A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib for the Treatment of Chronic Myelomonocytic Leukemia (CMML): A Phase 2 Expansion
Phase: PHASE2
Conditions: Chronic Myelomonocytic Leukemia, Leukemia
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
 
A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and 
Efficacy of Ruxolitinib for the treatment of Chronic Myelomonocytic Leukemia 
(CMML): A Phase 2 Expansion 
 
NCT03722407 
 
 
Version 5 
August 20, 2020 

1 
 
Funding: 
INCYTE 
*Principal Investigator: 
Eric Padron, MD 
Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
Telephone: 813-745-8264 
e-mail address: Eric.Padron@moffitt.org 
SubInvestigators 
Rami Komrokji, MD 
Jeffrey E Lancet, MD 
Kendra Sweet, MD 
Bijal Shah, MD 
David Sallman, MD 
Chetasi Talati, MD 
Andrew Kuykendall, MD 
Timothy Kubal, MD 
MCC 19727 Study Title: A Sequential Two-Stage Dose Escalation 
Study to Evaluate the Safety and Efficacy of Ruxolitinib for the treatment 
of Chronic Myelomonocytic Leukemia (CMML): A Phase 2 Expansion. 
 
 
Sponsor: 
Moffitt Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
Quincy Mo, PhD 
Previous Version: 
4 
Date: 
01/30/2020 
Version: 
5 
Date: 
08/20/2020 

2 
 
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): A Phase 2 Expansion. 
 
Study 
Objectives 
P
UPrimary Objectives: 
1. 
To determine overall response rates as measured by the international working group 
MDS/MPN criteria. 
S
USecondary  Objectives: 
1. 
To determine the time to AML transformation of patients on ruxolitinib. 
2. 
To determine the median overall survival. 
3. 
To determine the duration of response achieved as in secondary endpoint one. 
4. 
To determine the change in symptom score from baseline to week 16. 
5. 
To determine the change in spleen volume at 16 weeks. 
6. 
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. 
7. 
To determine if a correlation exists between inflammatory cytokine secretion in the 
peripheral blood and response to ruxolitinib in CMML patients. 
Study 
Endpoints 
P
U  Primary: 
1. 
Proportion of subject achieving clinical benefit defined as hematologic 
improvement, complete remission, partial remission, or stable disease by the 
IWG MDS/MPN criteria at week 16 
S
U  :econdary 
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 
TSS Total Symptom Score at baseline and at week 16. 
5. 
>35% decrease in splenic volume as measured by CT Scan if applicable 
6. 
Mutational status in our CMML patients by sanger sequencing of JAK2, c-CBL, 
N-RAS, K-RAS, RUNX-1, TET2, SRSF2, EZH2, ASXL1, and DNMT3a 
(pretreatment and progression). 
7. 
Changes in cytokine secretion of peripheral blood at baseline and week 16 as 
previously described1. 

3 
 
 
Eligibility 
Criteria 
Inclusion Criteria: 
1. 
Confirmed diagnosis of CMML using the World Health Organization (WHO) 
classification (appendix D). 
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. 
Patients 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 have a negative pregnancy test at time of screening 
and baseline visits and 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. 
9. 
Must have symptomatic splenomegaly and/or an MPN-SAF TSS>17. 
E
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 patients. 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. 
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 TSS). 
d. Concurrent medication review. 
2. Routine physical examination to include vital signs, height and weight. 

4 
 
 
3. Bone marrow examination, including cytomorphology, cytogenetic assessment, 
and flow cytometry analysis. 
4. Laboratoryassessments: 
• 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, calcium, chloride, glucose, sodium, 
potassium, bicarbonate, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, total protein, LDH, and 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. 
5. Review and record any blood and blood supportive care products for the prior 8 weeks. 
6. CT scan of the abdomen to measure splenic volume. 
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. . 
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). Patients will 
not take the morning dose of ruxolitinib at the first regularly scheduled visit.. On all other days 
corresponding to study visits, patients 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. 
Patients will also be instructed to take ruxolitinib without respect to food, as previous data 
demonstrate no change in drug kinetics or absorption. All patients will be given 40 mg/day 
divided in equal BID doses. A maximum of 29 patients will be treated at the MTD identified in 
phase I of 20mg BID. See study calendar for assessment on study. 
Dose 
delay/modif 
-ications 
Dose delays/modifications are allowed for those patients enrolled in phase II as described in 
section 6. 
Duration of 
Therapy 
Patients will be treated for a total of 16 weeks. For patients responding at week 16, treatment may 
continue until one of the following criteria applies: 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Unacceptable adverse event(s). 
• 
Patient decides to withdraw from the study. 
• 
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 MDS/MPN criteria. 
Duration of 
Follow-Up 
Patients will be followed as per calendar on treatment for 17 weeks. After 17 weeks, patients 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. Patients removed 
from the study for unacceptable adverse events will be followed until resolution or stabilization of 
the adverse event. 
C
UCriteria for Removal from Study 
Study drug treatment can continue for patients receiving clinical benefit per IWG criteria, unless: 
one or more withdrawal criteria are met, or at the subject’s discretion, or if the study is 
terminated. 
*Subject Completion 

5 
 
 
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 experienced an adverse event (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/ 
*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. 
T
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 MDS/MPN criteria. 
• 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 
S
UStudy Design: 
This will be a two stage Simon’s phase 2 design. After testing the treatment dose on 10 patients in 
the first stage, the trial will be terminated if 1 or fewer achieve a clinical benefit. 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 
The first phase of the stage II will recruit 10 patients at 20mg BID ruxolitinib. If more than 1 
response are seen by 17 weeks on ruxolitinib, then a total of 29 patients will be accrued at 20mg 
BID to determine efficacy. 
Laboratory 
Correlates 
Phases 1 and 2 
Peripheral blood and Bone Marrow Aspirate will be collected and processed in the lab of Eric 
Padron in the Stabile Research Building (SRB) at the Moffitt Cancer and Research Institute as 
described in section 16. 

6 
 
 
 
1 OBJECTIVES 
 
1.1 
Primary Objective: 
To determine overall response rates as measured by the international working 
group MDS/MPN criteria. 
1.2 
Secondary Objectives: 
1.2.1 To determine the time to AML transformation of patients 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 week 16. 
1.2.5 To determine the change in spleen volume at 16 weeks. 
 
1.2.6 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. 
 
1.2.7 To determine if a correlation exists between inflammatory cytokine secretion in 
the peripheral blood and response to ruxolitinib in CMML patients. 
 
 
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 leukemia2. Prior to 
2001, the World Health Organization (WHO) classified CMML as a subtype of the 
myelodysplastic syndromes (MDS)3. 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 
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)4. JMML is a 

7 
 
lethal pediatric malignancy with clinical features similar to CMML and hallmarked 
by selective hypersensitivity to GM-CSF5. The reclassification of CMML has been 
substantiated by next generation sequencing techniques that have allowed for the 
massive genetic sequencing of myeloid malignancies6,7. 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 patients can display the predominant 
features of an MDS-like or MPN-like disease. The French-American-British (FAB) 
group was first to subdivide CMML patients into an MDS variant and MPN variant 
based on a white blood cell (WBC) count greater than 20K/dL8. The WHO later 
favored subdivisions based on a myeloblast percentage greater than 10% in the bone 
marrow aspirate because of its prognostic value4. 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 patients 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 patients9. 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 
myeloproliferative variant appears to be have response rates on the order of 10- 
15%10. 
 
Chronic Myelomonocytic Leukemia (CMML) is a rare disease with an incidence of 

8 
 
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- 
azacitidine11. Allogeneic stem cell transplant (ASCT) remains the only potential 
curative therapy. However, most patients 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 patients alive at 
5 years12. 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 patients 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 decade5. 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 
proliferation13. In the next study, Kotecha and colleges explored the downstream 
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. 

9 
 
This phenomenon was not seen in normal controls or other pediatric MPNs but was 
seen in five CMML patient samples14. 
 
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)15. 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 patients. 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 patients6. 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 
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 malignancies16. 

10 
 
Safety 
During the Phase I and Phase II development program, ruxolitinib was assessed in 
healthy volunteers, patients with various degrees of renal or hepatic impairment, in 
patients with rheumatoid arthritis, prostate cancer, multiple myeloma, myelofibrosis 
(MF), polycythemia vera (PV) and essential thrombocythemia (ET). The aggregate 
safety database for ruxolitinib included 679 patients 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 
patients). 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 patients 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 patients. There was no 
indication of a QT/QTc prolonging effect of ruxolitinib in single doses up that 
exceeded those proposed in this study17. 
Efficacy 
In two large phase 3 clinical trials, ruxolitinib has demonstrated efficacy in patients 
with high-risk myelofibrosis. The first trial randomly assigned patients to receive 

11 
 
15mg twice daily of ruxolitinib (155 patients) or placebo (154 patients). The primary 
endpoint of the study was defined as the proportion of patients 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 patients 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 patients 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 myelofibrosis specific quality-of-life scoring system, at 24 weeks in 45.9% of 
patients who received ruxolitinib as compared with 5.3% of patients who received 
placebo (P<0.001)18. The second trial randomly assigned patients to the same dose of 
ruxolitinib or best available therapy (BAT) defined by the treating physician. The 
primary end point was the percentage of patients with at least a 35% reduction in 
spleen volume at week 48 by MRI or computed tomography. A total of 28% of the 
patients 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 patients still having a response at a median follow-up of 12 
months19. 
 
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 
cytokinepleotropy, 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 16/20 patient samples tested20. 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 escalation21. 

12 
 
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 signaling22. 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 patients 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 
patients were enrolled to take BID ruxolitinib (dose not available). It is reported that 
2/4 CMML patients demonstrated some degree of clinical benefit23. 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. 
2.5 
A phase 1/2 clinical study of ruxolitinib in CMML 
We have performed a phase 1/2 study of ruxolitinib in CMML. This study included 
any patient with a WHO diagnosis of CMML irrespective of therapy. This phase 1 
study identified 20mg PO BID as the maximally tolerated dose of ruxoltinib in 
CMML and accrued 20 patients24. This study demonstrated broad range activity 
that was enriched in patients with splenomegaly and disease related symptoms. 
This was confirmed in the phase 2 study which accrued 29 patients and has 
presented in abstract form. Therefore, this phase 2 expansion will explore efficacy 
in only those CMML patients with either symptomatic splenomegaly and/or disease 
related symptoms defined by a Total Symptom Score of >17. 

13 
 
3 STUDY ENDPOINTS 
3.1 
Primary 
3.1.1 Proportion of subject achieving clinical benefit defined as hematologic 
improvement, complete remission, partial remission, or stable disease by the 
IWG MDS/MPN criteria at week 16 (see section 14) 
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 TSS) 
Total Symptom Score at baseline and at week 16. 
3.2.5 >35% decrease in splenic volume as measured by CT Scan if applicable 
3.2.6 Mutational status in our CMML patients by sanger sequencing of JAK2, c-CBL, 
N-RAS, K-RAS, RUNX-1, TET2, SRSF2, EZH2, ASXL1, and DNMT3a 
(pretreatment and progression). 
3.2.7 Changes in cytokine secretion of peripheral blood at baseline and week 16 as 
previously described1. 
 
4 PATIENT SELECTION / Eligibility Criteria 
4.1 
Inclusion criteria 
4.1.1 Confirmed diagnosis of CMML using the World Health Organization (WHO) 
classification (appendix D). 
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 Patients 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 

14 
 
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). 
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. 
4.1.9 Must have symptomatic splenomegaly and/or an MPN-SAF TSS >17. 
 
 
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. 

15 
 
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 patients. 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. 
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 2, Simon’s two stage design. A total of 10 patients will be treated 
during the first stage of phase 2 (stage 1) at 20mg BID. The trial 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 
All patients will self-administer ruxolitinib twice daily, 12 hours apart as an 
outpatient. On all days corresponding to study visits, patients 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). 
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 

16 
 
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). 
 
 
6.2 
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 (e.g., 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. 
6.3 
Permitted Medications 
6.3.1.1 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. Patients 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 patients with severe neutropenia and recurrent infections. Patients 
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. 
6.3.1.2 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). 
6.3.1.3 Aspirin 

17 
 
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. 
6.3.1.4 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. 
6.3.1.5 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 
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. 
 
6.4 
Prohibited Medications 
Patients 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 suggests 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. 

18 
 
7 Duration of Therapy 
Patients will be treated for a total of 16 weeks.  For patients responding at week 16, 
treatment may continue until one of the following criteria applies: 
7.1 
Inter-current illness that prevents further administration of treatment, 
7.2 
Unacceptable adverse event(s), 
7.3 
Patient decides to withdraw from the study, or 
7.4 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
7.5 
Evidence of disease progression by the IWG MDS/MPN criteria. 
 
8 Duration of Follow-Up 
 
Patients 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. Patients 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 experienced an AE that lead to withdrawal from the study. 
9.2 
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. 
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 

19 
 
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. 
• The study is terminated. 
• The subject becomes pregnant 
• The patients 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 MDS/MPN criteria. 
• 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. 
*Patients withdrawing from study can be tapered off of ruxolitinib over a 4 week period 
at the discretion of the investigator* 
10 DOSING DELAYS/MODIFICATIONS 
All patients 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 

20 
 
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 
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 
patients who discontinue from the study in order to determine overall survival and 
leukemia free survival. Investigators will contact patients every 6 months to 
determine if patients have undergone leukemic transformation, or death, and for the 
latter, the cause of death. 
10.2 Dose Adjustments in Ruxolitinib Tablets for Safety: 
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 patients 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 patients 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 

21 
 
then ruxolitinib must be discontinued with no potential for restart. The objective for 
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. 
 
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 B), plasma 
exposure of ruxolitinib increases approximately 2-fold. Thus, a dose reduction of ~ 
50% for ruxolitinib is appropriate for patients 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. 
10.3 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 weeks 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. 

22 
 
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 serious adverse event (SAE). 
To ensure patient safety, each SAE must be reported to the coordinating site and to Incyte 
(SafetyReporting@incyte.com) on the Incyte form provided within 24 hours of being 
made aware of the event. Moffitt Cancer Center and all participating sites will report 
SAEs by completing an SAE report in OnCore, the electronic data capture system. The 
SAE must be reported by email (affiliate.research@moffitt.org) to the External Site 
Coordination (ESC) office within 24 hrs. If applicable, the site should also follow 
protocol guidelines for additional reporting to government agencies. 
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: 

23 
 
• 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. 
• 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 

24 
 
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. 
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 

25 
 
investigator or treating physician.  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 
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 SafetyReporting@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 pharmacovigilance 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 patients 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 

26 
 
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 
contact. All SAEs will be reported to INCYTE SafetyReporting@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 SafetyReporing@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 

27 
 
Prompt notification of SAEs by the investigator to the FDA (and INCYTE 
SafetyReporting@incyte.com) is essential so that legal obligations and ethical 
responsibilities towards the safety of patients 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 
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 counts 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 patients 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 

28 
 
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. Patients must have a bone marrow biopsy and aspirate (including 
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. 
13.1 Baseline Assessment: within 4 weeks of starting treatment 
• Medical history including: 
o Disease characteristics such as date of diagnosis of CMML, WHO/FAB 
subtype, IPSS score, MD Anderson Scoring System (MDASC), prior 
treatments. 
o ECOG performance status. 
• Concurrent medication review. 
• Red blood cell and platelets transfusion past 8 weeks. 
• Routine physical examination to include vital signs, height and weight. 
• Bone marrow examination, including cytomorphology, cytogenetic assessment, 
and flow cytometry analysis. Possibly include NGS myeloid panel (it is not 
considered a deviation if cytogenetic, flow cytometry and NGS myeloid panel is not 
completed). 
• Laboratory assessments: 
o Hematology to include platelet count, hemoglobin, hematocrit, white blood 
cells (WBC) and WBC differential (including: neutrophils, eosinophils, 

29 
 
basophils, lymphocytes and monocytes), INR, PT, and PTT and reticulocyte 
count. 
o Clinical chemistries including BUN/urea, creatinine, chloride, sodium, 
potassium, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, bicarbonate, calcium, chloride, 
glucose, LDH, total protein, and 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 study medication. 
•Symptom Score using the Myeloproliferative Neoplasms Symptom Assessment 
Form (MPN-SAF). (See Appendix C). 
• CT scan of the abdomen to evaluate spleen volume. 
•Review and record any blood and blood supportive care products for the prior 8 
weeks. 
Re-screening  
Bone marrow biopsy and CT scan of the abdomen may not need to be repeated for a 
re-screening process if they are completed within 3 months from the time of 
consenting on the study. Although, all the other procedures including labs, 
Myeloproliferative Neoplasms Symptom Assessments, research labs (research lab 
exclude aspirate) will be performed during the re-screening process within 4 weeks 
prior to the start of the study treatment. 
Patient can be re-screened and start the first day of treatment on the same day if 
patient meets the eligibility criteria on the study. 
13.2 Treatment Period (weeks 1-16): 
13.2.1 
Ruxolitinib will be administered as a twice daily oral dose for a 4-week 
treatment cycle.  Patients will have a CBC with leukocyte differential performed 
weekly for the first 16 weeks. Serum chemistry will be performed weekly for 
first 4 weeks and then every 2 weeks through week 16. A BM aspirate and biopsy 
with cytogenetic analysis will be performed after cycle 2 and 4 (at the end of 
week8 and week16) to assess pathologic response, cytogenetic response and 
disease progression. For patients 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. 

30 
 
13.3 End of C4/ Week 16 Response Assessment: Patients will complete a response 
assessment (see Section 14) within one week after their last administration of 
ruxolitinib. . Physical exam, vital signs, concomitant medication, adverse event 
reporting, CBC, CT scan of the abdomen, serum 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. Bone marrow biopsy and aspirate will be 

31 
 
repeated after every 6 cycles (For patients who achieve CR, marrow CR, or PR a 
confirmation a one-time 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 End of Treatment assessment 
should be done within a week off treatment. 
13.5 
End Of Treatment: Patients discontinuing study early or any time after 
completing End of C4/Week 16 Response Assessment visit 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, 
CT scan of the abdomen, blood chemistry and BM aspirate and biopsy with 
cytogenetic analysis will be performed during the end of treatment visit. CT scan 
abdomen and BM aspirate and biopsy during EOT can be performed at the discretion 
of Coordinating Center PI. 
13.6 Off Treatment assessment: includes best response achieved, date of first 
response, date of loss of response, reason for discontinuation. 
13.7 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. 

 
Study 
Calendar 
Pre- 
Stu 
dy 
C1/ 
Wk 
1 
Wk 
2 
W 
k 
3 
Wk 
4 
C2/ 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
C3/ 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
C4/ 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
End of 
C4 
Respons 
e 
Assessm 
net 
Biweekly 
(every 
2 
weeks, after 
End  of  C4 
response 
assessmemt 
) 
Continuatio 
n 
Phase- 
Every        4 
weeks 
(if response) 
Off- 
Study or 
EOT- 
Ruxolitinib 
Dispensea 
X 
X 
X 
X 
X 
Xa1 
Informed 
consent 
X 
Demographics 
X 
Medical history 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
to include 
spleen 
assessment 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Height i 
X 
Weight 
X 
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 
X 
Retic Count 
X 
X 
X 
X 
X 
Serum 
chemistry b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X b1 
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 
X 
 
X 
X 

 
 
 
biopsy/aspirated 
*** 
B-HCG c 
X 
Lab. Correlates 
e 
X 
X 
X 
X 
X 
Prior CMML 
Treatments 
X 
CT scan 
Abdomenh 
X 
X 
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 
Off-treatment 
Assessment/Off 
-Study Follow- 
up/ CMML 
Summary Form 
X 
X 
a. Dose as assigned for cohort in phase 1, dose assigned as MTD in phase 2. Ruxolitinib dispensing will take place on day 1 of each 4 week cycle. 
Any lost study drug may be re-dispensed as needed. 
b. Albumin, alkaline phosphatase, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, potassium, total protein, AST, ALT, sodium, 
and total bilirubin. 
b1. Biweekly Serum chemistry is optional after the completion of End of C4 Response Assessment; however, it is mandatory to complete serum chemistry 
every cycle (monthly serum chemistry is required on the study protocol). 
c. Serum or urine pregnancy test (if women of childbearing potential). 
d. In addition to specimen required for pathologic review, and additional aspirate will be collected (goal volume of 30cc). BM biopsy will occur at 
screening, end of Week 8, and Week 16. Week 8 and Week 16 BM biopsies have a window of +/- 14 days. In the event patient has CR or PR see 
Section 13.2.1 for additional one time BM biopsy. 
e. In addition to specimen required for routine labs, 6 green top vials, 1 red top vial. 
f. The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF TSS) using ERT’s DiaryPro done by the patient. Data upload and 
device maintenance will occur at each scheduled visit through Week 16. Patient cannot be enrolled on the study protocol without ERT’s 
DiaryPro registration.  No waiver on the ERT handheld device will be given in any circumstances. 
g. BM aspirate and biopsy includes mutational panel should be performed every 6 cycles (window of +/- 14days) after completion of week 16 on 
the treatment. 

 
 
 
h. CT scan abdomen may be completed with/without contrast. 
i. Height is preferred to be recorded as a baseline; however, missing height during the screening process will not be a deviation on the study protocol.  
 
 
*End of C4/ Week 16 Response Assessmnet and End of Treatment: Patients will complete a response assessment within one week after their last administration of ruxolitinib. 
Patients 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 serum 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. Bone marrow biopsy and aspirate will be repeated after every 6 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 patients 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. 
*****Myeloproliferative Neoplasms Symptom Assessment Form: The Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF TSS) can be completed on paper in 
case an electronic assessment on ERT is not available on the day of screening and rescreening visits. In the event there is a discrepancy of MPN assessment score on paper and 
electronic assessment, the treating physician will determine which assessment will be used for eligibility purposes on the study. 
 
*****All dates are entered into the database (Oncore) in +/- one week from the date of visit complete 
 
****** During the pandemic or any contrary circumstances, monthly visits may me a zoom/virtual visit per Investigator discretion only after the completion of week 16 on the study 
protocol. However, patient have to complete all the safety labs and study-related procedures/tests on the study protocol. Any missed procedures will be a deviation excluding vital 
signs and physical exam. 

34 
 
14 MEASUREMENT OF EFFECT 
 
Definitions: 
Response and progression will be assessed according to modified International Working 
Group (IWG) MDS/MPN criteria (see section 14). 
Complete Response (CR) 
1. Bone Marrow: 
a. <5% myeloblasts and promonocytes 
b. < grade 1 reticulin fibrosis 
2. Peripheral Blood: 
a. WBC < 10 x 109 cells/L 
b. Hgb > 11g/dL 
c. Platelets > 100 x 109 cells/L 
d. Blasts 0% 
e. Neutrophil precursors < 2% 
f. Monocytes < 1 x 109 cells/L 
3. Extramedullary Disease 
a. Complete resolution of extramedullary disease present before therapy 
including palpable hepatosplenomegaly 
Complete Cytogenetic Response 
Resolution of previously present chromosomal abnormalities as seen on G band 
cytogenetics. 
Partial Response 
Normalization of peripheral counts and hepatosplenomegaly with bone marrow 
myeloblasts reduced by 50% but remaining >5% of cellularity except in cases of 
MDS/MPN with < 5% bone marrow blasts at baseline 
Marrow Response 
Optimal marrow response: Presence of all CR marrow criteria without 
normalization of peripheral blood indices. 
Partial marrow response: Bone marrow blasts reduced by 50% but remaining >5% 
of cellularity or reduction in grading of reticulin fibrosis from baseline on at least 
2 bone marrow evaluations at least 2 months apart. 
Clinical Benefit 
Requires 1 of the following in the absence of progression or CR/partial response and 
independent of marrow response to be considered clinical benefit. 
1. Erythroid Response: a)Hgb increase by >2.0 g/dL b)TI for >8 wk for patients 
requiring at least 4 packed red blood cell transfusions in the previous 8 wk 
Only red blood cell transfusions given based on physician’s judgment for a 
pretreatment Hgb of <8.5 g/dL will count in the red blood cell TI response 
evaluation 
2. Platelet response: a) Transfusion independence when previously requiring platelet 
transfusions of at least a rate of 4 platelet transfusions in the previous 8 wk. b) 
Pretreatment <20 3 109/L: increase from <20 x 109/L to >20 x109/L and by at least 
100% c) Pretreatment >20 x 109/L but < 100 x 109/L: absolute increase of >30 x 

35 
 
109/L 
3. Neutrophil response: a) Pretreatment <0.5 x 109/L at least 100% increase and an 
absolute increase >0.5x 109/L b) Pretreatment > .0.5 x 109/L and <1.0 x 109/L. At 
least 50% increase and an absolute increase >0.5 x 109/L 
4. Spleen response: A > 35% reduction in spleen volume as measured by CT-scan 
from baseline at week 16. 
5. Symptom response: Improvement in symptoms as noted by decrease of >50% as 
per the MPN-SAF TSS scoring in those with a MPN-SAF TSS>17 (modified 
from original MDS/MPN-IWG). 
 
 
Pathologic Response: Pathologic response is categorized as per the modified MDS/MPN 
IWG. Response parameters in the peripheral blood and/or bone marrow must be sustained 
for at least 4 weeks. See section 14. 
 
Symptom Assessment in CMML 
Symptoms of CMML will be assessed using the MPN-SAF TSS (see Appendix C). 
Patients 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. Patients 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 will be a two stage Simon’s phase 2 design. After testing the treatment dose 
on 10 patients in the first stage, the trial will be terminated if 1 or fewer achieve a 
clinical benefit. 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. 

36 
 
15.2 Sample Size/Accrual Rate 
The Simon’s optimal two-stage design will be employed to test the null  
hypothesis that response rate (RR) is less than 10% versus the alternative that RR 
greater or equal 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 sample 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 patients who have received any protocol treatment, 
regardless of patient eligibility. The number (%) of patients 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. 
Laboratory parameters will also be summarized using descriptive statistics. The 
number and proportion of patients with DLTs will be summarized. 
15.5 Efficacy Analysis: ITT 
 
This analysis will include all patients 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 patients achieving a response will be 

37 
 
summarized. A 95% exact binomial confidence interval of the proportion will 
also be provided for all participants treated at the 20mg BID. In addition, a second 
analysis of evaluable patients will be performed. Evaluable patients are defined as 
those who complete at least 8 weeks of therapy and complete their first treatment 
bone marrow biopsy and aspirate to evaluate study drug response. 
16 Laboratory Correlates 
Unless otherwise specified, all laboratory correlates will be performed in the laboratory 
of Eric Padron. 
H.LEE MOFFITT CANCER CENTER 
CC: ERIC PADRON 
STABILE RESEARCH BUILDING 
SRB 23234 
12902 MAGNOLIA DR TAMPA FL 33612 
16.1 Sample Collection 
At screening (see section 13.2) and weeks 5, 9, 13, and 17, 6 green tops and 1 
red top vial will be collected. Designated study personnel will collect the sample 
from the laboratory draw area. Peripheral blood will be collected in 6 green top 
(hepranized) 10 ml tubes and 1 red top (clot activator or no additive) 10 ml tube 
for a total of seven tubes and 70cc of peripheral blood. At screening, week 8 and 
end of week 16 (see study calendar), bone marrow aspirate will be collected in 
three lavender (EDTA) 10 ml tubes or a 60 ml heparinized syringe for a total of 
30cc.  These will be shipped to the laboratory as directed above within 24hrs and 
will be processed using RBC lysis buffer to remove RBC and debris at the H. Lee 
Moffitt Cancer Center. They will be additionally processed by centrifugation 
(1700rpm for 20 minutes) with FICOLL to collect the mononuclear cellular layer. 
This layer 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 red top samples 
will be processed by centrifugation and the supernatant (serum) collected and 
cryopreserved for later use labeled with a unique identifier that corresponds to 
each patient known only to the investigator and study personnel. 

38 
 
16.2 Genomic Studies 
Using portion of cryopreserved bone marrow aspirates, 100ug of DNA will be 
isolated as previously described. Next, a comprehensive sequencing of patients 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. 
 
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 
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 Patients (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 

39 
 
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 
Patients (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; patients 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, 
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 patients 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 patients 

40 
 
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. Regulatory 
documents and Case Report Forms will be reviewed/monitored internally by Moffitt’s 
Internal Monitors, periodically, throughout the conduct of the trial. The monitoring 
will include source data verification, utilizing research patients’ medical records. 
It will be monitored internally according to Moffitt Cancer Center Monitoring 
Policies. Monitoring will be performed regularly to verify data is accurate, complete, 
and verifiable from source documents; and the conduct of the trial is in compliance 
with the currently approved protocol/amendments, Good Clinical Practice (GCP), and 
applicable regulatory requirements. 
To obtain access to OnCore, the External Site Coordination (ESC) office Coordinator 
will supply forms required to be completed by the site staff. Once the completed 
forms are received, the site coordinator will receive DUO access, logon/password, 
and information on how to access OnCore. The ESC office will provide OnCore 
training to the site once initial access is granted and on an ongoing basis, as needed. 
 
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 
events, protocol violations and when applicable, internal audit results. 
Description of internal (PI) safety review and monitoring process: 

41 
 
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. 
 
17.7 Registration Procedures: 
All subjects must be registered with the External Site Coordination (ESC) office to 
be able to participate in a trial. The participating site must fax on 813-745-5666 
or email the completed study specific eligibility checklist and registration forms, 
supporting documents and signed informed consent to the Coordinating Center. 
Unsigned  or incomplete forms will  be returned to the site. Once documents are 
received, the ESC Research Coordinator will review them to confirm eligibility and 
to complete the registration process. If eligibility cannot be confirmed, the 
research coordinator will query the site for clarification or additional documents as 
needed. Subjects failing to meet all study eligibility requirements will not be 
registered and will be unable to participate in the trial. 
Upon completion of registration, the ESC Research Coordinator will provide the 
participating site with the study sequence number and randomization information, if 

42 
 
indicated. Within 24-48 hours after registration, it is the site’s 
responsibility to: 
• Enter the demographic and on-study patient information into the Oncore 
database. 
• Order investigational agent(s) if indicated per protocol. 
 
 
It is the responsibility of the participating Investigator or designee to inform the 
subject of the research treatment plan and to conduct the study in compliance with 
the protocol as agreed upon with Moffitt Cancer Center and approved by the site’s 
IRB. 
To register a patient send the completed signed eligibility checklist along with the 
patient registration form and supporting documentation to the ESC via email at  
affiliate.research@moffitt.org or via fax at 813-745-5666, Monday through Friday 
between 8:00AM and 5:00PM (EST). 
Required Documentation 
Before the study can be initiated at any site, the site will be required to provide 
regulatory documentation to the External Site Coordination (ESC) office at Moffitt 
Cancer Center. Sites must provide a copy of their informed consent to the ESC 
office for review and approval prior to submission of any documents to the site’s 
IRB. Any changes requested by the site’s IRB must be provided to the ESC staff for 
review and approval prior to resubmission to the IRB. 
The ESC office must receive the following trial specific documents either by 
hardcopy, fax, or email before a site can be activated for any trial: 
1. IRB Approval Letter that includes the protocol version and date 
2. FDA Related Forms 1572/1571/310 as appropriate 
3. Signed Protocol Title Page 
4. IRB Approved Consent Form 
5. Site Delegation of Authority Log 
6. Signed Financial Interest Disclosure Forms (principal and sub investigators) 
7. Updated Investigator/Personnel documents (CVs, licenses, GCP and HSP training 
certificates, etc.) as needed. 
8. Updated Laboratory Documents (certifications, normal ranges, etc.) as needed. 

43 
 
9. Signed protocol specific Task Order 
 
 
A study initiation teleconference will be held prior to the start of any study related 
activity at the site. Attendance is required for: 
• The site PI and appropriate research staff 
• Moffitt PI and ESC research coordinator 
 
The requirements of the protocol and all associated procedures and processes 
will be reviewed and agreed upon prior to the activation of the study. The ESC 
utilizes the EDC system, OnCore. OnCore training will be scheduled, if 
indicated, with the appropriate staff from the site. 
 
 
18. REFERENCES 
 
1. 
Niyongere S, Lucas N, Sansil S, et al. Comprehensive Inflammatory Cytokine 
Profiling Identifies IL-8/CXCL8 As Elevated, Associated with Proliferative Features, and 
Independently Prognostic in Chronic Myelomonocytic Leukemia (CMML): Am Soc 
Hematology; 2016. 
2. 
Emanuel PD. Juvenile myelomonocytic leukemia and chronic myelomonocytic 
leukemia. Leukemia. 2008;22(7):1335-1342. 
3. 
Vardiman J, Harris N, Brunning R. The World Health Organization (WHO) 
classification of the myeloid neoplasms. Blood. 2002;100(7):2292. 
4. 
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. 
5. 
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. 
6. 
Kohlmann A, Grossmann V, Klein H-U, et al. Next-generation sequencing 
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. 
7. 
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. 
8. 
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. 
9. 
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. 

44 
 
2009;10(3):223-232. 
10. 
Costa R, Abdulhaq H, Haq B, et al. Activity of azacitidine in chronic 
myelomonocytic leukemia. Cancer. 2010. 
11. 
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. 
12. 
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. 
13. 
Ramshaw H, Bardy P, Lee M. Chronic myelomonocytic leukemia requires 
granulocyte-macrophage colony-stimulating factor for growth in vitro and in vivo. 
Experimental …. 2002. 
14. 
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. 
15. 
Padron E, Painter JS, Mailloux AW, et al. GM-CSF Signaling Abnormalities in 
Chronic Myelomonocytic Leukemia. ASH Annual Meeting Abstracts. 
2011;118(21):1713-. 
16. 
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. 
17. 
INCYTE. Ruxolitinib Investigator's Broshure. 2012. 
18. 
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. 
19. 
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. 
20. 
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. 
21. 
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. 
22. 
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. 
23. 
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. 
24. 
Padron E, Dezern A, Andrade-Campos M, et al. A Multi-Institution Phase 1 Trial 
of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML). Clin 
Cancer Res. 2016. 

45 
 
 
18 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. 

46 
 
 
 
 
19 APPENDIX B: 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. 

47 
 
 
 
20 APPENDIX C: Myeloproliferative Neoplasms-Symptom Assesment Form 
(MPN-SAF) 
 
 

48 
 
 
 
 
 

49 
 
21 APPENDIX D: WHO CLASSIFICATION FOR CMML 
 
 
WHO Subtype 
Peripheral Blood 
Bone Marrow 
Chronic Myelomonocytic Leukemia 
*CMML-0 
*CMML-1 
***CMML-2 
*<2 percent blasts 
**<5 percent blasts 
***5-19 percent blasts 
persistant monocytosis >1000/ul 
+/- cytopenias 
Leukocytosis frequent 
*<5% myeloblasts 
**<5-9% myeloblast 
***10-19% blasts 
>10% dysplasia in 
affected lineage 
***Auer Rods 
The absence of the 
Philadelphia 
chromosome of bcr-abl 
fusion gene.