Clinical trial NCT01375140
Conditions: Myeloproliferative Diseases
Keywords: Myeloproliferative Diseases Myelofibrosis Post essential thrombocythemia/polycythemia vera Ruxolitinib INCB018424 Lenalidomide CC-5013 Revlimid Prednisone Interactive Voice Response System IVR
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-09-22; Completion date: 2018-09-05
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if the combination of ruxolitinib and lenalidomide can help to control MF. The safety of this study drug combination will also be studied.

Ruxolitinib is designed to stop certain proteins (called JAK1 and JAK2) that are found in MF cells from sending signals that may lead to the growth of cancer cells.

Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. This may decrease the growth of cancer cells.

Detailed description:
Study Drug Administration:

If you are found eligible to take part in this study, you will begin taking ruxolitinib by mouth 2 times every day during each 28-day cycle. You should take ruxolitinib one time in the morning and one time in the evening (about 12 hours apart). Ruxolitinib should be taken with a meal and a glass of water. If you miss a dose of ruxolitinib, you should not make up the dose or take any more before the next scheduled dose.

You will also take lenalidomide by mouth one time in the morning on Days 1-21 of each cycle. Lenalidomide capsules should be swallowed whole, and should not be broken, chewed, or opened. If a dose of lenalidomide is missed, it should be taken as soon as possible on the same day. If it is missed for the entire day, it should not be made up.

If your study doctor thinks it is needed or if you have side effects, your dose of ruxolitinib and/or lenalidomide may be stopped, lowered, or delayed for up to 8 weeks during the study.

During the study, you will need to return all unused study drug to the study staff at each clinic visit.

Additional Drugs:

If your disease has not responded to the study drugs after 3 cycles and the study doctor thinks it is in your best interest, you may begin taking prednisone along with the study drugs. Prednisone is a corticosteroid that is similar to a natural hormone made by your body. Prednisone is often given in combination with other chemotherapy drugs. You will take prednisone every morning during Cycles 4 and 5, then every other day during Cycle 6. After Cycle 6, you will no longer take prednisone. If you forget to take a does of prednisone and more than 8 hours have passed, wait until the next day to take prednisone again (or 2 days later if you are taking it every other day during Cycle 6).

If your doctor thinks it is needed, you may take aspirin during this study to help prevent blood clots from forming. If you are allergic to aspirin or cannot take aspirin, your doctor may recommend you take another type of drug to help prevent blood clots from forming.

Study Drug Diary:

You will be given a study drug diary before you begin taking the study drugs to write down what time you take each dose of the study drugs. You will need to bring the diary with you to each study visit so it can be reviewed.

You should bring the study drug (including empty bottles) with you to all of the study visits. You will be asked not to take your morning dose of study drug before your visits on Day 15 Cycle 1 and Day 1 on Cycle 2.

Study Visits:

On Day 1 of Cycles 1 and 2:

* You will have a physical exam, including measurement of your vital signs and weight.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Blood (about 3 teaspoons) will be drawn for routine tests and to check your kidney and liver function. This routine blood draw will include a pregnancy test if you are able to become pregnant.
* You will complete 2 questionnaires about your quality of life. The questionnaires should take about 10 minutes to complete. One of the questionnaires may be filled out on a computer. The study staff will help you use the computer.

On Days 8 and 22 of Cycles 1 and 2:

° Blood (about 3 teaspoons) will be drawn for routine tests. This routine blood draw will include a pregnancy test if you are able to become pregnant.

On Day 15 of Cycles 1 and 2:

* You will have a physical exam, including measurement of your vital signs and weight.
* You will be asked about any side effects you may be having.
* Blood (about 3 teaspoons) will be drawn for routine tests and to check your kidney and liver function. This routine blood draw will include a pregnancy test if you are able to become pregnant.

On Day 1 of Cycle 3 and every 3 to 6 Cycles after that:

* You will have a physical exam, including measurement of your vital signs and weight.
* You will have a review of any blood transfusions you may have had in the last 3 months.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Blood (about 3 teaspoons) will be drawn for routine tests and to check your kidney and liver function. This routine blood draw will include a pregnancy test if you are able to become pregnant.
* You will complete 2 questionnaires about your quality of life. The questionnaires should take about 10 minutes to complete.

You will have a bone marrow biopsy and aspirate after Cycles 3, 6, 9, and 12, and then when your doctor feels it is necessary.

Interactive Voice Response (IVR) System:

During the first 3 cycles, you will use the Interactive Voice Response (IVR) system once a month to tell the study staff about any side effects you may be having. The IVR system is an automated calling system that will allow you to press buttons on your phone to answer questions about any side effects you may be having. The study staff will give you instructions on how to use the IVR. If you are not able to use the IVR system, a member of the study staff will contact you instead.

After Cycle 3, a member of the study staff will call you at your home once a month to ask you about any side effects you may be having and to review the results of your blood tests.

Length of Study:

You may receive the study drug combination for up to 6 years. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

You will be considered off study after your follow-up visit.

End-of-Study Visit:

You will have an end-of-study visit the day you are taken off study. The following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs and weight.
* You will have a review of any blood transfusions you may have had in the last 3 months.
* You will be asked about any drugs you may be taking and any side effects you may be having.
* Blood (about 3 teaspoons) will be drawn for routine tests and to check your kidney and liver function. This routine blood draw will include a pregnancy test if you are able to become pregnant.
* You will complete 2 questionnaires about your quality of life. The questionnaires should take about 10 minutes to complete.
* You will have a bone marrow biopsy and/or aspirate to check the status of the disease.

Follow-up:

A member of the study staff will call you 30 days and 60 days after you have stopped taking the study drugs to ask how you are feeling and if you have had any side effects since your last visit.

This is an investigational study. Lenalidomide is not FDA-approved or commercially available for use in patients with MF. Ruxolitinib is FDA approved and commercially available for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis and post-essential thrombocythemia (post-ET) myelofibrosis. Lenalidomide is FDA-approved for the treatment of some forms of myelodysplastic syndrome (MDS) and multiple myeloma (MM). Its use in patients with MF is investigational.

Up to 49 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Ruxolitinib 15 mg orally twice daily continuously + Lenalidomide orally 5 mg/day on days 1-21, followed by 7 days of no therapy (28-day cycle). Prednisone will be added for patients who have not responded after 3 cycles of therapy. Prednisone 30 mg by mouth a day during cycle 4, 15 mg/day during cycle 5, and 15 mg every other day during cycle 6, and then it will be discontinued.
Interventions: intervention 1: Ruxolitinib intervention 2: Lenalidomide intervention 3: Prednisone
Intervention descriptions: intervention 1: 15 mg by mouth twice daily (BID), continuously in 28-day cycles. intervention 2: 5 mg by mouth each day on days 1-21, followed by 7 days of no therapy of each 28 day cycle. intervention 3: Prednisone will be added for patients who have not responded after 3 cycles of therapy.

30 mg by mouth a day during cycle 4, 15 mg/day during cycle 5, and 15 mg every other day during cycle 6, and then it will be discontinued.

Protocol documents:
Prot_SAP_000.pdf: 
2011-0269
November 2, 2015
Page 1
Protocol Page
EVALUATION OF RUXOLITINIB AND LENALIDOMIDE COMBINATION AS 
A THERAPY FOR PATIENTS WITH MYELOFIBROSIS
2011-0269
Core Protocol Information
Short Title 
Ruxolitinib and Lenalidomide for patients with Myelofibrosis
Study Chair: 
Srdan Verstovsek
Additional Contact:
Paula J. Cooley
Sandra L. Rood
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-792-7305
Unit:
428
Full Title: 
EVALUATION OF RUXOLITINIB AND LENALIDOMIDE COMBINATION AS A THERAPY FOR 
PATIENTS WITH MYELOFIBROSIS
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 06/23/2017
Version:
14
Submitted by:
Paula J. Cooley--5/17/2017 7:37:31 AM
OPR Action:
Accepted by:  Rosheta McCray -- 6/9/2017 10:41:51 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2011-0269
November 2, 2015
Page 2
Protocol Body
 


Page 1 of 26 
 
 
 
 
 
EVALUATION OF RUXOLITINIB AND LENALIDOMIDE COMBINATION AS A 
THERAPY FOR PATIENTS WITH MYELOFIBROSIS 
 
 
 
 
 
 
 
 
 
 
 
University of Texas 
MD Anderson Cancer Center 
Leukemia Department, Unit 428 
Telephone: 713-792-7305 
 
Principal Investigator: Srdan Verstovsek, M.D., Ph.D. 
 
 
 
 
 
 
 
 
 
 


Page 2 of 26 
 
1.0 
HYPOTHESIS AND OBJECTIVES 
 
Hypothesis 
Ruxolitinib (also known as INCB018424), a JAK1/2 inhibitor, and lenalidomide 
(immunomodulatory inhibitory drug; IMID) are effective and tolerable treatments for 
patients with myelofibrosis (MF).  Combination of these agents in patients with MF can 
improve the overall clinical response to therapy without causing excessive toxicity. 
 
Objectives 
Primary:   
- to determine the efficacy of the combination of INCB018424 with lenalidomide 
in patients with MF, in achieving objective improvements in disease status 
Secondary: 
- to determine the safety of the combination in patients with MF 
 
Exploratory: 
-  to explore time to response and duration of response  
- to explore the effect of the combination on anemia and transfusion dependence 
in patients with MF 
-  to explore changes in JAK2V617F allele burden 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1  Myelofibrosis with Myeloid Metaplasia 
Myelofibrosis with myeloid metaplasia (MF) is a rare clonal proliferative disorder of a 
pluripotent stem cell.  This clone subsequently induces fibrogenic cytokines and/or 
growth factors in the marrow, which stimulate the deposition of extracellular matrix 
proteins by polyclonal fibroblasts.  Megakaryocytic hyperplasia-dysplasia is frequently 
observed.  Invasion of the blood stream and colonization of extramedullary sites 
ensues, resulting in organomegaly and splenomegaly. Extensive marrow fibrosis and 
osteosclerosis may be observed in advanced MF, resulting in “dry taps”.  
 
The entity of MF can be either idiopathic (primary or agnogenic myeloid metaplasia), or 
representative of end-stage myeloproliferative diseases such as polycythemia vera (PV) 
or essential thrombocythemia (ET).  MF occurs in about 25% of patients with PV and in 
2% to 3% of patients with ET. In the early cellular phase of MF with minimal marrow 
fibrosis, the differential diagnosis includes Philadelphia-positive CML, PV, and ET that 
must be distinguished, based on cytogenetics and clinicopathologic features. Other 
entities that can induce myelophthisis include myelodysplastic syndrome (MDS), 
metastatic malignancies, lymphoma, Hodgkin’s disease, and plasma cell dyscrasias.  
MF must be differentiated from acute megakaryocytic leukemia (AML, M7 of the French-
American-British classification) and MDS with fibrosis. In acute megakaryocytic 
leukemia patients usually present with severe constitutional symptoms and 
pancytopenia but without organomegaly or peripheral blood myelophthisis. 
 


Page 3 of 26 
 
The clinical picture of MF involves constitutional symptoms (e.g., cachexia, night 
sweats, fatigue, fever), splenomegaly, anisopoikilocytosis with teardrop erythrocytes, 
progressive anemia, immature myeloid and erythroid precursors in the peripheral blood, 
elevated lactate dehydrogenase (LDH) levels, and fibrosis of the marrow (as evaluated 
by reticulin and trichome [collagen] stains).  The leukoerythroblastic picture is postulated 
to be related to both the intramedullary sinusoidal marrow and splenic hematopoiesis.  
 
The disease generally occurs in adults, with the median age ranging from 54 to 62 
years; 70% of the patients are over the age of 50 years.  In 40% of the patients, 
constitutional symptoms are present, including fever, weight loss, nocturnal sweating, 
pruritus, and bone pain.  Splenomegaly is present in 85% of the patients at diagnosis, 
and is massive in 10%.  Hematologic disease features include anemia in 50% to 70% at 
diagnosis and 25% will have severe anemia with hemoglobin level < 8.0 gm/dL.  
Approximately half of the patients present with an elevated white cell count (WBC), 28% 
with thrombocytosis (platelet count > 500 x 109/L, and 37% with thrombocytopenia 
(platelet count < 150 x 109/L).  Circulating blast cells are present in one-third of the 
patients. 
 
Complications of MF are varied.  Thrombotic obliteration of intrahepatic veins and 
splenomegaly may lead to portal hypertension; severe cases may be associated with 
ascites and/or variceal bleeding.  Left upper quadrant pain may herald splenic infarction; 
episodes are usually self-limited and may persist for several days.  Supportive care 
measures such as analgesics and hydration are usually sufficient; refractory cases may 
require splenectomy or irradiation. Extramedullary hematopoiesis (EMH) may occur in 
locations other than the liver or spleen; involvement of such sites may be managed by 
low-dose irradiation.  Liver involvement is associated with increased levels of plasma 
alkaline phosphatase.  Clinical manifestations of EMH include cardiac tamponade, 
papular skin nodules, pleural effusions, and spinal cord compression. 
 
Autoimmune phenomena have been observed, including Coomb’s positive autoimmune 
hemolytic anemia, nephrotic syndrome, antinuclear antibodies, rheumatoid factor, and 
lupus-type anticoagulant.  Postulated etiologies include clonality of the lymphoid 
population or activation by abnormal monocyte-macrophage interaction with the 
immune system. 
 
Adverse prognostic factors for survival include older age and anemia (hemoglobin < 10 
gm/dL).  The etiology for the latter finding is usually multifactorial and related both to 
marrow failure and hypersplenism.  Poor prognosis has also been correlated with 
leukocytosis, leukopenia, circulating blasts, increased numbers of granulocyte 
precursors, thrombocytopenia, abnormal karyotype, and hypercatabolic symptoms. The 
course of the disease is highly variable.  Median survival from time of diagnosis ranges 
from 5 to 6 years.  Progressive marrow failure, transformation into acute myeloid 
leukemia, and portal hypertension lead to demise. 
 
No standard therapy exists for MF.  Hydroxyurea is the most commonly used agent in 
the proliferative phases of the disease.  Interferon-alpha had yielded hematologic 


Page 4 of 26 
 
responses and reductions in splenomegaly (definitions varying among studies) 
especially those with proliferative phase, however, this agent tends to be poorly 
tolerated.  Agents used for the management of anemia include androgens and/or 
erythropoietin.  Splenectomy and/or splenic irradiation have been used to manage 
symptomatic splenomegaly.  Splenectomy has been associated with risk of leukemia 
transformation in some series, and splenic irradiation can result in severe 
myelosuppression. No medical therapy has been proven to prolong overall survival for 
these patients. Patients with an intact quality of life and no threatening hematologic 
abnormalities, such as erythrocytosis or thrombocytosis, have usually been considered 
to not require any therapy. 
 
In vitro data suggests that cytokines elaborated by megakaryocytes stimulate human 
bone marrow fibroblasts to divide and secrete collagens. In patients with MF, increased 
levels of transforming growth factor-beta (TGF-beta) have been observed in circulating 
peripheral blood mononuclear cells (PBMC) of megakaryocytic lineage.   
 
Increased levels of basic fibroblast growth factor (bFGF) have also been reported in 
patients with MF.  Both TGF-beta and bFGF are members of multifunctional polypeptide 
families that regulate cell growth and differentiation.  In addition to their potent fibrogenic 
activity, TGF-beta and bFGF regulate hematopoiesis by selective actions on primitive 
stem cells. Expression of TGF-beta in early CD34+ hematopoietic stem cells negatively 
regulated the cycle status; this effect could be abrogated by bFGF.  In addition, bFGF 
has been shown to augment the activity of stem cell factor (SCF), interleukin-3 (IL-3), 
granulocyte-macrophage colony stimulating factor (GM-CSF), or erythropoietin on 
committed progenitor cells.  Other cytokines/proteins that are disregulated in MF 
include; tumor necrosis factor-alpha (TNF-alpha) and angiogenic agents like vascular 
endothelial growth factor (VEGF).   
 
2.2 
INCB018424 
 
Rationale 
JAKs play an important role in signal transduction following cytokine and growth factor 
binding to their receptors. In addition, JAKs activate a number of downstream pathways 
implicated in the proliferation and survival of malignant cells including the STATs (signal 
transducers and activators of transcription), a family of important latent transcription 
factors. Aberrant activation of JAKs has been associated with increased malignant cell 
proliferation and survival in patients with Philadelphia chromosome negative MPD. The 
finding that peripheral blood from myeloproliferative disease (MPD) patients is capable 
of forming erythroid and megakaryocyte colonies in the absence of exogenous factors 
(which signal through JAKs) suggests that cells from these patients are intrinsically 
different than normal cells. Indeed, work from a number of laboratories led to the 
identification of multiple somatic mutations in genes associated with cytokine and 
growth factor signaling. These include a mutation in the pseudo-kinase domain of 
JAK2V617F (amino acid 617, valine to phenylalanine) that results in constitutive 
activation of JAK2 and downstream STATs. This mutation was found in > 90% of all PV 
patients and in approximately 50% of all ET and Myelofibrosis with Myeloid Metaplasia 


Page 5 of 26 
 
(MMM) patients. More recently, other mutations have been identified in MPD patients 
lacking the JAK2V617F mutation. For instance, additional activating mutations in JAK2, 
as well as a mutation in the thrombopoietin receptor (MPL), result in constitutive ligand-
independent JAK activation. Importantly, ectopic expression of each of these mutant 
genes has been demonstrated to be sufficient to cause MPD-like syndromes in mice.  
Moreover, even in MPD patients lacking a confirmed JAK2 mutation, the detection of 
STAT activation suggests dysregulated JAK activity. In fact, regardless of the mutational 
status of JAK2, the malignant cells expectedly retain their responsiveness to JAK 
activating cytokines and/or growth factors; hence, they may benefit from JAK inhibition.  
These findings, in addition to the limited life span of these patients and lack of beneficial 
therapies for the treatment of PMF and post-PV/ET MF, clearly support the evaluation of 
JAK inhibitor in these diseases. INCB018424 phosphate is an inhibitor of the Janus 
kinase family of protein tyrosine kinases (JAKs) that is currently under development for 
treatment of myeloproliferative disorders (MPD). 
 
Clinical Experience 
We conducted a phase 1−2 trial of INCB018424 in patients with JAK2 V617F−positive 
or JAK2 V617F−negative primary myelofibrosis, post–essential thrombocythemia 
myelofibrosis, or post–polycythemia vera myelofibrosis. A total of 153 patients received 
INCB018424 for a median duration of more than 14.7 months. The initial dose-
escalation phase established 25 mg twice daily or 100 mg once daily as maximum 
tolerated doses, on the basis of reversible thrombocytopenia. A dose-dependent 
suppression of phosphorylated signal transducer and activator of transcription 3 
(STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 
and in patients with the JAK2 V617F mutation. We studied additional doses and 
established that a 15-mg twice-daily starting dose, followed by individualized dose 
titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 
patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting 
for 12 months or more, and this therapy was associated with grade 3 or grade 4 
adverse events (mainly myelosuppression) in less than 10% of patients. Patients with 
debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had 
rapid improvement. Clinical benefits were associated with a marked diminution of levels 
of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.  
 
2.3 
Lenalidomide  
 
Lenalidomide is the lead compound in a proprietary class of Celgene compounds known 
as IMiDs® with immunomodulatory and anti-angiogenic properties that could confer 
antitumor and antimetastatic effects. It is a derivative of thalidomide, combining higher 
efficacy and lower toxicity than its parent compound. Lenalidomide has been 
demonstrated to possess anti-angiogenic activity through inhibition of bFGF, VEGF and 
TNF-alpha induced endothelial cell migration, due at least in part to inhibition of Akt 
phosphorylation response to bFGF.  In addition, lenalidomide has a variety of 
immunomodulatory effects.  Lenalidomide stimulates T cell proliferation, and the 
production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 beta and IL-6 and modulates IL-
12 production.  


Page 6 of 26 
 
 
Clinical experience in myelofibrosis with lenalidomide 
Two similarly designed but separate phase 2 studies involving single-agent 
lenalidomide in a total of 68 patients with symptomatic myelofibrosis were reported in 
one paper. Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if 
baseline platelet count < 100 x 10(9)/L) for 3 to 4 months with a plan to continue 
treatment for either 3 or 24 additional months, in case of response. Overall response 
rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. 
Response in anemia was deemed impressive in 8 patients whose hemoglobin level 
normalized from a baseline of either transfusion dependency or hemoglobin level lower 
than 100 g/L. Additional treatment effects in these patients included resolution of 
leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 
patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in 
JAK2(V617F) mutation burden (1 patient). Grade 3 or 4 adverse events included 
neutropenia (31%) and thrombocytopenia (19%). Authors concluded that lenalidomide 
engenders an intriguing treatment activity in a subset of patients with MF that includes 
an unprecedented effect on peripheral blood and bone marrow abnormalities. 
 
To investigate the safety and efficacy of the combination of lenalidomide and 
prednisone in patients with MF, 40 patients were treated. Therapy consisted of 
lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 109/L) on days 1 through 
21 of a 28-day cycle for six cycles, in combination with prednisone 30 mg/d orally during 
cycle 1, 15 mg/d during cycle 2, and 15 mg/d every other day during cycle 3. 
Lenalidomide therapy was continued indefinitely in patients exhibiting clinical benefit.  
The median follow-up was 22 months (range, 6 to 27). Responses were recorded in 12 
patients (30%) and are ongoing in 10 (25%). The median time to response was 12 
weeks (range, 2 to 32). According to the International Working Group for Myelofibrosis 
Research and Treatment consensus criteria, three patients (7.5%) had partial response 
and nine patients (22.5%) had clinical improvement durable for a median of 18 months 
(range, 3.5 to 24+). Overall response rates were 30% for anemia and 42% for 
splenomegaly. Moreover, 10 of 11 assessable responders who started therapy with 
reticulin fibrosis grade 4 experienced reductions to at least a score of 2. All eight 
JAK2V617F-positive responders experienced a reduction of the baseline mutant allele 
burden, which was greater than 50% in four, including one of whom the mutation 
became undetectable. Grade 3 to 4 hematologic adverse events included neutropenia 
(58%), anemia (42%), and thrombocytopenia (13%).  The combination of lenalidomide 
and prednisone induced durable clinical, molecular, and pathologic responses in MF. 
 
Most frequently reported adverse events reported during clinical studies with 
lenalidomide in oncologic and non-oncologic indications, regardless of presumed 
relationship to study medication include: anemia, neutropenia, thrombocytopenia and 
pancytopenia, abdominal pain, nausea, vomiting and diarrhea, dehydration, rash, 
itching, infections, sepsis, pneumonia, UTI, Upper respiratory infection, cellulitis, atrial 
fibrillation, congestive heart failure, myocardial infarction, chest pain, weakness, 
hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, generalized pain, 
dizziness, mental status changes, syncope, renal failure, dyspnea, pleural effusion, 


Page 7 of 26 
 
pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, tumor lysis syndrome, death not specified 
and fractures. Lenalidomide may cause breakdown products of the cancer cells to enter 
the blood stream, which may lead to heart rate abnormalities, kidney failure, muscle 
twitching, and/or muscle cramps (please refer to lenalidomide package insert or 
Investigator Brochure for a complete list of adverse events). 
 
 
3.0 
BACKGROUND DRUG INFORMATION 
 
3.1 
Ruxolitinib (INCB018424) (Refer to Investigator’s Brochure) 
 
INCB018424 phosphate, referred to herein as INCB018424, is a substituted 
pyrrolopyrimidine compound that acts as a potent and selective inhibitor of the Janus 
kinase family of enzymes. INCB018424 is a novel, potent, and selective inhibitor of the 
JAKs with modest selectivity for JAK2. INCB018424 potently (IC50 values < 5 nM) 
inhibits JAKs, yet it does not significantly inhibit (<30% inhibition) a broad panel of 26 
other kinases when tested at 200 nM (approximately 100 times the average IC50 value 
for JAK enzyme inhibition). Moreover, in cell-based assays relevant to the pathogenesis 
of MPDs, such as JAK-STAT signaling and the growth of cytokine-dependent lines, 
INCB018424 demonstrated excellent potency (IC50 values of 80-141 nM). This effect 
was not due to general cytotoxicity, because INCB018424 (up to 25 μM) had no 
significant effect on the growth of cytokine-independent cell lines transformed by the 
Bcr-Abl oncogene. In addition, INCB018424 inhibited JAK/STAT signaling and growth of 
a cell line expressing the JAK2 mutant variant (JAK2V617F) that has been implicated in 
the pathogenesis of the majority of Philadelphia chromosome negative MPD. Additional 
details as to the in vitro pharmacology of INCB018424 may be found in the Clinical 
Investigator’s Brochure (CIB). 
 
INCB018424 was evaluated in two mouse models where either a cytokine-dependent 
multiple myeloma cell line, INA-6, or a cell line, BaF3, engineered to express 
JAK2V617F was inoculated. The ability of INCB018424 to inhibit JAK pathway signaling 
as well as tumor cell survival and growth was assessed in vivo. In vitro cell biology 
experiments have demonstrated that the potency of INCB018424 is very similar 
between the cytokine-dependent INA-6 myeloma cells, with wild type JAKs, and the 
BaF3 cells expressing a clinically relevant mutant JAK2. As such, the in vivo studies 
described herein characterize the ability of INCB018424 to inhibit wildtype JAK2 (using 
the INA-6 xenograft model) and MPD-related mutant JAK2 (using a mouse model of 
splenomegaly driven by cells expressing the mutant JAK2V617F). 
 
Treatment of mice with orally administered INCB018424 resulted in a dose-dependent 
suppression of STAT3 phosphorylation and tumor growth in the cytokine-dependent 
INA-6 xenograft model at doses ≥ 10 mg/kg BID. Moreover, oral administration of 
INCB018424 inhibited the dramatic splenomegaly in mice resulting from intravenous 
inoculation of the BaF3-JAK2V617F cells. Additional details as to the in vivo 
pharmacology of INCB018424 may be found in the Clinical Investigator’s Brochure 


Page 8 of 26 
 
(CIB). In summary, pharmacological data obtained in both in vitro and in vivo model 
systems support the potential utility of orally administered INCB018424 in the treatment 
of malignancies, including MPD such as PMF and Post-PV/ET MF. 
 
The chemical name of INCB018424 phosphate is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-
yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate (Figure 1). INCB018424 
phosphate has a molecular formula of C17H21N6O4P and a molecular weight of 
404.36. INCB018424 phosphate drug substance is a white to off-white powder, and is 
referred to herein as INCB018424. 
 
INCB018424 Phosphate Structural Formula 
 
 
 
INCB018424 drug product will be provided as 5 mg and 25 mg strength tablets. The 
tablet formulation contains the active ingredient along with commonly used excipients.  
All excipients are of compendial grade. The medication will be provided for free to 
participants in this study by the manufacturer, Incyte Inc. The 5 mg tablets are stable for 
six months at 40C/75% RH and at least 24 months at 25C/60% RH. The 25 mg tablets 
are stable for six months at 40C/75% RH and at least 36 months at 25C/60% RH. 
 
 
3.2 
Lenalidomide 
Lenalidomide will be supplied as 5 mg capsules for oral administration. Lenalidomide 
will be shipped directly to the patient through the Celgene’s RevAssist® program. 
Lenalidomide will not be provided for free to participants in this study, but will be 
provided upon insurance approval through commercial supply. Lenalidomide will be 
provided in accordance with the RevAssist® program.  Per standard RevAssist® 
requirements all physicians who prescribe lenalidomide for research subjects enrolled 
into this trial, and all research subjects enrolled into this trial, must be registered in and 
must comply with all requirements of Celgene’s RevAssist® program.  Prescriptions 
must be filled within 7 days.  Only enough lenalidomide for one cycle of therapy will be 
supplied to the patient each cycle. 
 
3.3 
Prednisone 
Prednisone will be used from commercially available supplies. 
 
4.0 
PATIENT ELIGIBILITY CRITERIA 
 
Inclusion criteria 


Page 9 of 26 
 
1. Diagnosis 
of 
myelofibrosis 
(either 
primary 
or 
post 
essential 
thrombocythemia/polycythemia vera) requiring therapy, including those previously 
treated and relapsed or refractory, or if newly diagnosed, with intermediate-1 or -2 or 
high risk according to International Working Group (IWG) criteria. 
2. Understanding and voluntary signing an IRB-approved informed consent form. 
3. Age ≥ 18 years at the time of signing the informed consent. 
4. Disease-free of prior malignancies for ≥ 2 years with exception of basal cell or 
squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast. 
5. ECOG performance status 0 to 2. 
6. Patients must have adequate organ function as demonstrated by the following: 
 Direct bilirubin < 2.0 mg/dL 
 Serum creatinine < 2.0 mg/dL. 
 SGPT  3 x upper limit of normal  
7. Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior to 
and again within 24 hours of starting lenalidomide and must either commit to 
continued abstinence from heterosexual intercourse or begin TWO acceptable 
methods of birth control, one highly effective method and one additional effective 
method AT THE SAME TIME, at least 4 weeks before she starts taking 
lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must 
agree to use a condom during sexual contact with a female of child bearing potential 
even if they have had a successful vasectomy.  All patients must be counseled at a 
minimum of every 28 days about pregnancy precautions and risks of fetal exposure.  
See Appendix J: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
8. All study participants must be registered into the mandatory RevAssist® program, 
and be willing and able to comply with the requirements of RevAssist®. 
9. Platelets >/= 100000/uL 
10. ANC >/= 1000/uL 
 
Exclusion Criteria 
1. Use of any other standard (e.g. hydroxyurea, anagrelide, growth factors) or 
experimental drug or therapy within 14 days or 5-half lives, whichever is longer, of 
starting study therapy and/or lack of recovery from all toxicity from previous therapy 
to grade 1 or better. 
2. Known prior clinically relevant hypersensitivity reaction to thalidomide, including 
the development of erythema nodosum if characterized by a desquamating rash. 
3. Prior therapy with lenalidomide or INCB018424. 
4. Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
5. Suspected Pregnancy, Pregnant or lactating females. 
                                            
† A female of childbearing potential is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 


Page 10 of 26 
 
6. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study or confounds 
the ability to interpret data from the study. 
7. Known positive for HIV or infectious hepatitis, type A, B or C. 
8. Known prior clinically relevant hypersensitivity to prednisone. 
9. Participants with prior history of thromboembolic disease (i.e. deep venous 
thrombosis (DVT) or pulmonary embolism (PE) within the last six months, as 
Lenalidomide has demonstrated a significantly increased risk of DVT or PE. 
10. Known to have a hypercoagulability syndrome (eg: antithrombin III, deficiency, 
anticardiolipin syndrome etc…)  
11. Concurrent use of strong inducers or strong inhibitors of CYP3A4 (strong inducers 
are rifampin and St. John’s Worth, carbamazepine, phenytoin, and barbiturates such 
as phenobarbital; strong inhibitors are HIV-antivirals, clarythromycin, itraconazole, 
ketoconazole, nefadozone, and telithromycin). 
12. Incarcerated persons are excluded from the protocol. 
 
5.0 
TREATMENT PLAN 
 
Four weeks on therapy is considered one cycle of therapy. INCB018424 and 
lenalidamide will be given orally in an outpatient setting. INCB018424 will be given 
continuously daily in 28-day cycles, and lenalidamide will be given on days 1-21 of 28 
day cycles.  Dosage for cycles can be reduced, increased or delayed based 
assessment of efficacy and on adverse events, if any occur, as described below.  
Delays of a maximum of 8 weeks are allowed from scheduled next cycle.  
 
Subjects will be asked to maintain a diary to record drug administration. Subjects will be 
asked to bring any unused study drug to the research center at their next visit.  
Research personnel will count and record the number of used and unused study drug 
capsules/tablets (both ruxolitinib and lenalidomide) at each visit and reconcile with the 
subject diary.  The study coordinator will question the patient regarding adherence to 
the dosing regimen, record the number of capsules/tablets and strengths returned in the 
carton, the date returned and determine treatment compliance before dispensing new 
medication to the study patient.  Compliance below 80% will require counseling of the 
patient by study site personnel. 
 
The planned dose and schedule of investigation of INCB018424 is 15 mg orally twice 
daily (BID), continuously in 28-day cycles. Lenalidomide will be taken orally 5 mg/day 
in the morning each day on days 1-21, followed by 7 days of no therapy of each 28-
day cycle; medication will be mailed to participants, per the RevAssist® Program. 
 
Twenty eight days is considered one cycle of therapy.  Attempts will be made to 
provide an adequate treatment period of at least 6 months unless significant toxicity 
observed, to account for delayed time to response observed with biologic agents. 
Responders will continue therapy for 6 years unless progression of disease or toxicity 
warranting discontinuation of therapy is observed. 
 


Page 11 of 26 
 
Prednisone will be added for patients who have not responded after 3 cycles of 
therapy.  It will be dosed orally at the dose of 30 mg/day during cycle 4, 15 mg/day 
during cycle 5, and 15 mg every other day during cycle 6, and then it will be 
discontinued. 
 
All patients will be registered in the Clinical Oncology Research system(CORE) at 
MD Anderson Cancer Center after the informed consent is signed.   
 
5.1 
Dose Modification  
 
 
Dose Level           INCB018424           Lenalidomide QD 
                                    mg BID           (Days 1-21 Q 4 weeks) 
 
Dose Level  +3  
 
25 
 
 
15 
Dose Level  +2 
 
20 
 
 
10 
Dose Level  +1 
 
20 
 
 
 5 
          Level   0  
 
15 
 
 
 5 
Dose Level   -1  
 
10 
 
 
 5  
Dose Level   -2 
 
10 
        5 mg every other day x 10 
Dose Level   -3 
 
 5 
        5 mg every other day X 10 
 
If drug-related grade 3 or 4 non-hematologic toxicity is attributable to one or both of the 
drugs, dose interruption of that particular drug(s) is mandatory. Patient who experience 
grade 3 drug related non-hematological toxicity may be given a subsequent course one 
dose level below the previous course, but the patient must have recovered to grade 
</=1 before institution of the next course. If a patient has drug-related grade 4 non-
hematologic toxicity, he/she may receive a subsequent courses at one reduced dose 
level after resolution of toxicity to grade </=1, only if approved by the Principal 
Investigator based on the clinical significance of the toxicity and only if patient has had 
derived a benefit from the therapy.  The dose of therapeutic agents can be decreased 
during a cycle, at the discretion of treating physician, for chronic grade 2 non-
hematologic toxicity. In specific circumstances, after discussion with the Principal 
Investigator, one of the two medications can be discontinued for safety.  Documentation 
of the reason(s) study drug is discontinued is required.  Other dose modifications may 
be considered as clinically indicated with documentation and approval of the PI 
 
 
During a cycle of therapy, dosing of INCB018424 and lenalidomide will be discontinued 
for platelet counts </= 35X109/L OR for ANC </= 500/uL.  Dosing of INCB018424 may 
resume at 5mg QD if the platelet count increases > 35X109/L AND ANC >500/uL, and 
can be increased to 5mg BID for the remainder of the cycle once platelet count is > 50 
X109/L AND ANC >1000/uL. Lenalidomide will not be restarted during this cycle. 
 
Patients who experience platelet count </= 35X109/L or ANC </= 500/uL during a cycle 
of therapy, will have a dose reduction of therapy by one dose level for subsequent 


Page 12 of 26 
 
cycles. A reduction of 2 dose levels may be considered if the myelosuppression was 
deemed severe and life threatening by the treating physician, and if it is in the patient's 
best interest. Reductions in dosing for therapy related anemia can be done at the 
discretion of the investigator. 
Patients may be escalated to the next higher dose level if ALL of the following criteria 
are met (for the study drug being dose escalated). (Applicable also for patients receiving 
only one study drug) 
1. 
no dose reductions due to toxicity were required in the prior 2 cycles 
2. 
no dose interruptions due to toxicity were required in the prior 2 cycles 
3. 
the prior cycle was not delayed due to toxicity 
4. 
the current cycle is not delayed due to toxicity 
5. 
Platelet count >/= 100X 109/L AND ANC >/= 1000/uL 
6. 
The patient has sub-optimal benefit defined as a failure to reduce palpable spleen 
length by at least 50% and/or suboptimal improvement in MF related symptoms as 
assessed by the investigator, and/or failure to improve cytopenia 
7. 
no development of new onset transfusion dependency 
  
 
Dose modifications/discontinuation for prednisone therapy will be at the discretion of the 
clinician but must be documented clearly when it happens. Prednisone dose 
modification/discontinuation will not require withdrawal from the study. Treatment of 
hyperglycemia with either oral hypoglycemic agents or insulin does not necessarily 
require discontinuation of prednisone if the hyperglycemia is controlled with these 
medications. 
 
5.2 
Initiation of a New Cycle of Therapy 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
 
The ANC is >/= 1,000/μL; 
 
The platelet count is > 50 x109/L,  
 
Any drug-related grade 3-4 adverse event that may have occurred has resolved to 
≤ grade 1 severity; 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle will not be initiated until the toxicity has resolved as described 
above.  If drug dosing was interrupted during the previous cycle or if the new cycle is 
delayed due to toxicity newly encountered on the scheduled Day 1, then the new cycle 
will be started when the criteria above are met AND with at least a one-level dose 
reduction. Treatment with INCB018424 may continue at 5mg QD so long as 
ANC>500/uL AND platelets > 35x109/L or at 5mg BID so long as ANC>/= 1000/uL AND 
platelets > 50x109/L while waiting to initiate a new cycle.   If after a 4 week delay, the 
platelet count remains > 50x109/L but </= 75x109/L, the next cycle therapy may begin 
with INCB018424 dosed at 5mg BID and the dose of lenalidomide reduced by at least 1 
dose level from the prior cycle. If the prior cycle was at dose level -2 or -3 then 
lenalidomide (and prednisone if started) must be discontinued and the patient may 
continue therapy with INCB018424 alone following dosing rules.   
 


Page 13 of 26 
 
If the toxicity has not resolved as described above within 8 weeks of the scheduled start 
date for the cycle, the patient will discontinue treatment.   In unusual circumstances this 
rule may be modified by the Principal Investigator if felt to be in the best interest of the 
patient (for example, responding patient with neutropenia or low platelets, that resolve 
past 6 weeks may be restarted on therapy); this case must be fully documented. 
 
5.3     Concomitant Therapy 
All supportive measures consistent with optimal subject care will be given throughout 
the study.  Concomitant medications will be captured in the CRF beginning at 
screening. Packed red blood cell or platelet transfusions are allowed when necessary.  
Growth factor use (including erythropoietin) is not allowed with the exception of the use 
of filgrastim (G-CSF) or pegfilgrastim, which is permitted ONLY when used to treat 
febrile neutropenia or in patients who have prolonged (one week or more) grade 3-4 
neutropenia, after approval from Principal Investigator. Concomitant use of cytotoxic 
chemotherapeutic agents (e.g. hydroxyurea), or other experimental drug or therapy for 
myelofibrosis while the subject is on study is prohibited.   Concurrent use of strong 
inducers or strong inhibitors of CYP3A4 (strong inducers are rifampin and St. John’s 
Worth; strong inhibitors are HIV-antivirals, clarythromycin, itraconazole, ketoconazole, 
nefadozone, and telithromycin) is prohibited.  
 
Lenalidomide increases the risk of thrombotic events in patients who are at high risk or 
with a history of thrombosis, in particular when combined with other drugs known to 
cause thrombosis. When lenalidomide is combined with other agents such as steroids 
(e.g. 
dexamethasone, 
prednisone), 
anthracyclines 
(Doxil, 
adriamycin) 
and 
erythropoietin the risk of thrombosis is increased.  Consideration should be given to the 
use of aspirin (81 or 100 mg) as prophylaxis as deemed appropriate (through 
commercial supply, not provided by the Incyte or Celgene companies).   When the 
platelet count falls below 35 X109/L, aspirin prophylaxis should be discontinued until the 
platelet count is > 35 X109/L and stable (not less than prior measurement) or increasing 
on two consecutive measurements at least 4 days apart. 
 
5.4 
Pharmacokinetic Assessment 
 
Blood samples will be collected for pharmacokinetic (PK) analysis at three different time 
points. Patient medical number will be changed to a code that could only be deciphered 
by the principal investigator, thus preserving patient confidentiality. This collection will 
involve an additional procedure (a needle stick) at these time points. Time of the dose 
taking and PK sample draw time will be recorded in the draw sheets that are part of 
patients’ medical records. Blood samples will be centrifuged to obtain plasma and 
stored at -20° C until shipment to Incyte Corp., who will perform the testing. 
 
5.5 
Pretreatment Evaluation  
 
History and physical exam including vital signs, body weight and height, and spleen 
and liver measurements. This also includes a transfusion history for 3 months prior 
to day 1 and concomitant medication notation (within 14 days of study day 1) 


Page 14 of 26 
 
 
CBC and differential, electrolytes (Na, K, Cl HCO3), creatinine, uric acid, BUN, 
glucose, total bilirubin, and SGPT, PT/PTT, INR (within 14 days of study day 1). 
 
Bone marrow biopsy and aspirate (within 3 months of study day 1) with 
cytogenetics (if not done before) and JAK2V617F status and allele burden.  
 
Urinalysis (within 14 days of study day 1) 
 
ECG (within 14 days of study day 1) 
 
Pregnancy test (for FCBP only) with a sensitivity of at least 50 mIU/mL, within 10 – 
14 days prior to and again within 24 hours of starting lenalidomide. 
 
Myelofibrosis Symptom Assessment Form (MFSAF) questionnaire and MDASI (MD 
Anderson Symptom Inventory) questionnaire (within 3 days of study day 1) 
 
5.6 
Evaluation During Study 
 
Directed history and physical examination including vital signs, body weight, and 
spleen and liver measurements prior to each cycle for the first 3 cycles then every 3 
to 6 cycles. This also includes a transfusion history for previous cycle of therapy 
and concomitant medication notation. 
 
CBC and differential, electrolytes (Na, K, Cl HCO3), creatinine, BUN, glucose, total 
bilirubin, and SGPT weekly for 2 cycles, then every 2 weeks while on therapy.  
Those responding patients continuing therapy past 6 cycles and on a stable dose 
level without interruption or delay for 4 cycles may have blood tests done monthly)   
 
Bone marrow aspiration with cytogenetics (if abnormal pre-therapy), JAK2V617F 
allele burden (if JAK2V617F mutation present pre-therapy) after cycle 3,6,9,12 and 
then as determined appropriate by the investigator. 
 
Response assessment (IWG-MRT) monthly for first 3 cycles, then every 3 to 6 
cycles 
 
Pregnancy test, urine or blood, (sensitivity of at least 50 mIU/mL) every week x 4, 
then every 4 weeks for all FCBP with regular menstrual cycles, or every 2 weeks if 
irregular cycles. 
 
Optional blood samples (20-50cc) on day 1 of cycle 2 for pharmacokinetics (PK) at 
approximately 0.5-1 hour, 2-4 hours, and 4-8 hours post ruxolitinib dose (3 time 
points). Not all research samples may be collected at all time points. 
 
Collect any unused study drug and review patient study drug dosing diary for 
compliance; 
 
Assessment of AEs using the NCI CTEP CTCAE, version 4.0 (published 
28 May 2009) 
 
Myelofibrosis Symptom Assessment Form (MFSAF) questionnaire every 
cycle x3, then every 3 to 6 cycles 
 
MDASI (MD Anderson Symptom Inventory) questionnaire administration: 
patients will complete the paper or tablet PC version of the MDASI at every 
cycle x3, then every 3 to 6 cycles. Patients will be instructed in the use of an 
Interactive Voice Response (IVR) system that will be used to assess 
symptoms with the MDASI weekly for first 3 cycles of therapy when patients 
do not have clinic appointments. If patients do not respond to an IVR call, 
the research coordinator will attempt to personally contact the patient by 
telephone to complete the MDASI. 
 


Page 15 of 26 
 
 
Outside Physician Participation During Treatment 
 
 MDACC Physician communication with the outside physician is required prior to 
the patient returning to the local physician. 
This will be documented in the patient record 
 A letter to the local physician outlining the patient's participation in a clinical trial 
will request local physician agreement to supervise the patient's care (Appendix 
L) 
 Protocol required evaluations outside MDACC will be documented by telephone, 
fax or e-mail.  Fax and/or e-mail will be dated and signed by the MDACC 
physician, indicating that they have reviewed it. 
 Changes in drug dose and/or schedule must be discussed with and approved by 
the MDACC physician investigator, or their representative prior to initiation, and 
will be documented in the patient record. 
 A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
 Documentation to be provided by the local physician will include drug 
administration records, progress notes, reports of protocol required laboratory 
and diagnostic studies and documentation of any hospitalizations. 
 The home physician will be requested to report to the MDACC  
physician investigator all life threatening events within 24 hours of documented 
occurrence. 
 Patients will return to MDACC every 2 weeks during Cycles 1 and 2, monthly for 
2 cycles, then every 3 to 6 months as long as on the study for evaluation. 
 
  
The patient will be contacted by the PI and his staff 30 days and 60 days after 
discontinuation of protocol +/-7 days to assess for AE’s, unless the patient receives 
further cytotoxic chemotherapy treatment. 
 
 
5.7 
Criteria for Removal from the Study 
Treatment with study drugs is to be discontinued when any of the following occurs: 
 
Lack of therapeutic effect (any effort should be made to provide therapy to the 
patient in a safe way for at least 3-6 cycles for proper assessment of potential 
efficacy) 
 
Adverse event(s) that, in the judgment of the Investigator, may cause severe or 
permanent harm or which rule out continuation of study drug. 
 
Withdrawal of consent 
 
Lost to follow up 
 
Death 
 
Suspected pregnancy 


Page 16 of 26 
 
 
6.0 
CRITERIA FOR RESPONSE  
Best overall response will be categorized according to the International Working Group 
Criteria: 
Complete remission (CR): Requires all of the following in the absence of both 
transfusion and growth factor support;  
 
Complete resolution of disease-related symptoms and signs including palpable 
hepatosplenomegaly. 
 
Peripheral blood count remission defined as hemoglobin > 11 g/dL, platelet count ≥ 
100 x 109/L, and absolute neutrophil count ≥ 1.0 x 109/L. 
 
Normal leukocyte differential including disappearance of nucleated red blood cells 
and immature myeloid cells in the peripheral smear, in the absence of 
splenectomy.* 
 
Bone marrow histological remission defined as the presence of age-adjusted 
normocellularity, < 5% myeloblasts, and an osteomyelofibrosis grade of ≤ 1.**  
 
 
Partial remission (PR): Requires all of the above criteria for CR except the 
requirement for bone marrow histological remission. However, a repeat bone marrow 
biopsy is required in the assessment of PR and may or may not show favorable 
changes that do not however fulfill criteria for CR. 
 
Clinical improvement (CI): Requires one of the following in the absence of both 
disease progression (as outlined below) and CR/PR assignment (CI response is 
validated only if it lasts for ≥ 8 weeks). 
 
A ≥ 2 g/dL increase in hemoglobin level or becoming transfusion independent 
(applicable only for patients with baseline hemoglobin level of < 10 g/dL).§ 
 
Either a ≥ 50% reduction in palpable splenomegaly of a spleen  that is ≥ 10 cm at 
baseline or a spleen that is palpable at > 5 cm at baseline becomes not palpable.§§ 
 
A ≥ 100% increase in platelet count and an absolute platelet count of ≥ 50,000 x 
109/L. (applicable only for patients with baseline platelet count of < 50 x 109/L). 
 
A ≥ 100% increase in ANC and an ANC of ≥ 0.5 x 109/L (applicable only for patients 
with baseline absolute neutrophil count of < 1 x 109/L). 
 
Progressive disease: Requires one of the following:¶ 
 
Progressive splenomegaly that is defined by the appearance of a previously absent 
splenomegaly that is palpable at > 5 cm below the left costal margin or a ≥ 100% 
increase in palpable distance for baseline splenomegaly of 5-10 cm or a ≥ 50% 
increase in palpable distance for baseline splenomegaly of > 10 cm. 
 
Leukemic transformation confirmed by a bone marrow blast count of ≥ 20%.  
 
An increase in peripheral blood blast percentage of ≥ 20% that lasts for ≥ 8 weeks. 
 
Stable disease: None of the above. 
 
Relapse: Loss CR, PR, and CI. In other words, a patient with CR or PR is considered to 
have undergone relapse when he or she no longer fulfils the criteria for CI. 


Page 17 of 26 
 
 
*Because of subjectivity in peripheral blood smear interpretation, CR does not require 
absence of morphological abnormalities of red cells, platelets, and neutrophils.  
 
** In patients with CR, a complete cytogenetic response is defined as failure to detect a 
cytogenetic abnormality in cases with a pre-existing abnormality. A partial cytogenetic 
response is defined as 50% or greater reduction in abnormal metaphases. In both 
cases, at least 20 bone marrow- or peripheral blood-derived metaphases should be 
analyzed. A major molecular response is defined as the absence of a specific disease-
associated mutation in peripheral blood granulocytes of previously positive cases. In the 
absence of a cytogenetic/molecular marker, monitoring for treatment-induced inhibition 
of endogenous myeloid colony formation is encouraged. §Transfusion dependency is 
defined by a history of at least 2 units of red blood cell transfusions in the last month for 
hemoglobin of < 8.5 g/dL that was not associated with clinically overt bleeding. Similarly, 
during protocol therapy, transfusions for hemoglobin of ≥ 8.5 g/dL is discouraged unless 
it is clinically indicated. 
 
§§In splenectomized patients, palpable hepatomegaly is substituted with the same 
measurements. 
 
¶It is acknowledged that worsening cytopenia might represent progressive disease but 
its inclusion as a formal criterion was avoided because of the difficulty distinguishing 
disease-associated from drug-induced myelosuppression. However, a decrease in 
hemoglobin of ≥ 2 g/dL, a 100% increase in transfusion requirement, and new 
development of transfusion dependency, each lasting for more than 3 months after the 
discontinuation of protocol therapy can be considered disease progression. 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1  Serious Adverse Event Reporting (SAE) for M. D. Anderson-
Sponsored IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
ꞏ 
Death 
ꞏ 
A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
ꞏ 
Inpatient hospitalization or prolongation of existing hospitalization 
ꞏ 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
ꞏ 
A congenital anomaly/birth defect. 
 
 


Page 18 of 26 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
ꞏ 
Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an SAE if 
deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
ꞏ 
All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional Review 
Board Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs 
and Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
 
ꞏ 
All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
 
ꞏ 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 
ꞏ 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
 
ꞏ 
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
ꞏ 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 


Page 19 of 26 
 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
  
 
7.2 
Expedited reporting by investigator to Incyte and Celgene 
 
Serious adverse events (SAE) are defined above.  The investigator will inform Incyte 
and/or Celgene of any SAE within 24 hours of being aware of the event via email and/or 
fax. Respective companies will to be informed based on the attribution of a given SAE:  
 
1. 
Due to INCB018424 alone – These SAEs will only to be reported to INCYTE.  
2. 
Due to the Lenalidomide – These SAEs will only be reported to CELGENE.  
3. 
Due to both the INDB018424 and the Lenalidomide – These SAEs will be 
reported to INCYTE and CELGENE.  
4. 
All pregnancies will be reported to both companies.  
 
If the investigator can’t associate causality with one or the other alone then causality 
needs to be associated with the combination of the products.  These SAEs will go to both 
INCYTE and CELGENE.   
 
Adverse events will be documented in the medical record and entered into the case 
report form. PDMS/ CORe will be used as the electronic case report form for this 
protocol. Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each event 
for all subjects enrolled on the trial. SAEs must be documented on MDACC “Internal SAE 
Report Form for Prompt Reporting”. This form must be completed and supplied to Incyte 
and/or Celgene within 24 hours/1 business day at the latest on the following working day.  
The initial report must be as complete as possible, including details of the current illness 
and (serious) adverse event, and an assessment of the causal relationship between the 
event and the investigational product(s).  Information not available at the time of the initial 
report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up MDACC SAE reporting form.  
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject or the female partner of a male subject 
occurring while the subject is on study drug, or within 60 days of the subject’s last dose 
of study drug, are considered immediately reportable events. Study drug is to be 
discontinued immediately in a female patient and the patient instructed to return any 
unused portion of the study drug to the investigator(s).  The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Incyte and Celgene 
immediately by phone and facsimile using the MDACC AE report form. The female 
should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for 
further evaluation and counseling. 
 


Page 20 of 26 
 
The Investigator(s) will follow the female subject until completion of the pregnancy, and 
must notify Incyte and Celgene of the outcome of the pregnancy as a follow-up to the 
initial AE report. If the outcome of the pregnancy meets the criteria for immediate 
classification as a SAE (i.e., spontaneous or therapeutic abortion [any congenital 
anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, or 
congenital anomaly [including that in an aborted fetus]), the Investigator(s) should follow 
the procedures for reporting SAEs (i.e., report the event to Incyte and Celgene within 24 
hours of the Investigator’s knowledge of the event). In the case of a live “normal” birth, 
Incyte and Celgene should be advised within 24 hours of the Investigator’s knowledge of 
the event. All neonatal deaths that occur within 30 days of birth should be reported, 
without regard to causality, as SAEs.  In addition, any infant death after 30 days that the 
Investigator(s) suspects is related to the in utero exposure to the study drug should also 
be reported to  Incyte and Celgene within 24 hours of the Investigators’ knowledge of the 
event. If the female is found not to be pregnant, any determination regarding the 
subject’s continued participation in the study will be determined by the principal 
investigator. 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
All subjects meeting the eligibility criteria that have signed a consent form and have 
begun treatment will be evaluable for response. This is a two stage, phase II trial 
designed to assess the effect of therapy in subjects with Primary, Post Polycythemia 
Vera, or Post Essential Thrombocythemia Myelofibrosis (PMF, post-PV MF, or post-ET 
MF). Secondary objective is to determine the safety of therapy in this population.  
 
The primary objective of this study is to assess efficacy in terms of the objective 
response rate (complete and partial response, and clinical improvement by IWG-MRT) 
in patients with MF.  The Min-Max two-stage design proposed by Simon will be 
implemented.  Sample size and decision criteria are chosen to reduce the expected 
accrual if the treatment is ineffective in regard to response relative to having no interim 
stopping rule.  The target response rate is 50%.  A response rate of 35% or less will be 
considered unacceptable and treatment with the therapy will be discontinued. Given the 
response rates stated above, if the probability of inappropriately accepting a poor 
therapy is 10% (alpha=0.1), a total sample size of 49 patients will result in 80% power 
(beta =0.2).  
 
In the first stage of the design, a total of 31 patients will be enrolled and the study will be 
put on hold to assess response.  If 10 or fewer patients respond to the combination 
therapy, after being treated for 6 months or discontinued due to excessive toxicity or 
lack of efficacy, then the study will be terminated and the therapy will be declared 
ineffective. Those patients who stopped receiving one of the two study drugs due to 
safety reasons will be counted as failures in the efficacy analysis. However, if 11 or 
more patients respond, up to an additional 18 patients will be enrolled to complete the 
study. 
 


Page 21 of 26 
 
After a total of 49 patients have been enrolled into the study, if 21 or fewer patients 
respond to the therapy, the therapy will be declared ineffective.  However, if greater 
than 21 patients respond to the therapy, the therapy will be considered efficacious.  The 
probability of early termination due to unacceptable response rate is 46% under the null 
hypothesis. 
 
Data from all subjects who receive any study drug will be included in the safety 
analyses. Subjects who entered the study and did not take any of the study drug and 
had this confirmed, will not be evaluated for safety. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible. We will follow standard reporting guidelines for adverse events (Appendix C; 
Leukemia-specific Adverse Event Recording and Reporting Guidelines).  
 
Descriptive statistics will be utilized to assess time to response and response duration.    
Duration of response: duration of response is defined as the date at which the 
subject’s objective status is first noted to be a CR, PR or CI to the date progression (no 
longer meeting criteria for either CR, PR or CI) is documented (if one has occurred).  
Patients who continue to respond as of the data cut-off date will be censored as of the 
date of their last assessment documenting continued response. 
Time to response: The time to response is defined as the time from study registration 
to the first date at which the subject’s objective status was classified as a response (CR, 
PR or CI). In subjects who do not achieve a response, time to response will be 
censored at the subject’s last evaluation date. The distribution for each of these event-
time variables (duration of response and time to response) will be estimated by Kaplan-
Meier curves.  
Anemia:  Descriptive statistics will be used to explore improvements in anemia and 
transfusion dependence.  The following outcomes will be summarized: mean changes in 
hemoglobin at monthly intervals. The proportion of transfusion independent patients not 
requiring transfusions on study who experience an increase of 2 g/dL in their 
hemoglobin relative to baseline, the proportion of transfusion dependent patients 
(defined as requiring a transfusion of 2 units PRBCs monthly for 3 months (12 weeks) 
prior to starting the trial) who become transfusion independent (not requiring a 
transfusion of PRBCs over a period of 3 months (12 weeks) while on study), the 
proportion of transfusion dependent patients who become transfusion independent and 
have a 1 g/dL increase in hemoglobin relative to baseline, and the proportion of 
transfusion independent patients requiring a transfusion while on study. 
JAK2V617F Allele burden:  Change in JAK2V617 allelle burden from baseline to each 
visit where it is measured. 
 
This phase II clinical trial will have a stopping rule based on toxicity defined as an 
adverse events considered to be at least possibly related to treatment. In particular, 
accrual to the study will be temporarily suspended if: a) 2 or more among the first 10 
subjects treated on this trial experiences a Grade 4 non-hematologic toxicity or a 


Page 22 of 26 
 
serious adverse event that is felt to be drug related. b) 20% or more of subjects (when 
more than 10 subjects have been accrued) experience a Grade 4 non-hematologic 
toxicity or serious adverse event that is felt to be drug related. After consideration by 
the study team (study chair, statistician), a decision will be made as to whether accrual 
can resumed after approval of the appropriate IRB. 
 
9.0 
REFERENCES 
  
1. Thalidomide and lenalidomide in primary myelofibrosis. 
 
Holle N, de Witte T, Mandigers C, Schaap N, Raymakers R. 
 
Neth J Med. 2010 Aug;68(1):293-8.  
2. Lenalidomide plus prednisone results in durable clinical, histopathologic, and 
molecular responses in patients with myelofibrosis. 
 
Quintás-Cardama A, Kantarjian HM, Manshouri T, Thomas D, Cortes J, Ravandi F, 
Garcia-Manero G, Ferrajoli A, Bueso-Ramos C, Verstovsek S. 
 
J Clin Oncol. 2009 Oct 1;27(28):4760-6.  
3. The evolving role of lenalidomide in the treatment of hematologic malignancies. 
 
Kastritis E, Dimopoulos MA. 
 
Expert Opin Pharmacother. 2007 Mar;8(4):497-509.  
4. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. 
 
Tefferi A, Cortes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL, Hogan WJ, Litzow 
MR, Allred JB, Jones D, Byrne C, Zeldis JB, Ketterling RP, McClure RF, Giles F, 
Kantarjian HM. 
 
Blood. 2006 Aug 15;108(4):1158-64.  
5. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. 
 
Quintás-Cardama A, Kantarjian H, Cortes J, Verstovsek S. 
 
Nat Rev Drug Discov. 2011 Feb;10(2):127-40. 
6. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. 
 
Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, 
Estrov Z, Fridman JS, Bradley EC, Erickson-Viitanen S, Vaddi K, Levy R, Tefferi A. 
 
N Engl J Med. 2010 Sep 16;363(12):1117-27. 
7. Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative 
neoplasms and psoriasis. 
 
Mesa RA. 
 
IDrugs. 2010 Jun;13(6):394-403. 
8. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic 
implications for the treatment of myeloproliferative neoplasms. 
 
Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen 


Page 23 of 26 
 
X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, 
Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S. 
 
Blood. 2010 Apr 15;115(15):3109-17.  


Page 24 of 26 
 
 APPENDIX I: SCHEDULE OF ASSESSMENTS  
 
 
Procedure 
Screening Period 
14 days from Day 1 (first 
day of study drug 
administration) 
Cycle 19.and 2 
Cycle 39. 
After Cycle 3 or at 
discontinuation9. 
Day 
15 
Day 
8 
Day 
15 
Day  
22 
Every 28 days 
Every 3 to 6 Cycles  
(84 to 168 days) 
Informed Consent signing  
X 
 
 
 
 
 
 
Medical History (including prior MF-
directed therapies)  
X 
 
 
 
 
 
 
Physical examination1 
X 
X 
 
X 
 
X 
X 
Vital Signs and Weight,Height11 
X 
X 
 
X 
 
X 
X 
Transfusion History2 
X2 
 
 
 
 
X 
X 
MFSAF and MDASI questionnaires 
 
X 
 
 
 
X 
X 
Pregnancy test (for FCBP only)3 
X 
X 
X 
X 
X 
X 
X 
CBC and differential6 
X 
X 
X 
X 
X 
X6 
X6 
Serum Chemistry4 
X 
X 
X 
X 
X 
X6 
X6 
12-Lead ECG and urinalysis 
X 
 
 
 
 
 
 
Bone Marrow Aspirate and Biopsy7 
X 
 
 
 
 
 
X8 
Correlative studies for PK: 
       Peripheral blood sample x3 
- 
X10 
 
 
 
 
 
Assess and Record adverse events 
X 
X 
 
X 
 
X 
X 
Record concomitant 
therapies/procedures 
X 
X 
 
- 
 
X 
X 
Response Assessment 
 
 
 
 
X 
X 
X 
1. Includes measurement of spleen and liver. 
2. Subjects must have 3 months documented transfusion history prior to Day 1. 
3. Pregnancy test, urine or blood, with a sensitivity of at least 50 mIU/mL, within 10 – 14 days prior to and again within 24 hours of starting lenalidomide; then every week x 4, then monthly 
for all FCBP with regular menstrual cycles, or every 2 weeks if irregular cycles. 
4. sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, total bilirubin, alanine aminotransferase, and glucose. Uric Acid, PT/PTT and INR need be done only pre-
therapy. 
5. If not done within 3 days of Day 1. 
6. CBC with differential and serum chemistries will be done weekly for 2 cycles, then every 2 weeks while on therapy. Those responding patients continuing therapy past 6 cycles and on a 
stable dose level without interruption or delay for 4 cycles may have blood tests done monthly. 
7. Bone Marrow Aspirate and Biopsy (can be done within 3 months) includes standard cytogenetic analysis and JAK2 mutation testing (quantitative PCR for allele burden). Cytogenetic 
test and JAK2 mutation test do not need to be repeated during the study in patients with known normal chromosomes or without mutation. BM collected after Cycle 3,6,9,12 and then as 
determined appropriate by the investigator.  
8. May be omitted if so decided by the treating physician. Should be done to confirm complete response and when clinically indicated.  


Page 25 of 26 
 
9. All scheduled visits will have a +/- 7 days window unless otherwise stated. In between required MD Anderson visits, mandatory visits may be done at the local referring doctor’s office at 
minimum every 28 days (+/- 7 days);, this will also include phone contact by the study staff. The discontinuation visit will be considered as such on the date the patient is taken off the 
protocol. The patient will be contacted by the PI 30 days and 60 days after discontinuation of protocol +/-7 days to assess for AE’s. 
10. on day 1 of cycle 2 for pharmacokinetics (PK) at approximately 0.5-1 hour, 2-4 hours, and 4-8 hours post Ruxolitinib dose (3 time points). 
11. Height at screening only 
 
 
 


Page 26 of 26 
 
APPENDIX II 
 
International Working Group for Myelofibrosis Research and Treatment Prognostic scoring system   
 
Risk group 
No. of factors 
Median survival 
(mo; 95% CI) 
Proportion of 
deaths, % 
Low 
 
0 
135 (117-181) 
32 
Intermediate-1 
1 
95 (79-114) 
50 
Intermediate-2 
2 
48 (43-59) 
71 
High 
 3 or more 
27 (23-31) 
73 
Risk factors include: age >65 years, constitutional symptoms, hemoglobin <10g/dL, white blood cell count >25x109/L, Blood blasts > 1%.