of screening. 
 
UExclusion Criteria: 
1. Any of the following lab abnormalities:  
• 
Platelet count of less than 35,000/uL 
• 
Absolute Neutrophil Count (ANC) less than 250/uL 
• 
Serum Creatinine ≥ 2.0 
• 
Serum total bilirubin >1.5x ULN  
2. Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not 
commercially available) for the treatment of CMML within 28 days of the first day of study 
drug treatment.  
3. Prior history of metastatic malignancy in past 2 years 
4. Any serious medical condition or psychiatric illness that will prevent the subject from signing 
the informed consent form or will place the subject at unacceptable risk if he/she participates 
in the study.  
5. Concurrent use of GM-CSF. G-CSF could be used for the short-term management of 
neutropenic infection.  Stable doses of erythropoietin stimulating agents that were started >8 
weeks from first ruxolitinib dose or corticosteroids that were being administered prior to 
screening are allowed. 
6. Uncontrolled current illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
7. Pregnant women are excluded from this study because ruxolitinib has not been studied in 
pregnant subjects. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with ruxolitinib, breastfeeding should be 
discontinued if the mother is treated with ruxolitinib. 
8. Patients who have participated in other interventional (treatment-related) clinical trials within 
30 days of enrollment are excluded. 
 
 
 
 
Baseline 
Assessment 
(within 4 
weeks of 
starting 
treatment) 
1. Medical history including: 
a. disease characteristics such as first diagnosis of CMML, WHO/FAB subtype, IPSS score, MD 
Anderson Scoring System (MDASC), prior treatments.  
b. ECOG performance status.  
c. The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) at baseline and at 
best response. 
d. Concurrent medication review. 
2. Routine physical examination to include vital signs, height and weight. 
3. Bone marrow examination, including cytomorphology, cytogenetic assessment, 


 
 
5
and flow cytometry analysis.  
4. Laboratory assessments: 
• Hematology to include platelet count, hemoglobin, hematocrit, white blood cells 
(WBC) and WBC differential (including: neutrophils, eosinophils, basophils, 
lymphocytes and monocytes), INR, PT, PTT, and reticulocyte count. 
• Clinical chemistries including BUN/urea, creatinine, sodium, potassium, 
alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, total bilirubin, albumin. 
• Urine or serum pregnancy test for females of childbearing potential will be 
performed at Screening or on Day 1, prior to first dose of study medication.289/00 
5. Review and record any blood and blood supportive care products for the prior 8 weeks. 
Treatment 
plan 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 11.  Appropriate dose modifications for ruxolitinib are described in 
Section 10.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's CMML. Ruxolitinib will be 
supplied by INCYTE as 5mg tablets containing ruxolitinib.  
 
Ruxolitinib will be self-administered as a twice-daily oral dose for a continuous treatment cycle.  
Ruxolitinib tablets will be taken approximately 12 hours apart (morning and night). Subjects will 
not take the morning dose of ruxolitinib at the first regularly scheduled visit. Drug will be 
administered in the clinic in order to obtain adequate biomarker assessment. On all other days 
corresponding to study visits, subjects will take the morning dose of study drug prior to the visit, 
and will note on the subject reminder card the time that medications were taken. 
 
Subjects will also be instructed to take ruxolitinib without respect to food, as previous data 
demonstrate no change in drug kinetics or absorption.  The first patient will be given 10 mg/day 
divided in equal BID doses.  Dose escalation guidelines are detailed below in section 10. In 
phase II of the study, a maximum of 29 subjects will be treated at the MTD identified in phase I. 
See study calendar for assessment on study. 
 
Dose 
delay/modif
-ications 
All subjects enrolled in phase 1 will start treatment on the assigned dose per cohort based on the 
dose escalation algorithm provided. Dose delays/modifications will not be allowed in phase 1 as it 
will interfere with the primary endpoint of this study. Dose delays/modifications are allowed for 
those subjects enrolled in phase II as described in section 6. 
Definition 
of Dose-
Limiting 
Toxicity 
 
Dose-limiting toxicity (DLT) is defined as any grade 4 hematologic toxicity and any grade 3 or 
greater non-hematologic toxicity except nausea that is controlled by antiemetic therapy based on 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Grade 3 
metabolic/electrolyte abnormalities that are not clinically significant, and are adequately 
controlled within 72 hours are not to be considered a DLT. To discern disease specific versus drug 
specific myelosuppression, Grade 4 thrombocytopenia will be defined as a decrease of ≥ 50% of 
baseline and a level of < 25,000/uL. Grade 4 neutropenia will be defined as a decrease of ≥ 50% 
of baseline and a level of <500/uL. Subjects will be evaluated for DLTs during the first and 
second cycles of therapy, i.e. 8 weeks for purpose of deciding the dose for next cohort (see dose 
escalation schema) but DLTs will continue to be evaluated and reported through all cycles on 
study. 
Duration of 
Therapy 
Subjects will be treated for a total of 16 weeks.  For subjects responding at week 16, treatment 
may continue until one of the following criteria applies: 
• 
Dose-limiting toxicity is reached, 
• 
Inter-current illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
• 
Evidence of disease progression by the IWG 2006 criteria.  
Subjects who wish not to continue treatment will complete their end of study visit at week 16. 


 
 
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Subjects who were not enrolled in the MTD cohort can increase to the MTD after week 16 if 
the participant still meets the eligibility criteria. Responding patients will be able to 
continue treatment until marketing  approval of ruxolitinib for CMML. 
 
 
Duration of 
Follow-Up  
 
Subjects will be followed as per calendar on treatment for 17 weeks. After 17 weeks, subjects 
who continue on study will be followed monthly. Off study data on AML transformation and 
overall survival will be updated every 6 months or until death, whichever occurs first.  Subjects 
removed from the study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
 
UCriteria for Removal from Study 
Study drug treatment can continue for subjects receiving clinical benefit, unless: one or more 
withdrawal criteria are met, or at the subject’s discretion, or if the study is terminated, or until the 
marketing approval for CMML 
*Subject Completion 
A subject will be considered to have completed the study if the subject meets 
at least 1 of the following criteria: 
- The subject has completed 16 weeks of treatment with study medication with no improvement. 
- The subject died during the study. 
- The subject withdrew from study including subjects who experience a DLT. 
- The subject experienced an AE that lead to withdrawal from the study. 
 
*Subject Withdrawal from Study 
A subject may voluntarily withdraw from study medication or withdraw consent from the study at 
any time. The investigator may also, at his or her discretion, discontinue a subject from 
participating in the study at any time. The investigator will record the date and the reason for 
subject withdrawal from the study.8/ 
00289/00 
*Subject Withdrawal from Study Medication 
If the subject is permanently withdrawn from treatment with study medication, but does not 
withdraw consent, the investigator must make every effort to have the subject complete all 
withdrawal assessments at the time of withdrawal, and complete all scheduled follow-up visits. 
 
UTreatment with study medication must be discontinued if (Withdrawal Criteria)U: 
• No clinical benefit has been attained after 16 weeks of treatment.  
• Evidence of Disease progression according to IWG 2006 criteria. 
• 
a subject experiences a DLT.   
• a subject becomes pregnant. 
• a subject is significantly non-compliant with the requirements of the protocol; 
• a subject has an adverse experience that would, in the investigator’s  
judgment, make continued participation in the study an unacceptable risk 
 
Follow up 
on study 
See calendar page 36 
Statistics 
UStudy Design: 
 
This study will use a dose escalation, “rolling 6”design in Phase 1. Subjects will be allocated to 
starting doses of 10 mg/d to 40mg/d (divided in two equal doses) escalated by 10 mg/day for each 
cohort according to the predetermined algorithm outlined below in Table 1 (section 6.4). Each 
cohort will include 6 subjects.  After testing the treatment dose on 10 patients in the first stage, the 
trial will be terminated if 1 or fewer desired respond. If the trial goes on to the second stage, a 
total of 29 patients will be studied. If the total number responding is less than or equal to 5, the 
drug is rejected. 
 
*Sample Size/Accrual Rate 


 
 
7
If dose escalation is completed as planned a maximum of 53 (24 phase 1 and 29 in phase 2) are 
expected to enroll at a rate of 3 subjects every 1 month for stage I. The first phase of the stage II 
will recruit 10 subjects at the MTD. If 1 response are seen by 17 weeks on Ruxolitinib, then a 
total of 29 subjects will be accrued at the MTD to determine efficacy. Maximum accrual is 53 
subjects. 
 
UAnalysis of the following secondary endpoints will be of exploratory nature: 
1. Acute myeloid leukemia (AML) transformation according to WHO criteria. 
2. Overall survival (OS). 
3. Duration of response. 
4. The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) at 
baseline and at best response. 
5. 
>50% decrease in splenic length as measured by physical exam 
6. The suppression of pSTAT5 intracellular signaling after ruxolitinib in CMML 
subjects (pretreatment, at 1-2hr post treatment, cycle 2, cycle 4, and 
progression.)  
7. Determine number of colonies formed in the presence of GM-CSF and/or 
ruxolitinib (pretreatment and progression) as a future predictor of response. 
8. Mutational status in our CMML subjects by sanger sequencing of JAK2V617F, 
c-CBL, N-RAS, K-RAS,RUNX-1, TET2, SRSF2, EZH2, ASXL1, and 
DNMT3a (pretreatment and progression). 
9. Mutational status of JAK2 tyrosine kinase at time of progression by deep 
sequencing of JAK2 to include M929I, Y931C, G935R, R938L, I960V, E985K. 
(pretreatment and at progression) 
 
Laboratory 
Correlates 
Phases 1 and 2 
The pharmacokinetics of ruxolitinib has been extensively studied in subjects with myeloid 
malignancies. Ruxolitinib is quickly absorbed with peak levels at 1 to 3 hours after ingestion of 
the tablet. Because of this, subjects will take their first dose of ruxolitinib in the clinic. At that 
time, and three hours after taking the tablet, peripheral blood will be collected and processed in 
the lab of P.K. Epling-Burnette in the Stabile Research Building (SRB) at the Moffitt Cancer and 
Research Institute as described in section 16. 
 
Using processed peripheral blood, pSTAT5 will be measured by flow cytometry at the time of 
tablet ingestion and 3 hours later. Bone marrow aspirates will also be used to perform colony 
formation assay as described in section 16 and to collect a minimum of 100 ug of DNA to 
interrogate the mutational status of the cohort studied as described in section 16. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 OBJECTIVES 
 


 
 
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1.1 
Primary Objective: 
1.1.1 To evaluate the safety and tolerability of ruxolitinib in CMML subjects at 
diagnosis or relapse. 
1.1.2 To determine overall response rates as measured by the international working 
group criteria (2006). 
1.2 
Secondary Objectives: 
1.2.1 To determine the time to AML transformation of subjects on Ruxolitinib. 
1.2.2 To determine the median overall survival.  
1.2.3 To determine the duration of response achieved as in secondary endpoint one.  
1.2.4 To determine the change in symptom score from baseline to best response. 
1.2.5 To determine the change in spleen length at 16 weeks 
1.2.6 To determine the change in downstream targets of JAK2 on  ruxolitinib. 
1.2.7 To determine if the in vitro activity of ruxolitinib correlates to response rates. 
1.2.8 To determine if a correlation exist between the presence of the known recurrent 
mutations (JAK2, c-CBL, N-RAS, K-RAS, RUNX-1, TET2, SRSF2, EZH2, 
ASXL1, and DNMT3a) and response to ruxolitinib.   . 
1.2.9 To determine non-V617F JAK2 mutations at end of study or progression and their 
clinical relevance in the context of ruxolitinib. 
 
 We recognize that this is a small study and the secondary objectives are of 
exploratory nature. 
 
2 BACKGROUND 
 
2.1 
Chronic Myelomonocytic Leukemia 
 
Chronic Myelomonocytic Leukemia (CMML) is a clonal malignancy characterized 
by cytopenias with or without leukocytosis, marrow dysplasia, monocytosis, 
splenomegaly, and a propensity to transform to acute myeloid leukemia1. Prior to 
2001, the World Health Organization (WHO) classified CMML as a subtype of the 
myelodysplastic syndromes (MDS)2. However because CMML exhibits clinical and 
pathologic features of a MDS and of a Myeloproliferative Neoplasm (MPN), it was 
reclassified by the WHO as a member of the Myelodysplastic/Myeloproliferative 


 
 
9
Neoplasms (MDS/MPN) highlighting its nosologic complexity. CMML shares this 
WHO designation with atypical Chronic Myeloid Leukemia (aCML), Refractory 
Anemia with Ringed Sideroblasts and Thrombocytosis (RARS-T), and the pediatric 
counterpart of CMML, Juvenile Myelomonocytic Leukemia (JMML)3. JMML is a 
lethal pediatric malignancy with clinical features similar to CMML and hallmarked 
by selective hypersensitivity to GM-CSF4. The reclassification of CMML has been 
substantiated by next generation sequencing techniques that have allowed for the 
massive genetic sequencing of myeloid malignancies5,6. The occurrence of recurrent 
mutations in CMML and MDS are now known to be different in both type and/or 
frequency suggesting that these diseases represent distinctly different entities. The 
clinical behavior of CMML is unique in that it displays features of an MDS and of an 
MPN within the same patient. However, CMML subjects can display the predominant 
features of an MDS-like or MPN-like disease. The French-American-British (FAB) 
group was first to subdivide CMML subjects into an MDS variant and MPN variant 
based on a white blood cell (WBC) count greater than 20K/dL7. The WHO later 
favored subdivisions based on a myeloblast percentage greater than 10% in the bone 
marrow aspirate because of its prognostic value3. Irrespective of these subdivisions, 
recent genomic advances have yet to translate to effective, CMML specific therapies 
and thus the current standard-of-care in CMML remains the use of drugs developed 
for MDS.   
 
For instance, in 2009, Fenaux and colleges reported the results of a randomized phase 
III trial that demonstrated a survival advantage (24.5mo vs 15mo) for 5-azacitidine, a 
DNA methyltransferase (DNMT) inhibitor, when compared with induction 
chemotherapy, low dose cytarabine, or best supportive care in subjects with higher 
risk MDS and CMML. However, only 22 CMMLs were included in this study and 
unequal randomization did not allow for subset analysis of these subjects8. Despite 
this, 5-azacitidine gained FDA approval for the treatment of CMML and has become 
the first line therapy of choice. Subsequent retrospective reports have suggested that 
the rates of hematologic improvement in CMML are similar to MDS but that this 
similarity is lost when analyzing the myeloproliferative variant of CMML alone.  The 


 
 
10 
myeloproliferative variant appears to be have response rates on the order of 10-15%9. 
 
Chronic Myelomonocytic Leukemia (CMML) is a rare disease with an incidence of 
approximately 0.3 per 100,000. The prognosis is poor with a median overall survival 
ranging between 12 and 20 months that is not known to be improved by 5-
azacitidine10. Allogeneic stem cell transplant (ASCT) remains the only potential 
curative therapy. However, most subjects are ineligible secondary to age related 
exclusion. Those that can undergo transplant face a high degree of morbidity and 
unacceptable transplant related mortality with only a small fraction of subjects alive 
at 5 years11. From an economic perspective, an ASCT is costly as are the prophylactic 
antibiotics necessary to prevent life threatening infection and the immuno-
suppressants needed to control graft versus host disease as a result of the transplant. 
To make matters worse, there are very few clinical trials available in CMML relative 
to other hematologic malignancies. This, in combination with its dismal prognosis 
and lack of standard therapies makes the outlook of subjects with CMML quite grim. 
There is a clear need for new CMML-specific therapies in this orphaned disease.  
 
2.2 
GM-CSF signaling and Chronic Myelomonocytic Leukemia 
 
GM-CSF hypersensitivity, as defined by increased hematopoietic colony formation in 
methylcellulose when exposed to low dose GM-CSF, has been a known feature of 
JMML for over a decade4. The obvious clinical similarities between JMML and 
CMML have lead to studies, including our own, investigating the nature of GM-CSF 
signaling in CMML. The first such study in 2002, Ramshaw and colleges showed that 
spontaneous hematopoietic colony growth could be achieved in CMML patient 
samples and that this was inhibited by E21R, a GM-CSF specific antagonist, 
suggesting that autocrince or paracrine production of GM-CSF was important to in 
vitro CMML cell proliferation and differentiation. They also performed 
transplantation experiments in a NOD/SCID murine model that was transgenically 
modified to secrete human GM-CSF or not. Only those CMML cells transplanted in 
the GM-CSF transgenic mouse engrafted demonstrating an in vivo requirement for 
proliferation12. In the next study, Kotecha and colleges explored the downstream 


 
 
11 
signals elicited by the GM-CSF receptor in JMML. Despite the fact that JMML is 
predominantly a RAS-mediated disease, Kotecha and colleges demonstrated that it 
was STAT5 and not ERK that was hyperphosphorylated in the presence of GM-CSF. 
This phenomenon was not seen in normal controls or other pediatric MPNs but was 
seen in five CMML patient samples13. 
 
Our laboratory has confirmed these results by demonstrating that CMML primary 
samples are sensitive to very low doses of GM-CSF as measured by STAT5 
phosphorylation (n=20)14. We have also shown that GM-CSF inhibition is important 
to CMML viability by introducing KB-003, a highly specific monoclonal antibody to 
GM-CSF developed by KaloBios pharmaceuticals. Despite the molecular and clinical 
heterogeneity observed in CMML, all samples tested (n=10) showed decrease 
proliferation and viability when exposed to GM-CSF blockade and the vast majority 
of samples tested (n=20) showed GM-CSF dependent STAT5 activation (Yp) at 
lower doses of GM-CSF compared to controls and compared to other cytokines 
within the CMML subjects. Further it was the immature monocytes (CD33+/CD14+) 
that seemed most sensitive to this inhibition, leaving the rest of the bone marrow 
unaffected.  
 
2.3 
Ruxolitinib 
Ruxolitinib is an FDA-approved agent for the treatment of myelofibrosis. It is a 
potent inhibitor of JAK1 and JAK2 (nM IC50) that has been tested in a wide array of 
JAK/STAT dependent processes. In JAK/STAT dependent cell lines, ruxolitinib 
demonstrates IC50 values of 80-300 nM and can inhibited JAK/STAT signaling and 
growth in cell lines expressing the constitutively active JAK2 mutant (JAK2V617F) 
that is present in approximately 15% of CMML subjects5. The JAK2V617F 
abnormality has been broadly implicated in the pathogenesis of the majority of 
Philadelphia chromosome negative MPNs. It is because of this that INCYTE, the 
makers of ruxolitinib, have targeted MPNs in its initial drug development. To this 
end, in vivo studies have demonstrated that Ruxolitinib improves splenomegaly and 
survival in a murine JAK/STAT dependent MPN model after only 3 weeks of 


 
 
12 
treatment. Treatment with ruxolitinib also reduced inflammatory cytokines and 
pSTAT3 levels in these mice suggesting an in vitro and in vivo effect in JAK/STAT 
dependent malignancies15.   
Safety 
During the Phase I and Phase II development program, ruxolitinib was assessed in 
healthy volunteers, subjects with various degrees of renal or hepatic impairment, in 
subjects with rheumatoid arthritis, prostate cancer, multiple myeloma, myelofibrosis 
(MF), ploycythemia vera and essential thrombocythemia.  The aggregate safety 
database for ruxoltinib included 679 subjects treated in 6 studies. Hematologic events 
were the most frequently reported adverse events (AE)s however, the majority of 
these were of Grades 1-2, seldom leading to study drug discontinuation (<1% of 
subjects). Increased rates of anemia did result in an increase in packed red blood cell 
(PRBC) transfusion requirements for some ruxolitinib-treated patients but platelet 
transfusions while on ruxolitinib were rare.  No Grade 4 events as it relates to 
biochemistry laboratory abnormalities of alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) or cholesterol were reported. The Phase III safety dataset in 
MF patients shows that it was appropriate to individually adjust doses for patients 
according to their tolerability and efficacy. However, 124 patients (41.2%) required 
no dose reduction, indicating the starting dose of 15mg or 20mg BID was appropriate 
for these individuals. Of the 177 patients who had dose reduction, 91 patients (51%) 
had only one. Interruptions of dosing were less frequent than dose reductions, with 
215 patients (71.4%) requiring no dose interruption. Of the 86 patients who had dose 
interruptions, 59 patients (19.6%) had only one dose interruption. The Phase III safety 
dataset in MF subjects showed that the only notable imbalances (ruxolitinib versus 
placebo or best available therapy [BAT]) in AEs related to hemorrhagic events were 
in Grade 1-2 skin and soft tissue bruising which did not lead to dose reduction or 
discontinuation. Similarly, the only notable imbalances (ruxolitinib versus placebo or 
BAT) in AEs related to infections were urinary tract infections and herpes zoster 
infections. A thorough QT study was conducted in 50 healthy subjects. There was no 
indication of a QT/QTc prolonging effect of ruxolitinib in single doses up that 
exceeded those proposed in this study16.  


 
 
13 
Efficacy 
In two large phase 3 clinical trials, ruxolitinib has demonstrated efficacy in subjects 
with high-risk myelofibrosis. The first trial randomly assigned subjects to receive 
15mg twice daily of ruxolitinib (155 subjects) or placebo (154 subjects). The primary 
endpoint of the study was defined as the proportion of subjects with a reduction in 
spleen volume of 35% or more at 24 weeks by means of magnetic resonance imaging 
(MRI). The primary end point was reached in 41.9% of subjects in the ruxolitinib 
group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen 
volume was durable as 67.0% of the subjects with a response had the response for 48 
weeks or more. There was an improvement of 50% or more in the total symptom 
score, a myleofibrosis specific quality-of-life scoring system, at 24 weeks in 45.9% of 
subjects who received ruxolitinib as compared with 5.3% of subjects who received 
placebo (P<0.001)17. The second trial randomly assigned subjects to the same dose of 
ruxolitinib or best available therapy (BAT) defined by the treating physician. The 
primary end point was the percentage of subjects with at least a 35% reduction in 
spleen volume at week 48 by MRI or computed tomography. A total of 28% of the 
subjects in the ruxolitinib group met the primary endpoint as compared with 0% in 
the group receiving the best available therapy (P<0.001). At 48 weeks, the mean 
palpable spleen length had decreased by 56% with ruxolitinib but had increased by 
4% with the best available therapy. The median duration of response with ruxolitinib 
was not reached, with 80% of subjects still having a response at a median follow-up 
of 12 months18. 
 
2.4 
Rationale for Ruxolitinib in CMML 
GM-CSF signaling is both dysregulated and important for CMML survival in vitro 
and in vivo (see section 2.2). Although GM-CSF signaling is hallmarked by cytokine 
pleotropy, it appears that STAT5 is preferentially activated in the CMML disease 
phenotype. Our laboratory has shown that targeting GM-CSF activation leads to 
decreased viability in primary CMML patient samples. In the late 1990s, efforts were 
made to target this pathway. Frankel and colleges developed a GM-CSF molecule 
fused to diphtheria toxin that was highly toxic to CMML myeloid progenitors in 


 
 
14 
16/20 patient samples tested19. This led to a phase I clinical trial in relapsed/refractory 
acute leukemias. Unfortunately, unacceptable hepatoxicity was seen, even at 
moderate doses of compound, that did not allow for dose escalation20. This 
hepatotoxicity is now thought to be Kupffer cell mediated. 
 
The JAK kinases are the sentinel kinases responsible for the key phosphorylation 
event in many cytokine receptors, including GM-CSF. Parganas and colleges 
developed a JAK2 deficient murine model that showed that JAK2 is required to elicit 
GM-CSF mediated signaling21. Considering this, our laboratory explored JAK1/2 
pharmacologic inhibition with SD1029 in primary CMML cells. SD-1029 is a 
selective JAK1/JAK2 (µM IC50) inhibitor that is not available for clinical use and 
has a similar JAK inhibition profile to ruxolitinib. In 3 CMML patient samples tested, 
SD-1029 increased apoptosis and decreased viability by ANNEXIN-V and DAPI 
staining in a dose dependent fashion. None of these subjects tested harbored a 
JAK2V617F mutation. Lastly, Ravandi and colleges recently published the results of 
a phase 2 trial using ruxolitinib in refractory leukemias. In this cohort, 4 CMML 
subjects were enrolled to take BID ruxolitinib (dose not available). It is reported that 
2/4 CMML subjects demonstrated some degree of clinical benefit22. Although the 
nature of the benefit was not expounded upon, it provides further proof-of-principle 
that JAK inhibition may indeed result in responses in this disease. Our preliminary 
data, in addition to the extensive data demonstrating the role of GM-CSF in CMML, 
provides compelling evidence to explore JAK1/2 inhibition with ruxolitinib as a 
therapeutic target in CMML.  
3 STUDY ENDPOINTS 
3.1 
   Primary 
3.1.1 The maximum tolerated dose (MTD) of ruxolitinib for the treatment of CMML. 
The MTD is defined as the highest dose where less than 33% of subjects 
experience a drug related predefined dose limited toxicity (DLT).  
3.1.2 Proportion of subject achieving clinical benefit defined as hematologic 
improvement, complete remission, partial remission, or stable disease by the IWG 
2006 criteria (see appendix B) 


 
 
15 
3.2 
   Secondary 
3.2.1 Acute myeloid leukemia (AML) transformation according to WHO criteria. 
3.2.2 Overall survival (OS). 
3.2.3 Duration of response. 
3.2.4 The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) at 
baseline and at best response. 
3.2.5 >50% decrease in splenic length as measured by physical exam if applicable 
3.2.6 The suppression of pSTAT5 intracellular signaling after ruxolitinib in CMML 
subjects (pretreatment, at 1-2hr post treatment, cycle 2, cycle 4, and progression.)  
3.2.7 Determine number of colonies formed in the presence of GM-CSF and/or 
ruxolitinib (pretreatment and progression) as a future predictor of response. 
3.2.8 Mutational status in our CMML subjects by sanger sequencing of JAK2, c-CBL, 
N-RAS, K-RAS,RUNX-1, TET2, SRSF2, EZH2, ASXL1, and DNMT3a 
(pretreatment and progression). 
3.2.9 Mutational status of JAK2 tyrosine kinase at time of progression by deep 
sequencing of JAK2 to include M929I, Y931C, G935R, R938L, I960V, E985K. 
(pretreatment and at progression) 
  
4 PATIENT SELECTION 
4.1 
Eligibility criteria 
4.1.1 Confirmed diagnosis of CMML using the World Health Organization (WHO) 
classification (appendix E). 
4.1.2 Age >18 years at the time of obtaining informed consent.   
4.1.3 Must be able to adhere to the study visit schedule and other protocol 
requirements.  
4.1.4 Subjects must be able to provide adequate BM aspirate and biopsy specimens for 
histopathological analysis and standard cytogenetic analysis during the screening 
procedure.  
4.1.5 An Eastern Cooperative Oncology Group (ECOG) performance status score of 
0,1, or 2 is required.  
4.1.6 Women of childbearing potential must have a negative pregnancy test at time of 
screening and baseline visits and agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse 


 
 
16 
1) for at least 28 days before starting study drug; 2) while participating in the 
study; and 3) for at least 28 days after discontinuation from the study. The two 
methods of reliable contraception must include one highly effective method (i.e. 
intrauterine device [IUD], hormonal [birth control pills, injections, or implants], 
tubal ligation, partner’s vasectomy) and one additional effective (barrier) method 
(i.e. latex condom, diaphragm, cervical cap).  
4.1.7 Must understand and voluntarily sign an informed consent form. 
4.1.8 Must have a life expectancy of greater than 3 months at time of screening. 
4.2 
Exclusion Criteria 
4.2.1 Any of the following lab abnormalities:  
4.2.1.1 Platelet count of less than 35,000/uL 
4.2.1.2 Absolute Neutrophil Count (ANC) of less than 250 cells/uL 
4.2.1.3 Serum Creatinine ≥2.0 
4.2.1.4 Serum total bilirubin >1.5 x ULN  
4.2.2 Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are 
not commercially available) for the treatment of CMML within 28 days of the 
first day of study drug treatment.  
4.2.3 Any serious medical condition or psychiatric illness that will prevent the subject 
from signing the informed consent form or will place the subject at unacceptable 
risk if he/she participates in the study.  
4.2.4 Concurrent use of GM-CSF. G-CSF could be used for the short-term management 
of neutropenic infection.  Stable doses of erythropoietin stimulating agents that 
were started >8 weeks from first ruxolitinib dose or corticosteroids that were 
being administered prior to screening are allowed. 
 
4.2.5 Uncontrolled current illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
4.2.6 History of metastatic malignancy in the preceding 2 years.  
4.2.7 Pregnant women are excluded from this study because ruxolitinib has not been 
studied in pregnant subjects. Because there is an unknown but potential risk for 


 
 
17 
adverse events in nursing infants secondary to treatment of the mother with 
ruxolitinib, breastfeeding should be discontinued if the mother is treated with 
ruxolitinib. 
4.2.8 Patients who have participated in other interventional (treatment-related) clinical 
trials within 30 days of enrollment are excluded. 
4.3 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
5 STUDY DESIGN 
This is a phase 1/2, two-stage, sequential cohort dose escalation study. In phase 1, 
subjects will be allocated to BID doses of 10 mg/d up to 40mg/d. The starting dose 
will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is 
reached, 10 additional subjects will be treated during the first stage of phase 2 (stage 
1) at the MTD. The tiral will be terminated if 1 or fewer respond. If the trial goes on 
to the second stage, a total of 29 patients will be studied to determine efficacy in 
phase 2. 
 
6 TREATMENT PLAN 
 
6.1 
Ruxolitinib administration 
Subjects will not take the morning dose of ruxolitinib at the first regularly scheduled 
visit. Drug will be administered in the clinic in order to obtain adequate biomarker 
assessment. On all other days corresponding to study visits, subjects will take the 
morning dose of study drug prior to the visit, and will note on the subject reminder 
card the time that medications were taken. Reported adverse events and potential 
risks are described in Section 11.  Appropriate dose modifications for ruxolitinib are 
described in Section 10.  No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient's 
CMML. 
6.1.1 Ruxolitinib will be supplied by INCYTE as tablets that will be self-
administered BID orally, with or without food approximately 12 hours apart 
(morning and night). 


 
 
18 
6.1.2 The dosage strength is 5 mg/tablet Ruxolitinib phosphate (free base 
equivalent). Administration instructions will be provided at Study Visits. The 
administration instructions will state that medication is “For Investigational Use 
Only”.  Ruxolitinib 5 mg tablets are packaged as 60 count in high-density 
polyethylene (HDPE) bottles. The bottles will include labeling “New Drug - 
Limited by Federal (USA) Law to Investigational Use. The bottles of tablets 
should be stored at room temperature, 15°C to 30°C (59°F to 86°F). Dose 
escalation guidelines are detailed below in section 6.5. In phase II of the study, a 
maximum of 29 subjects will be treated at the MTD identified in phase I.   
 
6.2 Definition of Dose-Limiting Toxicity 
Dose-limiting toxicity (DLT) is defined as any grade 4 hematologic toxicity and any 
grade 3 or greater non-hematologic toxicity except nausea that is controlled by 
antiemetic therapy based on the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  Criteria for Grade 3 renal toxicity are consistent with 
prescribing information with respect to renal impairment and safe use of ruxolitinib. 
Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are 
adequately controlled within 72 hours are not to be considered a DLT. To discern 
disease specific versus drug specific myelosuppression, Grade 4 thrombocytopenia 
will be defined as a decrease of ≥ 50% of baseline and a level of < 25,000/uL. Grade 
4 neutropenia will be defined as a decrease of ≥ 50% of baseline and a level of 
<500/uL.  Previous clinical trials testing ruxolitinib reported a hematologic nadir of 8 
weeks. As such, DLTs during the first and second cycle of therapy, i.e. 8 weeks, will 
be used for the purpose of deciding the dose for next cohort (see dose escalation 
schema) but DLTs will continue to be evaluated and reported through all cycles on 
study. Management and dose modifications associated with the above adverse events 
are outlined in Section 11.   
 
6.2.1 Dose escalation will proceed according to the following scheme: 
 
 
Dose Escalation Schedule 
 
 


 
 
19 
Dose Level 
Dose of Ruxolitinib (per day given in equal BID 
doses) 
 
Level 1 
 
10 mg 
 
Level 2 
 
20 mg 
 
Level 3 
 
30 mg 
 
Level 4 
 
40 mg 
 
 
6.3 
Definition of Maximum Tolerated Dose 
The maximum tolerated dose (MTD) is defined as the highest dose where < 33% of 
subjects experience DLT.  
 
Dose Escalation Scheme 
In phase 1 of this study, subjects will be allocated to starting doses (10 mg/d to be 
escalated up to 40mg/d, which is outlined in the table above). The second phase of the 
study (phase 2) will enroll a maximum of 29 subjects at the MTD determined in 
phase 1. In each cohort in the phase I study, up to 6 subjects will be enrolled. Based 
on whether DLTs are observed during 8 weeks of treatment, the dose for the 
subsequent cohort will be determined. If no DLT is observed during an 8 week period 
then another 6 subjects will be enrolled at the next dose level (see section 6.2.1 table). 
If 1 DLT is observed after three subjects are enrolled then dose escalation will 
continue at the same dose level until 6 total patients are enrolled. If a total 1 of 6 
subjects enrolled experience at DLT after all subjects have had an 8 week monitoring 
period then dose escalation can proceed. If 2 or more of 6 total subjects experience a 
DLT then dose escalation is complete and the MTD will be the antecedent dose level. 
Dose escalation will proceed according to the following scheme.  Dose-limiting 
toxicity (DLT) is defined above.   
6.3.1 Dose Escalation Rules of Rolling Six Design 
Cohort 
DLT Data 
Enrolling Dose level 
No. 
Enrolled 
No. 
DLTs 
No. without 
DLT 
No. with Pending 
Data 
MTD Not Exceeded 
2 
0,1 
Any 
Any 
n 


 
 
20 
2 
2 
0 
0 
n-1 
3 
0 
0,1,2 
3,2,1 
n 
3 
0 
3 
0 
n+1 
3 
1 
0,1 
2,1 
n 
3 
1 
2 
0 
n 
3 
>1 
Any 
Any 
n-1 
4 
0 
0,1,2 
4,3,2 
n 
4 
0 
3 
1 
n 
4 
0 
4 
0 
n+1 
4 
1 
0,1 
3,2 
n 
4 
1 
2 
1 
n 
4 
1 
3 
1 
n 
4 
>1 
Any 
Any 
n-1 
5 
0 
0,1,2 
5,4,3 
n 
5 
0 
3,4 
2,1 
n 
5 
0 
5 
0 
n+1 
5 
1 
0,1 
4,3 
n 
5 
1 
2 
2 
n 
5 
1 
3,4 
1,0 
n 
5 
>1 
Any 
Any 
n-1 
6 
0 
0,1,2 
6,5,4 
Suspend 
6 
0 
3,4 
3,2 
Suspend 
6 
0 
5,6 
1,0 
n+1 
6 
1 
0,1 
5,4 
Suspend 
6 
1 
2 
3 
Suspend 
6 
1 
3,4 
2,1 
Suspend 
6 
1 
5 
0 
n+1 
6 
>1 
Any 
Any 
n-1 
      Adapted from Skolnik, et al. Shortening the Timeline of Pediatric Phase I Trials: 
The Rolling Six Design. JCO 2008 n=current dose level. n+1=dose escalation. n-
1=dose de-escalation. Pending data=less than 8 weeks of follow-up data. 
 
 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
All concomitant medications and medication history for 2 weeks MUST be recorded 
in the eCRF, and include: drug name, dose, frequency of administration, start and 
stop dates, and indication. All prior medications used to treat CMML will be recorded 
regardless of when they were received by the subject. Information collected for these 
medications will include dates of use, best treatment response (eg, disease 
improvement, stabilization of disease or no improvement/disease progression), and 
reasons for stopping therapy. Any change in dosage of any concomitant medication 
(change in dose or frequency) MUST be recorded in the eCRF, to include: drug name, 
dose, frequency of administration, start and stop dates and indication.  


 
 
21 
6.5 
Permitted Medications 
6.5.1.1 Growth Factors 
Erythropoiesis-stimulating agents (ESAs) are allowed for anemia during the 
study as per accepted standards in the treatment of CMML as long as the ESA 
was initiated >8 weeks prior to the first dose of ruxolitinib. Subjects who enter 
the study on ESAs should continue at the same dose schedule until the optimal 
dose of study medication has been established. G-CSF is allowed during the 
study for subjects with severe neutropenia and recurrent infections. Subjects 
who enter the study on G-CSF should continue at the same dose schedule until 
the optimal dose of study medication has been established. GM-CSF is not 
permitted at any time during the study as preclinical evidence suggests that 
GM-CSF may be important for CMML proliferation and survival.  
6.5.1.2 Systemic corticosteroids  
Systemic corticosteroid doses greater than the equivalent of 10 mg 
prednisolone per day is not permitted, unless use is part of an ruxolitinib-dose 
tapering strategy. (see section 7 Optional Dose Tapering Strategy). 
6.5.1.3 Aspirin 
Aspirin in doses exceeding 162 mg per day is not permitted. Low dose aspirin 
(≤ 162 mg/day) and non steroidal anti-inflammatory agents (acetaminophen, 
Ibuprofen) may be used. 
6.5.1.4 Medications that are inhibitors of CYP3A4 
When concomitant administration of a potent systemic inhibitor of CYP3A4 
metabolizing enzymes (ketoconazole, clarithromycin, itraconazole, 
nefazodone and telithromycin, see section 7) that is required for subject 
management, the dose of ruxolitinib tablets must be adjusted as described in 
section 7. Based on the low overall bioavailability of topical ketoconazole, 
with very low systemic levels seen following topical administration, no dose 
adjustment of ruxolitinib is needed for use with topical ketoconazole.  
6.5.1.5 Blood Products 
The use of blood products to include packed red blood cells (PRBCs) and 
platelet transfusions are permitted and to be given at the discretion of the 


 
 
22 
treating physician. Recommended guidelines for transfusion include a platelet 
threshold of 10,000/L for platelet transfusion and a hemoglobin threshold of 
8g/dL for PRBC transfusion.  
 
6.6 
Prohibited Medications  
Subjects must abstain from using prohibited prescription or non-prescription 
drugs within 7 days or 5 half-lives (whichever is longer) prior to the first dose of 
study medication and until completion of follow-up procedures ( Exclusion 
Criteria ). The following medications are prohibited during the study: 
• Any prior or concomitant use of another JAK inhibitor. 
• Any investigational medication other than the study drugs.  
• Use of the potent inducers of CYP3A4, rifampin and St John’s Wart, is not 
permitted at any time during participation in the study. 
• The GM-CSF growth factor receptor agonists must not be used. Preclinical 
evidence suggest that it is important for CMML proliferation and survival and it is 
directly upstream for JAK2, the target of ruxolitinib. GM-CSF must not have been 
used for at least 28 days prior to receiving the first dose of study drug. 
7 Duration of Therapy 
Subjects will be treated for a total of 16 weeks.  For subjects responding at week 16, 
treatment may continue until one of the following criteria applies: 
7.1 
Dose-limiting toxicity is reached, 
7.2 
Inter-current illness that prevents further administration of treatment, 
7.3 
Unacceptable adverse event(s), 
7.4 
Patient decides to withdraw from the study, or 
7.5 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
7.6 
Evidence of disease progression by the IWG 2006 criteria.  
Subjects who wish not to continue treatment will complete their end of study visit at 
week 17. Subjects who were not enrolled in the MTD cohort can increase to the MTD 
after week 17 if the participant still meets the eligibility criteria. Responding patients 
will be able to continue until marketing approval of ruxolitinib for CMML. 


 
 
23 
 
8 Duration of Follow-Up  
 
Subjects will be followed as per calendar on treatment for 17 weeks. After 17 weeks 
patient who continue on study will be followed monthly. Off study data on AML 
transformation and overall survival will be updated every 6 month or until death, 
whichever occurs first. Subjects removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event. 
9 Criteria for Removal from Study 
9.1 
Subject Completion 
A subject will be considered to have completed the study if the subject meets at least 
1 of the following criteria: 
9.1.1 The subject has completed 16 weeks of treatment with study medication 
with no improvement. 
9.1.2 The subject died during the study. 
9.1.3 The subject withdrew from study including subjects who experience a 
DLT. 
9.1.4 The subject experienced an AE that lead to withdrawal from the study. 
9.2 
Subject Withdrawal from Study 
9.2.1 A subject may voluntarily withdraw from study medication or withdraw consent 
from the study at any time. The investigator may also, at his or her discretion, 
discontinue a subject from participating in the study at any time. The investigator 
will record the date and the reason for subject withdrawal from the study.8/ 
9.3 
Subject Withdrawal from Study Medication 
If the subject is permanently withdrawn from treatment with study medication, but 
does not withdraw consent, the investigator must make every effort to have the 
subject complete all withdrawal assessments at the time of withdrawal, and complete 
all scheduled follow-up visits. Treatment with study medication must be discontinued 
if: 
• The subject withdraws consent. 
• Further participation would be injurious to the subject’s health or well-being in 
the Investigator’s medical judgment. 


 
 
24 
• The study is terminated. 
• Marketing approval of CMML 
• The subject becomes pregnant  
• The subjects exhibits leukemic transformation (as evidenced by bone marrow 
blast counts of at least 20%, or peripheral blast counts of at least 20% lasting at least 
8 weeks. 
• No clinical benefit has been attained after 16 weeks of treatment.  
• Evidence of Disease progression according to IWG 2006 criteria. 
• a subject experiences a DLT.   
• a subject is significantly non-compliant with the requirements of the protocol. 
• a subject has an adverse experience that would, in the investigator’s judgment, 
make continued participation in the study an unacceptable risk. 
10 DOSING DELAYS/MODIFICATIONS 
All subjects enrolled in the phase 1 portion will start treatment on the assigned dose 
per cohort based on the dose escalation algorithm provided.  No dose delays or 
modifications are allowed during this period. All subjects enrolled in the phase 2 
portion may have the following dose delays/modifications once the MTD has been 
defined.   
Ruxolitinib may be held by the Investigator at any time if there is concern about subject 
safety. Dosing must be halted immediately if either of the following occurs: 
• Platelet counts fall below 10,000/μL and/or a life-threatening bleeding event 
• Febrile neutropenia 
Dosing may be reinstated following dose interruption using the re-start schema detailed 
in below.  
10.1 Dose Adjustments. 
In order to provide sufficient data to make the dose adjustment decisions, it is 
recommended that hematology parameters be obtained weekly and at least two times 
weekly for platelet count < 25,000/μL or ANC < 500/μL. In the event that any subject 
permanently discontinues the study drug, regardless of reason, reasonable efforts 
should be made to have the subject return for an early termination visit. If the drug 
discontinuation is being contemplated for a reason other than low platelet count or 


 
 
25 
low ANC, the use of a tapering strategy should be considered (see below). The date 
the subject discontinued the study drug and the specific reason for discontinuation 
will be recorded in the eCRF; eg, reasons such as discontinued due to inadequate 
efficacy or withdrawn due to adverse event. This information will be used to 
summarize the reasons for study discontinuation. Efforts will be made to follow 
subjects who discontinue from the study in order to determine overall survival and 
leukemia free survival. Investigators will contact subjects every 6 months to 
determine if subjects have undergone leukemic transformation, or death, and for the 
latter, the cause of death.  
10.2 Dose Adjustments in Ruxolitinib Tablets for Safety. 
Dose adjustments apply to the phase 2 portion of this study. There are no dose 
adjustments allowed during phase 1. Dosing must be held if platelet counts decline 
below 10,000/μL or if a life-threatening bleed occurs with a platelet count below 
20,000/μL. Doses must be decreased for platelet count values that decline greater than 
50% of baseline and are greater than 25,000/μL to 75% of the defined MTD. Doses 
must be decreased for platelet count values that decline greater than 50% of baseline 
and are below 25,000/μL to 50% of the defined MTD. The dosing scheduled should 
be maintained at BID dosing to assure appropriate pharmacokinetics. Dose reductions 
should be executed by decreasing the individual dose and not the frequency of 
administration. In order to provide sufficient data to make the dose adjustment 
decisions, it is recommended that hematology parameters be obtained as defined in 
section 10.1. Dosing may be restarted or increased following recovery of platelet 
counts to acceptable levels. The following is the recommended dose restart/increase 
strategy: 
In subjects whom drug was held, ruxolitinib may be restarted at 50% of the MTD 
after platelet count has improved to pre-ruxolitinib baseline levels and/or febrile 
neutropenia has resolved for at least 2 weeks. In subjects whom drug dose was 
decreased, ruxolitinib may be increased to the previous dose (MTD) after platelet 
count has improved to pre-ruxolitinib baseline levels and/or febrile neutropenia has 
resolved for at least 2 weeks. If criteria is met for discontinuation/dose modification 
then ruxolitinib must be discontinued with no potential for restart. The objective for 


 
 
26 
restarting or escalating after a reduction for safety is to find the highest safe dose of 
ruxolitinib for each subject, with increases in dose generally not more than in 
increments of 5 mg BID and not more often than every 2 weeks.  Subjects who were 
not enrolled in the MTD cohort can increase to the MTD after week 17 if the 
participant still meets the eligibility criteria. Non hematological toxicity dose 
adjustment criteria 
10.3 Dose Reductions for Concomitant CYP Inhibitor Usage 
Ruxolitinib is metabolized in the liver by the cytochrome (CYP) P450 metabolizing 
enzyme system, predominantly by the 3A4 isozyme. With concomitant dosing of 
potent CYP3A4 inhibitors such as systemic ketoconazole (see Appendix C), plasma 
exposure of Ruxolitinib increases approximately 2-fold. Thus, a dose reduction of ~ 
50% for Ruxolitinib is appropriate for subjects who take systemic ketoconazole or 
other potent CYP3A4 inhibitors systemically as concomitant medication. BID doses 
will be decreased to the corresponding once daily dose as follows: 
• If dose is 20 mg BID, change dose to 20 mg QD 
• If dose is 15 mg BID, change dose to 15 mg QD 
• If dose is 10 mg BID, change dose to 10 mg QD 
• If dose is 5 mg BID, change dose to 5 mg QD 
• If dose is 5 mg QD, no dose change is required. 
Potent inhibitors of CYP3A4 include systemic ketoconazole, clarithromycin, 
itraconazole, nefazodone and telithromycin. NOTE: once the course of therapy using 
a CYP3A4 inhibitor has been completed, the subject should resume his/her prior BID 
dose regimen of study drug beginning the next day. 
10.4 Dose Reductions for Hepatic Impairment  
Hepatic impairment will be classified by the NCI Organ Dysfunction Working 
Group criteria. Any hepatic dysfunction classified as moderate or severe will 
require the treating physician to hold study drug until two week after hepatic 
dysfunction can be classified as mild or normal by NCI criteria. Ruxolitinib may be 
restarted at 50% of the MTD. If moderate or severe hepatic impairment occur a 
second time in the same subject, ruxolitinib will be discontinued. 
 


 
 
27 
11 ADVERSE EVENTS:  REPORTING REQUIREMENTS 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.All Adverse events will be reported to 
the principle investigator, Eric Padron and study coordinator at 813-745-5758. 
 
11.1 Definition of an AE 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. Note: An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
(new or exacerbated) temporally associated with the use of a medicinal product. 
Events meeting the definition of an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication (overdose per se will not be 
reported as an AE/SAE). “Lack of efficacy” or “failure of expected pharmacological 
action” per se within the duration of initial ruxolitinib treatment/exposure of 16 weeks 
will not be reported as an AE or SAE. However, the signs and symptoms and/or 
clinical sequelae resulting from lack of efficacy will be reported if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 


 
 
28 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
• Death due to the disease being studied. 
11.2 Definition of an SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term “life-threatening” the definition refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.   
• Requires hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. Hospitalization for elective treatment 
of a pre-existing condition that did not worsen from baseline is not considered an AE. 
• Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
• Is a congenital anomaly/birth defect 
• All treatment related grade 4 non-hematologic laboratory abnormalities assessed 
using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.0. 


 
 
29 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
11.3 Relationship to Investigational Product 
It is a regulatory requirement for investigators to assess relationship to investigational 
product based on information available. The assessment should be reviewed on 
receipt of any new information and amended if necessary. “A reasonable possibility” 
is meant to convey that there are facts/evidence or arguments to suggest a causal 
relationship. Facts/evidence or arguments that may support “a reasonable possibility” 
include, e.g., a temporal relationship, a pharmacologically-predicted event, or positive 
dechallenge or rechallenge. Confounding factors, such as concomitant medication, a 
concurrent illness, or relevant medical history, should also be considered. 
11.4  Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline should be recorded as per the NCI-CTC 
AE criteria. However, these laboratory results are to be recorded as AEs or SAEs if 
deemed clinically significant in the medical and scientific judgment of the 
investigator or treating physician.0 Any clinically significant safety assessments that 
are associated with the underlying disease are not to be reported as AEs or SAEs, 
except for findings judged by the investigator or treating physician to be more severe 
than expected for the subject’s condition or death. Data will be collected for typical 
disease-related events such as anemia, leukocytopenia or worsening of 


 
 
30 
thrombocytopenia. All infections experienced during the study are to be recorded as 
AEs or SAEs. 
11.5 Disease-Related Events and/or Disease-Related Outcomes Not 
        Qualifying as SAEs 
During the study period, the following conditions will not qualify as an AE or SAE 
provided they are not considered attributable to study medication: 
• cases of disease progression. 
11.6 Pregnancy 
Any pregnancy that occurs during study participation must be reported. To ensure 
subject safety, each pregnancy must be reported to the FDA with CC notification to 
INCYTE IncytePhVOpsIST@incyte.com   within 2 weeks of learning of its 
occurrence. The pregnancy must be followed up to determine outcome (including 
premature termination) and status of mother and child. Pregnancy complications and 
elective terminations for medical reasons must be reported as an AE or SAE. 
Spontaneous abortions must be reported as an SAE.5Any SAE occurring in 
association with a pregnancy, brought to the investigator’s attention after the subject 
has completed the study and considered by the investigator as possibly related to the 
investigational product, must be promptly reported to the pharmacovigiliance group 
at the H. Lee Moffitt Cancer Center. In addition, the investigator must attempt to 
collect pregnancy information on any female partners of male study subjects who 
become pregnant while the subject is enrolled in the study. Pregnancy information 
must be reported to the H. Lee Moffitt Cancer Center as described above. 
11.7 Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. AEs will be collected from the start 
of Investigational Product and through the follow-up contact. SAEs will be collected 
over the same time period as stated above for AEs. However, any SAEs assessed as 
related to study participation (e.g., investigational product, protocol mandated 
procedures, invasive tests, or change in existing therapy) will be recorded from the 
time a subject consents to participate in the study up to and including any follow-up 


 
 
31 
contact. All SAEs will be reported to INCYTE IncytePhVOpsIST@incyte.com  
within 24 hours, as indicated.  
11.8 Prompt Reporting of Serious Adverse Events and Other Events 
to the FDA with notification to INCYTE 
 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, 
must be reported by the investigator. In addition, any SAEs which occur as a result of 
protocol specific diagnostic procedures or interventions must also be reported. SAEs 
brought to the attention of the investigator at any time after cessation of ruxolitinib 
and considered by the investigator to be related or possibly related to ruxolitinib must 
be reported to FDA with notification to INCYTE IncytePhVOpsIST@incyte.com   if 
and when they occur. Additionally, in order to fulfill international reporting 
obligations, SAEs that are related to study participation (e.g., procedures, invasive 
tests, change from existing therapy) or are related to a concurrent medication will be 
collected and recorded from the time the subject consents to participate in the study 
until he/she is discharged. 
 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time 
Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours* 
“SAE” data collection 
tool 
24 hours* 
Updated “SAE” 
data collection tool 
Pregnancy 
2 Weeks* 
Pregnancy 
Notification Form 
2 Weeks* 
Pregnancy Follow-
up Form 
• From the time point when the SAE or pregnancy became known to reporter. 
 
11.9 Regulatory Reporting Requirements for SAEs 
Prompt notification of SAEs by the investigator to the FDA (and INCYTE 
IncytePhVOpsIST@incyte.com ) is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects are met. The sponsor-investigator has a 
legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. The sponsor-
investigator will comply with  specific regulatory requirements relating to safety 


 
 
32 
reporting to the regulatory authority, /Institutional Review Board (IRB), the FDA, 
notification to INCYTE, and sub-investigators.2Investigator safety reports are 
prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and those policies set forth by the FDA and are forwarded to 
investigators and INCYTE as necessary. An investigator who receives an investigator 
safety report describing an SAE(s) or other specific safety information (e.g., summary 
or listing of SAEs) from the H. Lee Moffitt Cancer Center will file it with the CIB 
and will notify the IEC /IRB, if appropriate according to local requirements. 
 
12 PHARMACEUTICAL INFORMATION 
 
12.1 Packaging and Labeling 
Ruxolitinib 5 mg tablets are packaged as 60 count in high-density polyethylene 
(HDPE) bottles. The bottles will include labeling “New Drug - Limited by Federal 
(USA) Law to Investigational Use.  
12.2 Preparation 
Tablets will be provided to the site and no specific preparation of study medication is 
required prior to administration. 
12.3 Handling and Storage 
Investigational product must be dispensed or administered according to procedures 
described herein. Only subjects enrolled in the study may receive investigational 
product, in accordance with all applicable regulatory requirements. Only authorized 
site staff may supply or administer investigational product. All investigational 
products must be stored in a secure area with access limited to the investigator and 
authorized site staff and under physical conditions that are consistent with 
investigational product-specific requirements. The bottles of tablets should be stored 
at room temperature, 15°C to 30°C (59°F to 86°F). Any unused investigational 
product will be returned to INCYTE for destruction or destroyed at the institution per 
institutional policy (if allowable).  
13 Study Calendar 
All screening evaluations will be performed within 4 weeks prior to the start of 
ruxolitinib treatment.  Subjects must have a bone marrow biopsy and aspirate (including 


 
 
33 
cytogenetics) performed within 4 weeks prior to the start of treatment.  All transfusion 
and pre-transfusion Hgb or platelet count must be recorded for the 8 weeks prior to 
initiation of study treatment. Strict adherence to the visit schedule is required.  In the 
event that a visit or test cannot be scheduled on the exact visit day, a window of ± 7 days 
is allowable. Bone marrow aspiration and biopsy exams can be done within a 14 day 
window of the allotted date. Tests (including bone marrow biopsies and aspirates) done 
within the screening period prior to signing informed consent are allowed for use in this 
study. 
13.1 Baseline Assessment: within 4 weeks of starting treatment 
Medical history including: 
• disease characteristics such as first diagnosis of CMML, WHO/FAB subtype, 
IPSS score, MD Anderson Scoring System (MDASC), prior treatments.  
• ECOG performance status. 
• Concurrent medication review. 
• red blood cell and platelets transfusion past 8 weeks if available. 
• Routine physical examination to include vital signs, height and weight. 
• Bone marrow examination, including cytomorphology, cytogenetic assessment, 
and flow cytometry analysis.  
• Laboratory assessments: 
o Hematology to include platelet count, hemoglobin, hematocrit, white blood cells 
(WBC) and WBC differential (including: neutrophils, eosinophils, basophils, 
lymphocytes and monocytes), INR, PT, and PTT and reticulocyte count. 
o Clinical chemistries including BUN/urea, creatinine, sodium, potassium, 
alkaline phosphatase, alanine aminotransferase (ALT), aspartateaminotransferase 
(AST), , total bilirubin, bicarbonate, calcium, chloride, glucose, LDH, total protein, 
albumin. 
o Urine or serum pregnancy test for females of childbearing potential will be 
performed at Screening or on Day 1, prior to first dose of study medication. 
o •Symptom Score using the The Myeloproliferative Neoplasms Symptom Assessment 
Form (MPN-SAF). (see Appendix D) 


 
 
34 
Review and record any blood and blood supportive care products for the prior 8 
weeks. 
13.2 
UTreatment Period (weeks 1-16):  Ruxolitinib will be administered as a twice 
daily oral dose for a 4-week treatment cycle.  Subjects will have a CBC with 
leukocyte differential performed weekly; a blood chemistry will be performed weekly 
for first cycle and then q 2 weeks. A BM aspirate and biopsy with cytogenetic 
analysis will be performed after cycle 2 and 4 (weeks 8, 16) to assess pathologic 
response, cytogenetic response and disease progression. For subjects who achieve 
CR, marrow CR, or PR a confirmation bone marrow aspirate and biopsy should be 
obtained 4 to 8 weeks after documentation of CR, marrow CR, or PR. 
13.3 Week 16 End of Treatment: Subjects will complete a response assessment 
within one week after their last administration of ruxolitinib. Subjects discontinuing 
study early should complete their end of treatment visit within two weeks after their 
last dose of investigational product.  Physical exam, vital signs, concomitant 
medication, adverse event reporting, CBC, and blood chemistry and BM aspirate and 
biopsy with cytogenetic analysis will be performed.   
13.4 
Continuation Phase: After completing cycle 4 response assessments, 
responders may continue to receive ruxolitinib and the final week 16 dose in the 
absence of DLT or disease progression until marketing approval of ruxolitinib for 
CMML.  Bone marrow biopsy and aspirate will be repeated after every 4 cycles (For 
subjects who achieve CR, marrow CR, or PR a confirmation bone marrow aspirate 
and biopsy should be obtained 4 to 8 weeks after documentation of CR, marrow CR, 
or PR).  A CBC will be obtained and complete metabolic profile as per standard of 
care. The off treatment assessment should be done within a week off treatment.  
13.5 Off Treatment assessment: includes best response achieved, date of first 
response, date of loss of response, reason for discontinuation. 
13.6 Off study evaluation: include vital status, date of death/last contact, 
transformation to AML and the date of transformation to AML if applicable. This  
evaluation will be updated every 6 month for 2 years. 
 
 


 
 
35 
Study Calendar 
 
Pre-
Study 
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
 
Weeks  
18-48 
(if response) 
Monthly 
visits 
Off-Study or 
continue 
if 
responding 
as 
per 
previous 
weeks 
Ruxolitiniba 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Physical exam 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Vital signs 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Performance 
Status 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Concurrent 
medication 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, 
plts, 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retic Count 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Serum 
chemistry b 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
INR, PT, and 
PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X-------------------------------------------------------------------------------------------------X 
Adverse events will be summarized and reported prior to each cycle. 
 
 
 
 
Bone marrow 
biopsy/aspirated
*** 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
B-HCG c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lab. Correlates 
e 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 


 
 
36 
Prior CMML 
Treatments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion 
Log 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Response 
Assessments 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Symptom Score 
Scale f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Off-treatment 
Assessment/Off
-Study Follow-
up/ CMML 
Summary Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
a.      Dose as assigned for cohort in phase 1, dose assigned as MTD in phase 2 
b:      Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, potassium, total protein,  
AST, ALT, sodium, and total bilirubin. 
c:      Serum or urine pregnancy test (women of childbearing potential).  
d:      in addition to specimen required for pathologic review, and additional aspirate will be collected (goal volume of 30cc) 
e:       in addition to specimen required for routine labs, 6 green top vials, 1 red top vial; on week 1, peripheral blood will be collected twice: at 
time of first dose, and 3 hours after first dose. 
f:        The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) using ERT’s DiaryPro done by the patient. Data upload and 
device maintenance will occur at each scheduled visit. 
 
Week 16 Evaluation and End of Treatment: Subjects will complete a response assessment within one week after their last administration of ruxolitinib.  Subjects discontinuing 
study early should complete their end of treatment visit within two weeks after their last dose of investigational product.  Physical exam, vital signs, concomitant medication, 
adverse event reporting, CBC, and blood chemistry and BM aspirate and biopsy with cytogenetic analysis will be performed.   
**Continuation Phase: After completing cycle 4 response assessments, HI-platelet responders may continue to receive ruxolitinib and the final week 16 dose in the absence of DLT 
or disease progression until marketing approval of ruxolitinib for CMML.  Bone marrow biopsy and aspirate will be repeated after every 4 cycles. A CBC will be obtained and 
complete metabolic profile as per standard of care. The off treatment assessment should be done within a week off treatment.  
*** For subjects who achieve CR, marrow CR, or PR a confirmation bone marrow aspirate and biopsy should be obtained 4 to 8 weeks after documentation of CR, marrow CR, or 
PR. 
Off Treatment assessment: includes best response, date of first response, date of loss of response, reason for discontinuation. 
Off study follow up: include vital status, date of death/last contact, transformation to AML and the date of transformation to AML if applicable. This evaluation will be updated 
every 6 month for 2 years. 
**** all dates are +/- one week 


 
 
37 
 
 
14 MEASUREMENT OF EFFECT 
 
Definitions: 
Response and progression will be assessed according to modified International Working 
Group (IWG) 2006 criteria23(Appendix B).  Improvements must last ≥ 8 weeks. 
o Erythroid Response for pretreatment hemoglobin < 11 g/dl: 
≥ 1.5 g/dL increase in hemoglobin. 
For transfused subjects having pre-transfusion baseline hemoglobin ≤ 9 
g/dL, a reduction of 4 or more RBC units in the previous 8 weeks 
compared with pretreatment. 
o Platelet response for subjects with a pre-treatment platelet count < 50 x 109/L: 
Major platelet response:  An absolute increase of ≥ 30 x 109/L.  If platelets are 
< 20 x 109/L at baseline, then a 100% increase will qualify as a major platelet 
response.  If subjects are transfusion dependent at baseline, platelet 
transfusion independence sustained for 8 consecutive weeks will qualify as a 
major platelet response. 
Complete platelet response:  increase of platelet count to ≥ 100 x 109/L for 8 
consecutive weeks. 
o Neutrophil response with pretreatment ANC < 1 x 109/L: 
≥ 100% increase and an absolute increase of > 0.5 x 109/L 
Progression/relapse following hematological improvement: At least one of the 
following: 
Any newly developed (RBC/platelet) transfusion dependence, 
≥ 50% decrease from maximum response levels in granulocytes or platelets, 
or 
Reduction of ≥ 1.5 g/dL hemoglobin. 
o Complete Response (CR) 
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell lines 
Persistent dysplasia will be noted 
Peripheral blood: 
Hemoglobin ≥ 11 g/dL 
Platelets ≥ 100 x 109/L 
Neutrophils ≥ 1.0 x 109/L 
BLASTS <0% 
o Partial Response (PR) 
All CR criteria if abnormal before treatment, except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
o Marrow Complete Response (mCR) 
Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment 
Peripheral blood:  if HI responses, they will be noted in addition to 
marrow CR 


 
 
38 
o Stable Disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 weeks 
 Duration of Response: 
The duration of response is measured from the time measurement criteria are met 
for major or complete platelet response (which ever is first recorded) until the first 
date that disease progression defined by the bone marrow response outlined 
above, progression/relapse following a CR, marrow CR or PR, or 
progressions/relapse following hematological improvement (HI) as outlined 
above. 
 
Pathologic Response: Pathologic response is categorized as a CR, mCR or a PR.  
Response parameters in the peripheral blood and/or bone marrow must be sustained for at 
least 4 weeks. See appendix B. 
 
Symptom Assessment in CMML 
Symptoms of CMML will be assessed using the MPN-SAF (see Appendix D). Subjects 
will be issued a hand-held device (eDiary) on which to record symptoms of CMML. The 
subject will be instructed to complete the eDiary each night beginning on Day -4 or 
earlier of the screening phase (eg, 4 days prior to Cycle 1 Day 1) through treatment 
discontinuation. Subjects will bring the device to the study site at each study visit so that 
the device charging can be verified and accumulated data can be downloaded, as 
applicable. The device will then be returned to the subject at these same visits for 
continued use each night. The subject will return the device and the docking station for 
the final time at the EOT visit so that the data can be archived. Detailed directions for the 
administration of the eDiary will be provided in the Study Reference Manual. 
 
15 STATISTICAL CONSIDERATIONS 
 
15.1 Study Design 
This is a phase 1/2, two-stage, sequential cohort dose escalation study. In phase 1, 
subjects will be allocated to dose levels starting at 10 mg/d (BID dosing) 
according to the “rolling six” phase I design (see Section 6.2 for the definition of 
DLT and the dose levels employed and Section 6.4 for the dose escalation 


 
 
39 
schema). Enrollment to the next dose level will be as per the dose escalation rules 
table (6.4.1). Subjects who do not complete the first cycles of protocol treatment 
and drop out of the trial due to any reason other than experiencing a DLT will 
have to be replaced in order to determine a proper MTD. Phase 1 will continue 
until MTD is reached. The Phase 2, two-stage, study will enroll a total of 29 
patients to determine overall best response at the MTD. 
15.2 Sample Size/Accrual Rate 
If dose escalation is completed as planned, no more than 53 subjects are expected 
to enroll onto this study at a rate of approximately 3 subjects every month. For the 
Phase 2 study the Simon’s optimal two-stage design will be employed to test the 
null hypothesis that response rate (RR) equals to 10% versus the alternative that 
RR equals to 30%. If the treatment is actually not effective, there is a 0.05 
probability of concluding that it is. If the drug is actually effective, there is a 0.19 
probability of concluding that it is not.   The probability of early terminating the 
trial at the end of first stage under the null is 0.74.  After testing the treatment 
dose on 10 patients in the first stage, the trial will be terminated if 1 or fewer 
desired respond. If the trial goes on to the second stage, a total of 29 patients will 
be studied. If the total number responding is less than or equal to 5, the drug is 
rejected. A samnple size of 29 from Phase 2 produces a two-sided 95% CI with a 
width equal to 0.38 (±19) when the sample proportion is 0.50 that is the maximum 
width for a CI with an given sample sizes. 
15.3  Statistical Analysis Methods 
Demographic and clinical variables for the study patients will be summarized 
using descriptive statistics (mean, standard deviation, median, inter-quartile range, 
range, and frequency counts and percentages). Safety and efficacy data will be 
analyzed overall as well as separately for each dose cohort when appropriate. 
15.4 Safety Analysis 
This analysis will include all subjects who have received any protocol treatment, 
regardless of patient eligibility. The number (%) of subjects with adverse events, 
serious adverse events, and adverse events leading to treatment discontinuation 
will be reported.  Adverse events summary will be reported by type and severity.  


 
 
40 
Laboratory parameters will also be summarized using descriptive statistics. The 
number and proportion of subjects with DLTs will be summarized.   
15.5 
Efficacy Analysis: ITT 
 
This analysis will include all subjects who have received any protocol treatment, 
regardless of patient eligibility or duration of treatment. Those who have no 
response assessment data due to reasons such as drop out of the study, withdrawal 
consent, or lost to follow-up will be treated as non-responders for various 
response evaluations. The proportion of subjects achieving a complete platelet 
response will be summarized.  A 95% exact binomial confidence interval of the 
proportion will also be provided for all participants treated at the MTD. In 
addition, a second analysis of evaluable subjects will be performed. Evaluable 
subjects are defined as those who complete at least 8 weeks of therapy an 
complete there first treatment bone marrow biopsy and aspirate to evaluate study 
drug response. 
15.6  Analyses of Secondary Endpoints 
Analyses of the following secondary endpoints will be performed as well: 
15.6.1 Acute myeloid leukemia (AML) transformation according to WHO criteria. 
15.6.2 Overall survival (OS). 
15.6.3 Duration of response. 
15.6.4 The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF) at 
baseline and at best response. 
15.6.5 >50% decrease in splenic length as measured by physical exam if applicable 
15.6.6 The suppression of pSTAT5 intracellular signaling after ruxolitinib in CMML 
subjects (pretreatment, at 1-2hr post treatment, cycle 2, cycle 4, and progression.)  
15.6.7 Determine number of colonies formed in the presence of GM-CSF and/or 
ruxolitinib (pretreatment and progression) as a future predictor of response. 
15.6.8 Mutational status in our CMML subjects by sanger sequencing of JAK2, c-CBL, 
N-RAS, K-RAS,RUNX-1, TET2, SRSF2, EZH2, ASXL1, and DNMT3a 
(pretreatment and progression). 
15.6.9 Mutational status of JAK2 tyrosine kinase at time of progression by deep 
sequencing of JAK2 to include M929I, Y931C, G935R, R938L, I960V, E985K. 


 
 
41 
(pretreatment and at progression) 
 
We recognize that this is mainly a phase I study with an extension phase at the MTD. 
However, preliminary data on the above endpoints will prove to be very useful for further 
investigation of this protocol’s treatment. Such data will be summarized appropriately 
focusing mostly on the subjects treated at the MTD dose in an exploratory fashion. Both 
point estimates and 95% confidence intervals will be reported, if feasible. Time-to-event 
endpoints such as OS will be summarized using the Kaplan-Meier product-limit method. 
16 Laboratory Correlates 
Unless otherwise specified, all laboratory correlates will be performed in the laboratory 
of P.K. Epling-Burnette under the direction of Drs Burnette and Padron. 
H.LEE MOFFITT CANCER CENTER 
CC: ERIC PADRON 
STABILE RESEARCH BUILDING 
SRB-2 
12902 MAGNOLIA DR TAMPA FL 33612 
16.1 Sample Collection 
At Screening and weeks 1, 5, 9,13, and 17 (see study calendar), peripheral blood 
will be collected.  Designated study personnel will collect the sample from the 
laboratory draw area. Peripheral blood will be collected in six green top 
(heparinized) 10cc tubes and one red top (clot activator or no additive) 10cc tube 
for a total of seven tubes and 70cc of peripheral blood. At the time of the first 
dose, peripheral blood will be collected twice: once at the time of the first dose (or 
up to one hour prior to the first dose) in six green top 10 cc tubes and one red top 
10 cc tube, and again three hours after the first dose (+/- 30 minutes) in six green 
top 10 cc tubes and one red top 10 cc tube, for a total of 14 tubes and 140cc of 
peripheral blood. At Screening and weeks 8 and 16 (see study calendar), bone 
marrow aspirate will be collected in three lavender (EDTA) 10cc tubes for a total 
of 30cc. These will be shipped to the H. Lee Moffitt Cancer Center laboratory as 
directed above within 24hrs and will be processed first by centrifugation (730 rcf 
for 5 minutes) to collect the supernatant (plasma from green top or lavender top; 


 
 
42 
serum from red top). Green top and lavender top samples will be additionally 
processed by centrifugation (530 rcf for 20 minutes) with density gradient 
medium to collect the mononuclear cellular layer, followed by the addition of 
RBC lysis buffer to remove RBCs and debris. The mononuclear cells will be 
cryopreserved as previously described and stored in liquid nitrogen for later use 
labeled with a unique identifier that corresponds to each patient known only to the 
investigator and study personnel. The plasma and serum will be cryopreserved for 
later use labeled with a unique identifier that corresponds to each patient known 
only to the investigator and study personnel. 
16.2 pSTAT5 as a pharmacodynamic marker for ruxolitinib. 
At the time of the first dose the subjects’ (may be up to one hour prior to first 
dose) peripheral blood will be collected, processed and stored as above. 
Peripheral blood will again be drawn three hours after the first dose (+/- 30 
minutes) and be collected, processed and stored as above. Peripheral blood will 
also be collected at the assigned time points (see study calendar) and processed as 
above. These samples will be batched for analysis after 10 samples have been 
processed and cryopreserved. They will be reconstituted in STEM span and 20% 
FBS in the laboratory of P.K. Epling-Burnette. pSTAT5 will be measured using 
phos-flow cytometry as previously described at baseline, after one hour of serum 
free condition, and then stimulated with 0.1, 1, and 10 ng/ml of GM-CSF. The in 
vitro efficacy of ruxolitinib will also be evaluated by the addition of increasing 
doses of ruxolitinib and measurement pSTAT5 as above. 
16.3 In vitro hematopoietic colony formation  
Bone marrow aspirates will be collected as per the study calendar (page 36). 
Mononuclear cells from frozen aspirate from CMML subjects will be plated in 
methylcellulose for 14 days. Experimental Conditions will include no cytokine, 
GM-CSF, and with or without increasing doses of ruxolitinib. Colonies will be 
counted after 14 day and experimental conditions will be compared to evaluate 
ruxolitinib efficacy. The colony formation assay described remains the gold 
standard for in vitro differentiation and proliferation experiments in hematopoetic 
precursors. Our laboratory has been able to plate previously frozen cells with 


 
 
43 
GM-CSF inhibitors and detect differences in colony numbers. The vast majority 
of colonies detected in our preliminary data are of the GM-CFU type with an 
occasional GEMM-CFU colony. Our colony “read out” is defined as any 
hematopoietic cluster of greater than 50 cells regardless of morphology. It is 
anticipated that ruxolitinib will decrease colony formation in a dose dependent 
fashion and perhaps predict for in vivo efficacy. 
16.4 
Genomic Studies 
Using portion of cryopreserved bone marrow aspirates, 100ug of DNA will be 
isolated as previously described. Next, a comprehensive sequencing of subjects by 
NextGen sequencing of JAK2, c-CBL, N-RAS, K-RAS, RUNX-1, TET2, SRSF2, 
EZH2, ASXL1, and DNMT3a will be done in with pretreatment samples and end 
of study or progression. The isolated DNA will be sent to the laboratory of Dr. 
Omar Abdel-Waheb located on the campus of Memorial Sloan Kettering Cancer 
Center. Dr Abdel-Waheb has is a nationally recognized expert in the genomics of 
myeloid malignancies and has sequenced many patients for this comprehensive 
panel of gene mutations. 
16.5 JAK2 mutations as a mechanism of Ruxolitinib resistance 
Mutational status of JAK2 tyrosine kinase at time of progression by deep 
sequencing of JAK2 at pretreatment and at progression to include M929I, Y931C, 
G935R, R938L, I960V, E985K. Emerging reports have suggested mutations in 
JAK2 that may confer resistance to ruxolitinib. We will use samples from subjects 
taken at the above time, isolate DNA as previously described and amplify the 
JAK2 transcript by PCR. Next, gel extraction will be done and the entire JAK2 
coding region will be sequenced at the H. Lee Moffitt Cancer Center molecular 
genomics core. 
 
17 REGULATORY CONSIDERATIONS 
This research will be done in compliance with the applicable State and Federal laws and 
regulations and in compliance with ICH guidelines. The study description will be posted on 
the www.clinicaltrials.gov website in compliance with current regulations. The data and 
safety plan will be executed in accordance with ICH guidelines and in compliance with 
policy and procedures at the H. Lee Moffitt Cancer Center and Research Institute. The 


 
 
44 
following must be observed to comply with Food and Drug Administration regulations for 
the conduct and monitoring of clinical investigations; they also represent sound research 
practice: 
17.1 Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from 
Research Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 
CFR 46).  They must be followed to comply with FDA regulations for the conduct and 
monitoring of clinical investigations. 
17.2 Use of Specimens For Research 
The patient is free at any time in the future to decide not to provide specimens or to withdraw 
his/her specimens from further scientific research.  Such a decision will have UnoU impact 
on his/her treatment or other aspects of participation in this study. 
17.3 Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 
56) and the Office for Protection from Research Risks Reports:  Protection of Human 
Subjects (Code of Federal Regulations 45 CFR 46). 
17.4 Drug Accountability 
For each drug supplied for a study, an accountability ledger containing current and accurate 
inventory records covering receipt, dispensing, and the return of study drug supplies must be 
maintained.  Drug supplies must be kept in a secure, limited access storage area under the 
recommended storage conditions.  During the course of the study, the following information 
must be noted on the accountability ledger; the identification code of the subject to whom 
drug is dispensed, the date(s) and quantity of drug dispensed to the subject, and the date(s) 
and quantity of drug returned by the subject; subjects should return empty containers to the 
investigator, with the return noted on the ledger.  These Accountability Forms must be 
readily available for inspection and are open to FDA inspection at any time. 
17.5 RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 


 
 
45 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after marketing 
application approval.  If no application is filed, these records must be kept 2 years 
after the study is discontinued and the U.S. FDA and the applicable national and local 
health authorities are notified.   
17.6 Study Monitoring:  
As part of the responsibilities assumed by participating in the study, the Investigator 
agrees to maintain and have available for monitoring adequate case records (accurate 
source documents and CRFs) for the subjects treated under this protocol. In addition, 
the Investigator agrees to maintain all administrative documents, eg, IRB/IEC 
correspondence, investigational product and supplies shipment manifests, monitoring 
logs, or Moffitt Cancer Center/designee correspondence. The PI will be primarily 
responsible for monitoring of adverse events, protocol violations, and other 
immediate protocol issues.  The study coordinator will collect information of subjects 
enrolled at Moffitt and other institutions through the use of electronic or paper AE 
forms, CRF forms, End of Study forms, and Informed Consent forms.  
 
Internal Monitoring 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. The Case Report Forms 
will be reviewed by Moffitt’s Internal Monitors, periodically, throughout the conduct of the 
trial. The monitoring will include source data verification, utilizing research subjects’ medical 
records. 
 
On-site Audits 
The Investigator should promptly notify Moffitt Cancer Center or its authorized 
representative of any audits scheduled by any regulatory authorities and promptly 
forward copies of any audit reports received to Moffitt Cancer Center or its 
authorized representative. 
Data & Safety Monitoring Plan 
Identification of oversight responsibility:  
The PI has primary responsibility. 
The MCC Protocol Monitoring Committee (PMC);  
The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse 


 
 
46 
events, protocol violations and when applicable, internal audit results.  
Description of internal (PI) safety review and monitoring process: 
Responsible for identifying and reviewing adverse events biweekly: 
Principal Investigator  
Study team 
To be reviewed:  
Adverse events by grade (Gr. 3 or above using CTCAE v4.0) and attribution 
(expected or unexpected)  
Relationship to study drug/intervention  
Application of dose finding escalation/de-escalation rules  
Application of study designed stopping/decision rules  
Whether the study accrual pattern warrants continuation/action  
Protocol violations 
AEs will be reported along with all other data in the Oncore database. The PI or PI 
designate will report all adverse events to the Clinical Research Office (CRO). The 
CRO will report all SAEs to INCYTE, and all reportable SAEs to the IRB.   AE 
information will be entered into the CRO database. AE information will be managed 
by the CRO and will be made available to the PMC or appropriate monitoring body 
by designated members of the PMC or the study statisticians.  
 
 
 
 
 
18 REFERENCES 
 
1. 
Emanuel PD. Juvenile myelomonocytic leukemia and chronic myelomonocytic 
leukemia. Leukemia. 2008;22(7):1335-1342. 
2. 
Vardiman J, Harris N, Brunning R. The World Health Organization (WHO) 
classification of the myeloid neoplasms. Blood. 2002;100(7):2292. 
3. 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale 
and important changes. Blood. 2009;114(5):937-951. 
4. 
Emanuel P, Bates L, Castleberry R, Gualtieri R, Zuckerman K. Selective 
hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic 
myeloid leukemia hematopoietic progenitors. Blood. 1991;77(5):925. 
5. 
Kohlmann A, Grossmann V, Klein H-U, et al. Next-generation sequencing 


 
 
47 
technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic 
myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and 
RUNX1. Journal of Clinical Oncology. 2010;28(24):3858-3865. 
6. 
Jankowska AM, Makishima H, Tiu RV, et al. Mutational spectrum analysis of 
chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: 
UTX, EZH2, and DNMT3A. Blood. 2011;118(14):3932-3941. 
7. 
Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the 
acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 
1976;33(4):451-458. 
8. 
Fenaux P, Mufti G, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared 
with that of conventional care regimens in the treatment of higher-risk myelodysplastic 
syndromes: a randomised, open-label, phase III study. The Lancet Oncology. 
2009;10(3):223-232. 
9. 
Costa R, Abdulhaq H, Haq B, et al. Activity of azacitidine in chronic 
myelomonocytic leukemia. Cancer. 2010. 
10. 
Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic 
syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, 
using data from the NAACCR and SEER programs. Blood. 2008;112(1):45-52. 
11. 
Lim Z, Brand R, Martino R, et al. Allogeneic Hematopoietic Stem-Cell 
Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or 
Secondary Acute Myeloid Leukemia. Journal of Clinical Oncology. 2010;28(3):405-411. 
12. 
Ramshaw H, Bardy P, Lee M. Chronic myelomonocytic leukemia requires 
granulocyte-macrophage colony-stimulating factor for growth in vitro and in vivo. 
Experimental …. 2002. 
13. 
Kotecha N, Flores N, Irish J, et al. Single-cell profiling identifies aberrant STAT5 
activation in myeloid malignancies with specific clinical and biologic correlates. Cancer 
Cell. 2008;14(4):335-343. 
14. 
Padron E, Painter JS, Mailloux AW, et al. GM-CSF Signaling Abnormalities in 
Chronic Myelomonocytic Leukemia. ASH Annual Meeting Abstracts. 
2011;118(21):1713-. 
15. 
Quintas-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the 
selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of 
myeloproliferative neoplasms. Blood. 2010;115(15):3109-3117. 
16. 
INCYTE. Ruxolitinib Investigator's Broshure. 2012. 
17. 
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial 
of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. 
18. 
Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus 
best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. 
19. 
Frankel AE, Lilly M, Kreitman R, et al. Diphtheria toxin fused to granulocyte-
macrophage colony-stimulating factor is toxic to blasts from patients with juvenile 
myelomonocytic leukemia and chronic myelomonocytic leukemia. Blood. 
1998;92(11):4279-4286. 
20. 
Frankel A, Powell B, Hall P, Case L, Kreitman R. Phase I trial of a novel 
diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein 
(DT388GMCSF) for refractory or relapsed acute myeloid leukemia. Clinical cancer 
research. 2002;8(5):1004. 


 
 
48 
21. 
Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through 
a variety of cytokine receptors. Cell. 1998;93(3):385-395. 
22. 
Eghtedar A, Verstovsek S, Estrov Z, et al. Phase II study of the JAK kinase 
inhibitor ruxolitinib in patients with refractory leukemias, including post 
myeloproliferative neoplasms (MPN) acute myeloid leukemia (AML). Blood. 2012. 
23. 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal 
for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood. 2006;108(2):419-425. 
 


 
 
49 
  
19  APPENDIX A 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 


 
 
50 
 
20 APPENDIX B 
 
RESPONSE CRITERIA FOR SUBJECTS WITH CMML ACCORDING IWG 2006 
CRITERIA 
 
 
ALTERING DISEASE NATURAL HISTORY 
Complete remission (CR) 
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell lines 
Persistent dysplasia will be noted 
Peripheral blood: 
Hemoglobin ≥ 11 g/dL 
Platelets ≥ 100 x 109/L 
Neutrophils ≥ 1.0 x 109/L 
Blasts 0% 
Partial remission (PR) 
All CR criteria if abnormal before treatment, except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CR 
Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment 
Peripheral blood:  if HI responses, they will be noted in addition to marrow CR 
Stable disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 weeks 
Failure 
Death during treatment 
Disease progression characterized by worsening of cytopenias, increase in % of 
bone marrow blasts, or progression to a more advanced MDS FAB subtype than 
pretreatment 
Disease Progression (PD) 
For subjects with: 
Less than 5% blasts:  ≥ 50% increase in blasts to > 5% 
blasts 
5%-10% blasts:  ≥ 50% increase in blasts to > 10% blasts 
10%-20% blasts:  ≥ 50% increase in blasts to > 20% 
blasts 
20%-30% blasts:  ≥ 50% increase in blasts to > 30% 
blasts 
Any of the following: 
At least 50% decrement from maximum 
remission/response levels in granulocytes or platelets 
Reduction in hemoglobin (Hgb) concentration by ≥ 2 g/dL  
- Transfusion dependence 
CYTOGENETIC RESPONSE 
Complete 
Disappearance of the chromosomal abnormality without appearance of new ones 
Partial 
At least 50% reduction of the chromosomal abnormality 
HEMATOLOGICAL IMPROVEMENT (HI) 
Erythroid response (HI-E) 
(Pretreatment < 11 g/dL)  
Hgb increase by ≥ 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion 
number in the previous 8 weeks.  Only RBC transfusions given for a Hgb of ≤ 
9.0 g/dL pretreatment will count in the RBC transfusion evaluation 
Platelet response (HI-P) 
(Pretreatment < 100 x 109/L) 
Absolute increase of ≥ 30 x 109/L for subjects starting with > 20 x 109/L 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
Neutrophil response (HI-N) 
(Pretreatment < 1.0 x 109/L) 
At least 100% increase and an absolute increase of > 0.5 x 109/L 
 


 
 
51 
PROGRESSION/RELAPSE CRITERIA FOR SUBJECTS WITH CMML  
ALTERING DISEASE NATURAL HISTORY 
Disease Progression (PD) 
For subjects with: 
Less than 5% blasts:  ≥ 50% increase in blasts to > 
5% blasts 
5%-10% blasts:  ≥ 50% increase in blasts to > 10% 
blasts 
10%-20% blasts:  ≥ 50% increase in blasts to > 20% 
blasts 
20%-30% blasts:  ≥ 50% increase in blasts to > 30% 
blasts 
Any of the following: 
At least 50% decrement from maximum 
remission/response levels in granulocytes or 
platelets 
Reduction in hemoglobin (Hgb) concentration by ≥ 
2 g/dL  
                            Transfusion dependence 
Disease transformation 
Transformation to AML (30% or more blasts) 
Relapse after CR or PR 
At least one of the following: 
Return to pretreatment bone marrow blast % 
Decrement of ≥ 50% from maximum 
remission/response levels in granulocytes or 
platelets 
- Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion 
dependence 
HEMATOLOGICAL IMPROVEMENT 
Progression/relapse after HI  
At least one of the following: 
At least 50% decrement from maximum response 
levels in granulocytes or platelets  
Reduction in Hgb by ≥ 1.5 g/dL 
- Transfusion dependence 
 


 
 
52 
 
21 APPENDIX C: CYP3A4 Strong Inhibitors 
 
  
 HIV Antivirals: 
-indinavir 
-boceprevir 
-lopinavir/ritonavir 
-ritonavir 
-telaprevir 
-nelfinavir 
-saquinavir 
 
Others: 
-clarithromycin 
-conivaptan 
-grapefruit juice 
-mibefradil 
-posaconazole 
-voriconazole 
-itraconazole 
-ketoconazole 
-nefazodone 
-telithromycin 
 
 
* Dose reductions as in section 7 are required for strong inhibitors of the CYP3A4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
53 
22 APPENDIX D: Myeloproliferative Neoplasms-Symptom Assesment Form 
(MPN-SAF) 
 
 
 
 
 
 
 
 
 
 


 
 
54 
 


 
 
55 
 
23 APPENDIX E: WHO CLASSIFICATION FOR CMML  
 
 
WHO Subtype 
Peripheral Blood 
Bone Marrow 
Chronic Myelomonocytic Leukemia 
*CMML-1 
                              **CMML-2 
 
*<5 percent blasts 
**<19 percent blasts 
persistant monocytosis >1000/ul 
+/- cytopenias 
Leukocytosis frequent  
*<10% myeloblast 
**<19 percent blasts 
>10% dysplasia in 
affected lineage 
**Auer Rods 
The absence of the 
Philadelphia 
chromosome of bcr-abl 
fusion gene.