Clinical trial NCT02267278
Conditions: Myeloproliferative Diseases
Keywords: Myeloproliferative Diseases Myelofibrosis MF Primary or post essential thrombocythemia/polycythemia vera Ruxolitinib Jakafi INCB018424 INC424 Pracinostat Questionnaire Survey
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-01-12; Completion date: 2018-06-01
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if pracinostat, when given in combination with ruxolitinib, can help to control myelofibrosis (MF). The safety of this drug combination will also be studied.

This is an investigational study. Pracinostat is not FDA-approved or commercially available. It is currently being used for research purposes only. Ruxolitinib is FDA-approved and commercially available to treat MF.

The study doctor can explain how the study drugs are designed to work.

Up to 25 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will take ruxolitinib by mouth 2 times each day. You may take your dose of ruxolitinib with or without food.

You will also take pracinostat by mouth 1 time each day for 3 alternating days (for example Monday, Wednesday, Friday or Tuesday, Thursday, Saturday) every 3 weeks starting on Day 1 of Cycle 4. You will take your dose of pracinostat in the morning, about 30 minutes before or 2 hours after a meal. You should swallow your dose of pracinostat whole with a cup of water (about 8 ounces).

You will be given a study drug diary to write down when you take your dose of study drugs and if you miss or vomit any doses of study drug. You must bring the diary with you to the clinic on Day 1 of each cycle and at the end-of-treatment visit. You will also need to bring any leftover pills and any empty containers of the study drugs to the clinic when the study doctor tells you to do so.

Study Visits:

There are 28 days (4 weeks) in every study cycle. You will visit MD Anderson for regular study visits while participating in this study during Cycles 2-7, and then once every 3 cycles after that (Cycles 10, 13, 16, and so on).

Once during Cycles 2-7 and then once every 3 cycles after that (Cycles 10, 13, 16, and so on):

* You will have a physical exam.
* You will complete the questionnaire about your quality of life.

At your visits during Cycles 4, 5, and 6 and then once every 3 cycles starting with cycle 10 (cycles 10, 13, 16 and so on): You will have an EKG to check your heart function.

At your visits during Cycles 4, 5, and 7 and then every 3 cycles after that (Cycles 10, 13, 16, and so on) blood (about 1-2 teaspoons) will be drawn for cytokine testing.

At your visits during Cycles 7 and 13, and then every 6 cycles after that (Cycles 19, 25, 31, and so on), if the doctor thinks it is needed, you will have a bone marrow biopsy to check the status of the disease and for cytogenetic and genetic testing.

Every 2 weeks during the first 6 cycles and then about every 3 cycles after that, blood (about 2-3 tablespoons) will be drawn for routine tests. In between the mandatory visits to MD Anderson, you may choose to have these blood draws performed at a local lab or clinic closer to your home. The results will be sent to the study doctor.

Length of Treatment:

You may continue taking the study drugs for up to 4 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.

Your participation on the study will be over after the follow-up.

Follow-Up:

About 30 days after your last dose of study drugs, if you are not receiving another treatment for MF, you will be called by the study doctor or a member of the study staff and asked about any side effects you may be having. This call should last about 10 minutes.

Arms: arm 1: Ruxolitinib starting dose 15 mg orally twice/day in 28-day cycle (dose assigned based on platelet count, if low platelet count gradual up-titration from a starting dose of 5 mg) - given alone for first 3 months, then Pracinostat added at starting dose 60 mg orally once/day for 3 alternating days every 3 weeks starting Day 1 of Cycle 4.

Dose of Ruxolitinib may be increased or decreased prior to initiation of Pracinostat. Quality of Life Questionnaire.
Interventions: intervention 1: Ruxolitinib intervention 2: Pracinostat intervention 3: Questionnaire
Intervention descriptions: intervention 1: Ruxolitinib taken by mouth 2 times each day in a 28-day cycle. Patients receive Ruxolitinib alone for first 3 months, and then Pracinostat added. Starting dose of Ruxolitinib based on patients' platelet count. Dose of Ruxolitinib may be increased or decreased at discretion of treating physician prior to initiation of Pracinostat. intervention 2: Starting dose of Pracinostat 60 mg by mouth 1 time each day for 3 alternating days every 3 weeks starting on Day 1 of Cycle 4. intervention 3: Questionnaire regarding quality of life completed at baseline, within 3 days before Day 1 of Cycles 1 - 6, and then every 3 cycles after that.

Protocol documents:
Prot_SAP_000.pdf: 
2014-0445
October 23, 2016
Page 1
Protocol Page
EVALUATION OF RUXOLITINIB AND PRACINOSTAT COMBINATION AS A 
THERAPY FOR PATIENTS WITH MYELOFIBROSIS
2014-0445
Core Protocol Information
Short Title 
Ruxolitinib and Pracinostat Combination Therapy for Patients with MF
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 PRACINOSTAT COMBINATION AS A THERAPY FOR 
PATIENTS WITH MYELOFIBROSIS
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 06/01/2018
Version:
13
Submitted by:
Sandra L. Rood--10/23/2017 2:12:37 PM
OPR Action:
Accepted by:  Elizabeth Orozco -- 10/26/2017 1:34:18 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2014-0445
October 23, 2016
Page 2
Protocol Body
 


Page 1 of 33 
 
EVALUATION OF RUXOLITINIB AND PRACINOSTAT COMBINATION AS A 
THERAPY FOR PATIENTS WITH MYELOFIBROSIS 
 
 
1.0 
HYPOTHESIS AND OBJECTIVES 
 
Hypothesis 
Ruxolitinib (also known as INCB018424), a JAK1/2 inhibitor, and pracinostat (a histone 
deacetylase inhibitor; HDACi) 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/clinical activity of the combination of ruxolitinib 
with pracinostat as therapy in patients with MF 
Secondary: 
 
to determine the toxicity of the combination of ruxolitinib with pracinostat 
as therapy in patients with MF  
 
Exploratory: 
 to explore time to response and duration of response 
 to explore changes in bone marrow fibrosis  
 to explore changes in JAK2V617F (or other molecular marker) allele 
burden or changes in cytogenetic abnormalities 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1  Myelofibrosis 
Myelofibrosis (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.  
 
The entity of MF can be either idiopathic (primary) or representative of end-stage 
myeloproliferative 
diseases 
such 
as 
polycythemia 
vera 
(PV) 
or 
essential 
thrombocythemia (ET).  MF occurs in about 15-25% of patients with PV and in 5-10% of 
patients with ET. In the early cellular phase of MF with minimal marrow fibrosis, the 
differential diagnosis includes Philadelphia-positive chronic myeloid leukemia (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 


Page 2 of 33 
 
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. 
 
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 of 65 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 g/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 
g/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. 


Page 3 of 33 
 
 
Several therapies are available for MF, however no one therapy has demonstrated an 
ability to produce sustained remissions. In addition, currently available therapies are 
often limited by their myelosuppressive effects. Ruxolitinib, a JAK1/2 inhibitor, produces 
symptom 
and 
spleen-size 
responses, 
but 
may 
result 
in 
anemia 
and/or 
thrombocytopenia in a significant proportion of patients.  Hydroxyurea is another 
commonly used agent in the proliferative phases of the disease.  Interferon-alpha had 
yielded hematologic 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 dysregulated in MF 
include tumor necrosis factor-alpha (TNF-alpha) and angiogenic agents like vascular 
endothelial growth factor (VEGF).   
 
2.2 
Ruxolitinib 
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 


Page 4 of 33 
 
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 MF patients. More recently, other 
mutations have been identified in MPD patients lacking the JAK2V617F mutation. For 
instance, additional activating mutations in JAK2, mutation in the thrombopoietin 
receptor (MPL), and calreticulin (CALR) mutations result in constitutive ligand-
independent JAK-STAT 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 use of JAK inhibitor in these diseases. Ruxolitinib is a JAK1/2 
inhibitor that is currently FDA approved for the treatment of patients with intermediate 
and high risk MF. 
 
Ruxolitinib, has been shown to produce durable clinical benefits in terms of spleen 
volume reduction and improvement in constitutional symptoms with an acceptable 
toxicity profile1,2. Based on the results of two phase III studies (COMFORT-I, 
COMFORT-II)3,4  showing improvement in spleen size, symptom control and 
improvement in quality of life, ruxolitinib was approved for use in patients with 
intermediate or high-risk myelofibrosis by the FDA. There is also evidence of a benefit in 
overall survival (OS) in patients treated with ruxolitinib. An OS advantage (HR=0.58; 
95% CI, 0.39-0.85, p=0.005) in treated patients compared to historical controls has 
been reported5. In addition, an analysis of the COMFORT-I study confirmed that 
patients treated with ruxolitinib had an OS advantage compared with placebo (HR=0.58, 
95% CI, 0.36-0.95, p-0.03) with a median of 102 weeks of follow up6. Follow-up analysis 
of the COMFORT-II trial has also demonstrated an OS advantage for patients treated 
with ruxolitinib7.  
 
2.3 
Pracinostat 
Abnormal epigenetic silencing of important regulatory genes has been described in 
cancer, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).  
The reduction of acetylation status of histones is one mechanism for this silencing.  
Inhibitors of histone deacetylases (HDACs) have been extensively studied in both 
hematologic (‘liquid’) and solid tumors.  Histone deacetylases are enzymes involved in 
the remodeling of chromatin, and therefore, have a key role in the epigenetic regulation 
of gene expression.  There are currently two US Food and Drug Administration (FDA) 
approved HDAC inhibitors, one oral and one injectable, for the treatment of T-cell 
lymphoma. 
 


Page 5 of 33 
 
The investigational agent pracinostat is a rationally designed, potent, oral, pan-HDAC 
(including Class I, II, and IV isoforms) inhibitor with predictable pharmacokinetic (PK) 
properties.  The IC50, across a broad range of human cancers in in vitro cytotoxicity 
assays, ranged from 0.1 to 1.5 μM, with the lowest values noted in leukemia and 
lymphoma cell lines.  Synergistic interactions have been observed with multiple 
cytotoxic and targeted anti-cancer therapeutics; notably the combination index with 
azacitidine ranged from 0.44 to 0.55. 
Clinical Experience 
Pracinostat has been tested in more than 200 patients in multiple single agent and 
combination Phase I and pilot Phase II clinical trials and has been found to be generally 
well-tolerated at doses up to 60 mg given three times per week (e.g., Monday, 
Wednesday, Friday) for 3 weeks on an every-4-week schedule.  The most common 
manageable side effects often associated with drugs of this class, including pracinostat, 
are 
fatigue, 
gastrointestinal 
(GI) 
effects 
(nausea, 
vomiting, 
diarrhea), 
and 
myelosuppression.  
Pracinostat has demonstrated clinical evidence of both single-agent and combination 
clinical activity, including patients with advanced hematologic disorders.  Data from nine 
patients in a pilot Phase II clinical trial of pracinostat in combination with azacitidine in 
heavily-treated patients with advanced MDS showed an encouraging overall response 
rate (ORR).  This pilot study was conducted as an expansion cohort in the context of a 
Phase Ib trial of pracinostat in hematological malignancies to determine the efficacy and 
safety of the combination of pracinostat (60 mg orally every other day, 3 days a week, 
for 3 consecutive weeks) and azacitidine (75 mg/m2 IV daily x 5 days every 3 to 
6 weeks) given in 4-week cycles to patients with intermediate-2 (INT-2) or high risk 
MDS. 
Baseline patient characteristics included the following:  median age was 64 years 
(range, 22 to 73), white blood cells 2.4 x 109/dL (0.7 to 9.3), hemoglobin 10 g/dL 
(8.2 to 11), platelets 31 x 109/dL (14 to 269), and bone marrow blasts 7% (0% to 18%).  
Seven 
(78%) 
patients 
had 
therapy-related 
MDS 
with 
histories 
of 
prior 
chemotherapy/radiotherapy exposure (breast cancer [3], non-Hodgkin’s lymphoma [2], 
breast and ovarian cancer [1], and melanoma [1]).  Three patients had failed prior 
therapy: decitabine and haploidentical stem cell transplantation (N=1), lenalidomide 
(N=1), and decitabine and TXA-127 (N=1).  Patients received a median of 4 cycles.  All 
9 patients were evaluable.  The overall response rate (ORR; defined as complete 
remission [CR] + complete remission with incomplete blood count recovery [CRi] + 
partial response [PR]) was 8/9 (89%) and the CR+CRi rate was 7/9 (78%).  Five (56%) 
patients achieved a complete cytogenetic response.  Eight-week mortality was 0%.  
Only 1 (11%) patient died, and this was felt to be unrelated to study drug as it followed 
an allogeneic-stem cell transplantation.  The median duration of response was 45 days 
(0 to 229), 
and 
the 
combination 
was 
generally 
well-tolerated. 
Reasons 
for 
discontinuation were: transition to allogeneic-stem cell transplantation (N=5), no 
pracinostat availability by Sponsor (N=2), no response (N=1), and progression to AML 
(N=1).  All toxicities were Grade 1 or 2, with the most frequent being fatigue and nausea 
(56% each). Based on this data, Pracinostat is currently being tested in several Phase 2 


Page 6 of 33 
 
clinical trials in combination with azacitidine and decitabine for patients with advanced 
hematologic malignancies.  
 
Experience with pracinostat in MF is limited to one small study of 22 patients. Of them, 
18 (82%) carried the JAK2V617F mutation, with a median baseline allele burden of 
59.66% (range 19.85–94.95%). Seven (31%) patients had abnormal cytogenetics at 
study entry, including 2 patients who had a complex karyotype. Most patients (n = 20) 
were symptomatic at study entry with a performance status of 0 (n = 1 [5%]), 1 (n = 16 
[73%]), or 2 (n = 5 [22%]). The majority of patients entered the study having 
splenomegaly (n = 21 [95%]), with a median spleen size of 13 cm beneath the left costal 
margin (range 0–29 cm). Median follow-up was 5 months (range 1–11.3 months). 
Overall, 8 (36%) patients experienced clinical benefit from pracinostat therapy. Although 
when analyzed as a whole, the cohort of patients did not experience a significant 
reduction in spleen size, 6 (27%) patients experienced a reduction in splenomegaly 
(median reduction 3 cm, range 1–4 cm) (Fig. 1). However, no patient had a response 
that could be classified as splenomegaly clinical improvement by IWG criteria (i.e. 
spleen reduction of at least 50% from baseline). When only responders were 
considered, the reductions in spleen size from baseline were significant (p = 0.02). Two 
patients had anemia clinical improvement by IWG criteria, experiencing increments in 
their hemoglobin level from 9.1 g/dL at baseline to 11.1 g/dL and from 7.9 g/dL to 15.3 
g/dL at last follow-up, respectively. Five (50%) of 10 patients with hepatomegaly 
reduced their liver size by a median of 3 cm (range 1–6 cm). In summary, although a 
significant number of patients exhibited signs of clinical activity to pracinostat, only 2 
patients achieved a response according to IWG criteria (2 anemia responses as 
described). While all patients started pracinostat at 60 mg daily, 8 of them required at 
least one dose reduction to 50 mg and 1 patient required two dose reductions to 40 mg 
daily. Conversely, 6 patients had their dose of pracinostat increased to 80 mg daily due 
to lack of efficacy. Eight patients continued therapy at 60 mg daily. The most frequent 
side effect associated to pracinostat therapy was fatigue, which occurred in 20 (91%) 
patients, which was grade 1 in 17 and grade 2 in 3 patients. Other toxicities included 
pain (n = 5), peripheral edema (n = 4), and diarrhea (n = 3), all grade 1. Rates of grade 
3–4 neutropenia, anemia, and thrombocytopenia were 13%, 0%, and 21%, respectively. 
No patient had died during the conduct of the study and 1 remained on the study 
receiving pracinostat at 50 mg daily. Twenty-one patients were off study due to lack of 
response (n = 9), disease progression (n = 6), patient’s request (n = 2), unrelated 
medical problems (n = 3: surgery for aortic aneurism, prostate cancer, infection) and 
fatigue (n = 1). 
 
2.4 
Rationale for combining ruxolitinib and pracinostat as therapy for MF 
 
The rationale for the use of histone modifiers in MF relies on the fact that both JAK2 as 
well as JAK2V617F can translocate to the cell nucleus and phosphorylate specific lysine 
residues at histone H3 (H3Y41). The affinity of the transcriptional repressor 
heterochromatin protein 1α (HP1α) for histone H3 depends on the phosphorylation 
status of H3Y41. Phosphorylation of H3Y41 decreases the affinity of H3 to HP1α. JAK2 
inhibitors such as TG101209 or AT9283 abrogate nuclear H3Y41 phosphorylation, 


Page 7 of 33 
 
which increases chromatin-bound HP1α in cells, thus leading to repression of HP1α-
regulated genes such as lmo2. Of note, lmo2 is involved in leukemogenesis. Thus, the 
JAK2-H3Y41-HP1α pathway links JAK2 kinase activity to histone modifications, 
aberrant gene expression and leukemogenesis, thus providing the rationale for the use 
of agents that target histone modifications in combination with JAK2 inhibitors to more 
thoroughly suppress JAK2V617F signaling in JAK2-driven malignancies. Clinically, 
then, one might expect synergism of the two medication in terms of improving further 
the number of patients with clinically relevant reduction in organomegaly and MF-related 
systemic symptoms, possibly for a longer duration of time. In addition, it is possible that 
addition of an HDACi would bring additional benefits to patients, like improvement in 
blood cell count or improvement in bone marrow fibrosis. 
 
 
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). 
 


Page 8 of 33 
 
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 
(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 ruxolitinib. 
 
INCB018424 Phosphate Structural Formula 
 
 
 
Ruxolitinib will be provided upon insurance approval through commercial supply.  
 
 
3.2 
Pracinostat (Refer to Investigator’s Brochure) 
 
Investigational Product 
Structural formula: 
(free base) 
Chemical name: 
(2E)-3-{2-butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-
yl}- 
 
N-hydroxyacrylamide hydrochloride  
Common names: 
Pracinostat, SB939 
Pharmacologic class: 
histone deacetylase (HDAC) inhibitor 
Molecular mass: 
358.38 (free base) 
Salt Form: 
Hydrochloride 
Molecular formula: 
C20H30N4O2•2HCl 
N
N
NH
O
OH
N


Page 9 of 33 
 
 
Results from pharmacology studies showed that pracinostat inhibits predominantly 
Class I and II HDACs (Ki=16 to 240 nM).  It effectively inhibits acetylation of histones 
and various other target proteins in a variety of human tumor cell lines at the same 
concentrations as it inhibits proliferation and promotes apoptosis (IC50=0.1 to 1.5 μM).  
Lymphomas and tumors of hematological origin show the highest sensitivity. 
The antitumor activity of orally administered pracinostat has been demonstrated in 
several xenograft mouse models of solid and hematological malignancies including 
colorectal cancer, ovarian cancer, prostate cancer, AML, and B cell lymphoma.  In 
addition, antitumor activity has been shown in a transgenic murine model of early 
colorectal cancer.  In all of these in vivo models, pracinostat was well tolerated (<20% 
body weight loss) at doses of 100 mg/kg for up to 21 consecutive days and 
demonstrated dose-dependent antitumor effects (statistically significant reductions in 
tumor growth compared with vehicle control).  As observed in the in vitro cell studies, 
hematological malignancies are most sensitive to the anti-tumor effects of pracinostat. 
Overall, results from nonclinical studies provided appropriate justification for the safety 
and efficacy of pracinostat in the proposed patient populations. 
 
Drug Formulation, Availability, Administration and Toxicity Information 
Study Medication 
 
Investigational 
Product 
Dosage Form and Strength 
Manufacturer 
Pracinostat  
45 mg and 60 mg capsules 
KP 
Pharmaceutical 
Technology, Inc. 
 
Study Medication Labeling, Packaging, and Supply 
Pracinostat will be supplied by Helsinn Healthcare SA in 2 strengths: 45 mg and 60 mg. 
Each 45 mg and 60 mg capsule contains 45 mg or 60 mg of pracinostat (as free base), 
respectively, and the following inactive ingredients: microcrystalline cellulose, USP/NF 
(Avicel PH102) and magnesium stearate, USP/NF.  Pracinostat capsule size 1:  45 mg 
are flesh, opaque, hard gelatin capsules; 60 mg are Swedish orange and white, opaque, 
hard gelatin capsules. 
All study medications must be kept in a secure place under appropriate storage 
conditions.  Capsules are packaged in blister packs.  Pracinostat capsules should be 
stored at controlled room temperature, 15°C to 30°C (59°F to 86°F). 
 
Precautions and Risks Associated with the Study Medication Pracinostat  
Hematologic:  Treatment with pracinostat has been associated with cytopenias including 
anemia, thrombocytopenia, and neutropenia.  The incidence of cytopenias may 


Page 10 of 33 
 
increase with increasing doses of pracinostat.  Subjects participating in clinical trials of 
pracinostat should be monitored closely for adverse hematologic affects.  The effect of 
dose reduction on the amelioration of cytopenias has not been established; however 
prudent clinical management, including supportive care (appropriate use of transfusions 
and/or hematopoietic growth factors) and dose modification or discontinuation should be 
followed (see Section 5.1). 
Gastrointestinal:  Gastrointestinal disturbances, including nausea, vomiting, and 
diarrhea, have been reported in subjects treated with pracinostat.  Standard antiemetic 
and antidiarrheal medications and appropriate supportive care should be used per 
normal clinical practice in subjects participating in clinical trials of pracinostat.  Pre-
existing nausea, vomiting, and diarrhea should be adequately controlled before 
beginning therapy. 
QTc Prolongation/Cardiac:  Asymptomatic QTc interval prolongation has been observed 
during clinical trials of pracinostat.  Subjects with a prolonged QTc interval at Screening 
will not be permitted to participate in clinical trials of pracinostat.  Hypokalemia or 
hypomagnesemia should be corrected prior to pracinostat administration and 
consideration should be given to monitoring potassium and magnesium in symptomatic 
subjects (e.g., subjects with nausea, vomiting, diarrhea, fluid imbalance, or cardiac 
symptoms). 
General Signs and Symptoms:  Fatigue has been the most common AE reported in 
subjects receiving pracinostat and has frequently prompted dose reduction in subjects 
receiving >60 mg/day. Anorexia has also been commonly reported. Subjects 
experiencing debilitating fatigue or anorexia with weight loss may benefit from dose 
reduction or interruption of pracinostat treatment. 
Please refer to the IB for detailed information on the risks associated with the use of 
pracinostat. 
 
 
4.0 
PATIENT ELIGIBILITY CRITERIA 
 
Inclusion criteria 
1. Diagnosis of MF (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 
Prognostic Scoring System (IPSS). 
2. Palpable splenomegaly of more than or equal to 5 cm below left costal margin on 
physical exam 
3. Understanding and voluntary signing an IRB-approved informed consent form. 
4. Age ≥ 18 years at the time of signing the informed consent. 
5. Disease-free of other malignancies. 
6. ECOG performance status 0 to 2. 


Page 11 of 33 
 
7. Negative pregnancy test in females of childbearing potential (FCBP)† Male patients 
with female partners of child-bearing potential and female patients of childbearing 
potential are required to use two forms of acceptable contraception, including one 
barrier method, during their participation in the study and for 30 days following last 
dose. Acceptable forms of contraception include 1 highly effective method such as 
an intrauterine device (IUD), hormonal (birth control pills, injections, or implants), 
tubal ligation, or partner’s vasectomy and at least 1 additional approved barrier 
method such as a latex condom, diaphragm, or cervical cap. Female patients of 
childbearing potential must not be breast-feeding or planning to breast feed and 
must have a negative pregnancy test ≤7 days before first study treatment. 
8. QTcF interval ≤470 msec 
9. Normal serum potassium and magnesium levels 
10. 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 (unless considered to be 
related to MF or patient has known history of Gilberts)  
11. Platelets >/= 50 x 109/L  
12. ANC >/= 1 x 109/L  
 
Exclusion Criteria 
1. Prior therapy with a JAK inhibitor (other than ruxolitinib for less than 3 months 
duration and currently on it) or HDACi. Patients that are currently on ruxolitinib for 
less than 3 months of therapy are eligible.   
2. Use of any other standard or experimental therapy within 14 days of starting study 
therapy.   
3. Lack of recovery from all toxicity from previous therapy to grade 1 or baseline. 
4. Suspected pregnancy, pregnant or lactating females. 
5. Any condition, including the presence of laboratory abnormalities, which in the 
opinion of the treating physician 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. 
6. Known positive for HIV or infectious hepatitis, type A, B or C. 
7. Patients with gastrointestinal (GI) tract disease, causing the inability to take 
oral medication, malabsorption syndrome, a requirement for intravenous (IV) 
alimentation, prior surgical procedures affecting absorption, uncontrolled 
inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis) 
8. Cardiopulmonary function criteria: 
 Current unstable arrhythmia requiring treatment 
 History of symptomatic congestive heart failure (New York Heart 
Association [NYHA] Class III or IV)  
 History of myocardial infarction within 6 months of enrollment 
                                            
† 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 12 of 33 
 
 Current unstable angina 
 Family history of long QT syndrome  
 
 
5.0 
TREATMENT PLAN 
 
On this study 4 weeks of therapy is considered one cycle of therapy. Ruxolitinib and 
pracinostat will be given orally in an outpatient setting. Ruxolitinib will be given 
continuously daily in 28-day cycles. Patients will receive ruxolitinib alone for the first 3 
months, and then pracinostat will be added. Ruxolitinib provides maximum benefit 
usually within 3 months, therefore we add another agent to ruxolitinib after those initial 3 
months, in order not to compromise benefit of ruxolitinib with some new side effect from 
additional medication (pracinostat in this case). Starting dose of ruxolitinib will be based 
on patients’ platelet count, as per standard practice: 15 mg twice a day (BID) for 
patients with baseline platelet counts of 100‒200 × 109/L and 20 mg BID for those with 
baseline platelet counts >200 × 109/L. For patients with platelet counts of 50‒99 × 109/L, 
gradual up-titration from a starting dose of 5 mg BID is recommended. Dose of 
ruxolitinib may be increased or decreased at the discretion of the treating physician prior 
to initiation of pracinostat (see section 5.1). Patients who started ruxolitinib before 
enrollment into this study, will have the time they have been on ruxolitinib therapy 
counted toward the 3 cycles of ruxolitinib monotherapy, as per protocol.  When a 
dosage change of the Ruxolitinib is indicated (except for holding therapy due to toxicity) 
patients will continue taking their previously prescribed dosing level until the new supply 
of Ruxolitinib is available for use by the patient. 
Pracinostat is supplied as  45 and 60 mg capsules and will be self-administered (by the 
patient) one-time each day, 3 days a week for 3 weeks with doses approximately 48 
hours apart, followed by one week of rest. Study medication will be taken approximately 
30 minutes before a meal (e.g. breakfast) or >2 hours after a meal at approximately the 
same time each of the 3 days weekly (e.g., Monday, Wednesday, and Friday).  
Treatment cycles will be repeated every 28 days, unless delayed due to toxicity.  
Pracinostat should be taken with a glass of water; pracinostat is not to be taken with 
grapefruit or any other juice.  Patients should be instructed to swallow the capsules 
whole and to not chew or crush them. If vomiting occurs, no attempt should be made to 
replace the vomited dose. Nicotine may alter metabolism of pracinostat such that 
potential efficacy may be decreased and therefore we will encourage smoking cessation 
while on study. 
If the patient forgets to take his/her dose before noon, then the dose should be withheld 
that day and restarted the next dosing day in order to ensure approximately 48 hours 
between each dose.  For example, if a patient misses a dose on Monday, the dose can 
be restarted on Tuesday, and the other doses would be taken on Thursday and 
Saturday. 
Dosage of either drug for cycles can be reduced, increased or delayed based on the 
assessment of efficacy (lack of it) or due to adverse events, if any occur. Guidelines for 
reducing or increasing dosages are described in Section 5.1. Delays of a maximum of 8 
weeks are allowed from scheduled next cycle.  


Page 13 of 33 
 
 
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 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, 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. Attempt 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. 
Patients experiencing clinical benefit will continue therapy for 4 years unless 
progression of disease or toxicity warranting discontinuation of therapy is observed. 
 
5.1 
Dose Modification  
 
Non-hematologic toxicity: 
If drug-related grade 3 or 4 non-hematologic toxicity is attributable to one or both of the 
drugs, dose interruption of the drug(s) causing the toxicity, as assessed by the treating 
physician, 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 or baseline 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 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. 
 
Hematologic toxicity: 
Ruxolitinib may be administered and dose adjusted as per standard practice (see 
Tables below). Reductions in dosing for therapy related anemia can be done at the 
discretion of the investigator 
 
Ruxolitinib dose modifications recommended for patients with starting platelet 
count of at least 100 × 109/L*  
 
Dose at time of decline in platelet count 
Maximum dose 
based on platelet 
count after prior 
treatment 
interruption or 
dose reduction 
25 mg 
BID 
20 mg 
BID 
15 mg 
BID 
10 mg 
BID 
5 mg 
BID 
Current 
platelet count 
New dose to be used 


Page 14 of 33 
 
* Starting ruxolitinib doses of 15 mg BID for patients with platelet counts of 100 to 200 × 
109/L and 20 mg BID for those with a platelet count >200 × 109/L. Recommended dose 
modifications based on US prescribing information. 
For insufficient response, doses may be increased in 5-mg BID increments to a 
maximum of 25 mg BID, provided that platelet and neutrophil counts are adequate.  
BID: Twice daily 
 
Ruxolitinib dose modifications recommended for patients with a starting platelet 
count of at least 50 × 109/L but less than 100 × 109/L*  
* Starting ruxolitinib dose of 5 mg BID. Recommended dose modifications based on US 
prescribing information.  
See full prescribing information for a complete description of US Food and Drug 
Administration FDA-approved dosing of ruxolitinib in patients with intermediate or high-
risk MF. 
AE: Adverse event; ANC: Absolute neutrophil count; BID: Twice daily; QD: Once daily.   
 
While a patient is on both medications concurrently, dosing of pracinostat as well as 
ruxolitinib will be discontinued for platelet counts </= 25X 109/L OR for ANC </= 0.5 
x109/L.  Patients who experience platelet count </= 25X 109/L or ANC </= 0.5 x109/L 
≥125 × 109/L 
 
No 
change 
No 
change 
No 
change 
No 
change 
No 
change 
20 mg BID 
100 to <125 × 
109/L 
 
20 mg 
BID 
15 mg 
BID 
No 
change 
No 
change 
No 
change 
15 mg BID 
75 to <100 × 
109/L 
 
10 mg 
BID 
10 mg 
BID 
10 mg 
BID 
No 
change 
No 
change 
10 mg BID for 2 
weeks; if stable, 
may increase to 15 
mg BID 
50 to <75 × 
109/L 
 
5 mg 
BID 
5 mg 
BID 
5 mg 
BID 
5 mg 
BID 
No 
change 
5 mg BID for 2 
weeks; if stable, 
may increase to 10 
mg BID 
<50 × 109/L 
Hold 
Hold 
Hold 
Hold 
Hold 
Continue holding 
Current platelet count 
Dosing recommendation 
<25 × 109/L  
Interrupt treatment 
25 to <35 × 109/L AND <20% decrease during the 
prior 4 weeks 
Decrease dose by 5 mg QD or 
maintain the current dose if it is 5 
mg QD 
25 to <35 × 109/L AND ≥20% decrease during prior 
4 weeks 
Decrease dose by 5 mg BID or 
use 5 mg QD if the current dose 
is 5 mg BID or QD  
≥40 × 109/L AND ≤20% decrease during prior 4 
weeks, ANC >1 × 109/L, AND no dose reductions 
or treatment interruptions for AE or hematologic 
toxicity during the prior 4 weeks 
Increase dose by increments of 5 
mg QD to a maximum of 10 mg 
BID if response is insufficient 


Page 15 of 33 
 
during a cycle of therapy, will have a 
dose reduction of pracinostat by one 
dose level for subsequent cycles (see 
Table below).  
 
 
 
 
 
 
 
 
 
5.2 
Initiation of a new cycle of pracinostat and ruxolitinib 
A new course of pracinostat may begin on the scheduled Day 1 of a new cycle if: 
 
The ANC is >/= 0.5 X 109/L 
 
The platelet count is > 25x 109/L,  
 
Any drug-related grade 3-4 adverse event that may have occurred has resolved to 
≤ grade 1 severity or baseline 
 
Normal potassium and magnesium serum levels (hypokalemia or hypomagnesemia 
should be corrected prior to pracinostat administration) 
 
QTcF interval <500 msec (reversible causes of QTc prolongation should be 
corrected, e.g. hypomagnesemia and hypokalemia, and ECG repeated. Provided 
that the patient is asymptomatic and that QTc decreases below 500 msec, 
pracinostat administration may continue).   
 
 
If these conditions are not met on Day 1 of a new cycle, the subject will continue 
ruxolitinib alone (see guidelines for restarting/continuing ruxolitinib in the next 
paragraph) and be evaluated weekly and a new cycle of pracinostat will not be initiated 
until the toxicity has resolved as described above.  If pracinostat 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 of pracinostat will be started 
when the criteria above are met AND with at least a one-level dose reduction.  
 
Treatment with ruxolitinib may restart/continue at 5mg QD so long as ANC> 0.5x109/L 
AND platelets > 25x109/L (with approval of Principal Investigator, and documented) or at 
5mg BID so long as ANC>/= 1 x109/L AND platelets > 50x109/L while waiting to initiate 
a new cycle of pracinostat. If the toxicity has not resolved as described above within 8 
weeks of the scheduled start date for the new cycle of pracinostat, the patient may 
discontinue treatment with pracinostat and continue therapy with ruxolitinib alone. 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 8 weeks may be restarted on therapy); such case 
must be fully documented. 
 
Dose Level 
Pracinostat 
Level 0 
60 mg 
 
Dose Level -1 
45 mg 


Page 16 of 33 
 
5.3     Concomitant Therapy 
  
Supportive measures consistent with optimal patient care may be given throughout the 
study. Concomitant medications will be captured in the medical record and will not be 
recorded on the case report form. 
 Therapies considered necessary for the patient’s well-being may be administered 
at the discretion of the investigator. These therapies include, but are not limited 
to antibiotics, analgesics, antihistamines, or other medications.  Guidance for 
growth factors and transfusions of red blood cells, platelets, or fresh frozen 
plasma are described below: 
 Packed red blood cells (RBCs): Transfusions of 2 units of packed RBCs should 
be considered for a decline in hemoglobin to <8 g/dl or symptoms of 
cardiovascular compromise. The following transfusion thresholds and guidelines 
are recommended for study participants: 
o hemoglobin <8 g/dl, 2 units of packed RBCs; hemoglobin <7, three units of 
packed RBCs 
o Platelets: Six to 10 units of random donor platelets or one cytopheresis 
unit of single donor platelets should be administered to all subjects with 
signs of hemostatic failure (i.e., bleeding or petechiae) or life-threatening 
thrombocytopenia (i.e., platelet count < 10,000/µ L) 
o Growth factor use with epoetin, darbepoetin, or granulocyte colony-
stimulating factor must be terminated at least 14 days before initiation of 
study treatment and may not be used as part of supportive therapy while 
the patient is on study, except if in patients’ best interest after approval of 
PI (e.g. neutropenic fever) 
o Patients should not receive androgens or steroids for treatment of their 
anemia or thrombocytopenia as part of supportive therapy 
 Patients may receive hydrocortisone prophylactically to prevent 
transfusion reactions but chronic systemic steroid (above 5mg/day) 
are not allowed. 
 Over-the-counter products such as herbal preparations or dietary supplements 
with the exception of multivitamins, Ensure, and similar nutritional supplements 
are not allowed throughout the trial.  Patients should stop using these herbal 
medications at least 7 days prior to the first dose of study medication. 
Prohibited medications 
Drug interaction studies with pracinostat are ongoing. Medications that have possible 
risk of prolonging the QT interval and/or Torsades de Pointes (listed below) may have 
an unacceptable risk of co-administration with pracinostat and are prohibited during .  
courses in which pracinostat is administered. The following website was used as a 
guide: http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#. All concomitant 
medications that the subject is receiving both prior to enrollment and during study 


Page 17 of 33 
 
conduct must be carefully reviewed and monitored. Subjects should avoid grapefruit 
juice and Seville oranges. 
 
Prohibited drugs: Drugs that Have a Risk of Prolonging the QT Interval and/or Inducing 
Torsades de Pointes 


Page 18 of 33 
 
Albuterol (salbutamol) 
Alfuzosin 
Amantadine 
Amiodarone 
Amisulpride 
Amitriptyline 
Amoxapine 
Amphetamine 
Anagrelide 
Apomorphine 
Arformoterol 
Aripiprazole 
Arsenic trioxide 
Astemizole (Off US mkt) 
Atazanavir 
Atomoxetine 
Azithromycin 
Bedaquiline 
Bepridil (Off US mkt) 
Bortezomib 
Bosutinib 
Chloral hydrate 
Chloroquine 
Chlorpromazine 
Ciprofloxacin 
Cisapride (Off US mkt) 
Citalopram 
Clarithromycin 
Clomipramine 
Clozapine 
Cocaine 
Crizotinib 
Dabrafenib 
Dasatinib 
Desipramine 
Dexmedetomidine 
Dexmethylphenidate 
Dextroamphetamine (d-Amphetamine) 
Dihydroartemisinin+piperaquine 
Diphenhydramine (doses up to 25 mg per day 
allowed) 
Disopyramide 
Dobutamine 
Dofetilide 
Dolasetron 


Page 19 of 33 
 
Domperidone  
Dopamine 
Doxepin 
Dronedarone 
Droperidol 
Ephedrine 
Epinephrine (Adrenaline) 
Eribulin 
Erythromycin 
Escitalopram 
Famotidine 
Felbamate 
Fenfluramine  
Fingolimod 
Flecainide 
Fluconazole 
Fluoxetine 
Formoterol 
Foscarnet 
Fosphenytoin 
Furosemide (Frusemide) 
Galantamine 
Gatifloxacin  
Gemifloxacin 
Granisetron 
Grepafloxacin 
Halofantrine 
Haloperidol 
Hydrochlorothiazide 
Ibutilide 
Iloperidone 
Imipramine (melipramine) 
Indapamide 
Isoproterenol 
Isradipine 
Itraconazole 
Ivabradine  
Ketoconazole 
Lapatinib 
Levalbuterol (levsalbutamol) 
Levofloxacin 
Levomethadyl  
Lisdexamfetamine 
Lithium 
Mesoridazine  


Page 20 of 33 
 
Metaproterenol 
Methadone 
Methamphetamine (methamfetamine) 
Methylphenidate 
Metronidazole 
Midodrine 
Mifepristone 
Mirabegron 
Mirtazapine 
Moexipril/HCTZ 
Moxifloxacin 
Nelfinavir 
Nicardipine 
Nilotinib 
Norepinephrine (noradrenaline) 
Norfloxacin 
Nortriptyline 
Ofloxacin 
Olanzapine 
Ondansetron 
Oxytocin 
Paliperidone 
Pantoprazole 
Paroxetine 
Pasireotide 
Pazopanib 
Pentamidine 
Perflutren lipid microspheres 
Phentermine 
Phenylephrine 
Phenylpropanolamine 
Pimozide 
Pipamperone  
Posaconazole 
Probucol  
Procainamide  
Promethazine 
Protriptyline 
Pseudoephedrine 
Quetiapine 
Quinidine 
Quinine sulfate 
Ranolazine 
Rilpivirine 
Risperidone 


Page 21 of 33 
 
Ritodrine  
Ritonavir 
Roxithromycin  
Salmeterol 
Saquinavir 
Sertindole  
Sertraline 
Sevoflurane 
Sibutramine  
Solifenacin 
Sorafenib 
Sotalol 
Sparfloxacin  
Sulpiride  
Sunitinib 
Tacrolimus 
Tamoxifen 
Telaprevir 
Telavancin 
Telithromycin 
Terbutaline 
Terfenadine  
Tetrabenazine  
Thioridazine 
Tizanidine 
Tolterodine 
Toremifene 
Trazodone 
Trimethoprim-Sulfa 
Trimipramine 
Vandetanib 
Vardenafil 
Vemurafenib 
Venlafaxine 
Voriconazole 
Vorinostat 
Ziprasidone 
 
5.4 
Correlative studies 
 
Before initiation of therapy with pracinostat (C4D1), after one cycle of pracinostat 
therapy (C5D1), after 3 cycles (C7D1), and then every 3 cycles (C10, C13, C16,…) 
while on the study, peripheral blood will be collected if possible for measurements of 
inflammatory cytokine levels, expression of different proteins related to intracellular 


Page 22 of 33 
 
signaling, and methylation of genes. This will include collection of: one red top (10ml) 
and two purple top tubes (10ml each).  Bone marrow aspirate will be collected every 6 
cycles if possible (5ml purple top tube). 
 
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) 
 
CBC and differential, electrolytes (Na, K, Cl, Mg, HCO3), creatinine, uric acid, BUN, 
glucose, total and direct bilirubin, and SGPT, PT/PTT, INR (within 14 days of study 
day 1). 
 
Bone marrow biopsy and aspirate (within 1 month of study day 1, or within 3 
months of study day 1 if patient was not on any therapy).  
 
ECG (within 14 days of study day 1) 
 
Pregnancy test (for FCBP only) within 7 days of study day 1 
 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score 
(MPN-SAF TSS) questionnaire  
 
5.6 
Evaluation During Study 
 
Directed history and physical examination including vital signs, body weight, and 
spleen and liver measurements once each cycle on cycles 2-7, then once every 3 
cycles (C10, C13, C16, …). This also includes a transfusion history for previous 
cycle of therapy and concomitant medication notation. Spleen and liver 
measurements will be obtained by the physicians or physician assistants during the 
clinic visit and documented in the medical record. 
 
CBC and differential, electrolytes (Na, K, Cl, Mg, HCO3), creatinine, BUN, glucose, 
total bilirubin, and SGPT every 2 weeks for 6 cycles, then CBC with differential 
every cycle and electrolytes (Na, K, Cl, Mg, HCO3), creatinine, BUN, glucose, total 
bilirubin, and SGPT every 3 cycles and as deemed appropriate while on 
therapy. Therapy also includes the first 3 months of ruxolitinib alone. 
 
ECG will be performed prior to the first cycle of pracinostat (C4), then once during 
cycles 5 and 6, then every 3 cycles starting with cycle 10 (specifically, ECG should 
be performed approximately 90 minutes post pracinostat dosing on the day of visit 
to MD Anderson) 
 
Bone marrow aspiration and biopsy after cycles 6 (+/- 10 days) and 12 (+/- 10 
days), and if deemed appropriate by the investigator, every 6 cycles after cycle 12. 
 
Response assessment after cycle 3 and cycle 6, then every 6 cycles.  Assessment 
may not include bone marrow biopsy on all occasions. 
 
Collect any unused study drug and review patient study drug dosing diary for 
compliance during each cycle for the first 7 cycles then every 3 cycles. 
 
Continuous assessment of AEs  
 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score (MPN-SAF TSS) questionnaire during each cycle for the first 7 cycles 
then every 3 cycles. 
 


Page 23 of 33 
 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements within the +/- 10 day window. Variations in schedule of events and other 
protocol requirements that do not affect the rights and safety of the patient will not be 
considered as deviations.  Such variations may include laboratory assessments 
completed outside of schedule, occasional missed required research samples such as 
PK or PD.  All dose adjustments will be made according to the protocol unless 
discussed with the PI and do not exceed the dosages described in the protocol. 
 
 
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  
 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, 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 each cycle for the first 6 cycles then every 3 cycles 
as long as on the study for evaluation. 
 
The patient will be contacted by the PI and his staff 30 days after discontinuation of 
protocol +/-14 days to assess for AE’s, unless the patient receives further MF-directed 
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 


Page 24 of 33 
 
 
Lost to follow up 
 
Death 
 
Suspected pregnancy 
 
6.0 
CRITERIA FOR RESPONSE  
Best overall response will be categorized according to the International Working Group 
Criteria11: 
Complete remission (CR): Requires all of the following in the absence of both 
transfusion and growth factor support:  
 Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and 
 Peripheral blood: Hemoglobin ≥10 g/dL and <UNL; neutrophil count ≥ 1.0 × 109/L 
and <UNL; 
 Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells‡ and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
 
Partial remission (PR):  
 
 Peripheral blood: Hemoglobin ≥10 g/dL and <UNL; neutrophil count ≥1 × 109/L 
and <UNL; platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells  
and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH or 
 Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†, and 
peripheral blood: Hemoglobin ≥8.5 but <10 g/dL and <UNL; neutrophil count ≥1 × 
109/L and <UNL; platelet count ≥50, but <100 × 109/L and <UNL; <2% immature 
myeloid cells‡ and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
 
Clinical improvement (CI): The achievement of anemia, spleen or symptoms response 
without progressive disease or increase in severity of anemia, thrombocytopenia, or 
neutropenia§ 
   
Anemia response 
Transfusion-independent patients: a ≥2.0 g/dL increase in 
hemoglobin level|| 
Transfusion-dependent 
patients: 
becoming 
transfusion-
independent¶ 
Spleen response# 
A baseline splenomegaly that is palpable at 5-10 cm, below the 
LCM, becomes not palpable∗∗ or 


Page 25 of 33 
 
A baseline splenomegaly that is palpable at >10 cm, below the 
LCM, decreases by ≥50%∗∗ 
A baseline splenomegaly that is palpable at <5 cm, below the 
LCM, is not eligible for spleen response 
Symptoms response 
A ≥50% reduction in the MPN-SAF TSS†† 
 
Progressive disease:  
 Appearance of a new splenomegaly that is palpable at least 5 cm below the 
LCM or 
 A ≥100% increase in palpable distance, below LCM, for baseline 
splenomegaly of 5-10 cm or 
 A 50% increase in palpable distance, below LCM, for baseline splenomegaly 
of >10 cm or 
 Leukemic transformation confirmed by a bone marrow blast count of ≥20% 
or 
 A peripheral blood blast content of ≥20% associated with an absolute blast 
count of ≥1 × 10(9)/L that lasts for at least 2 weeks 
 
Stable disease:  Belonging to none of the above listed response categories 
 
Relapse:  
 No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
 Loss of anemia response persisting for at least 1 month or 
 Loss of spleen response persisting for at least 1 month 
 Recommendations for assessing treatment-induced cytogenetic and molecular 
changes. 
 Cytogenetic remission 
 
At least 10 metaphases must be 
analyzed for cytogenetic response 
evaluation and 
requires confirmation by repeat testing 
within 6 months window 
CR: eradication of a preexisting 
abnormality 
PR: ≥50% reduction in abnormal 
metaphases 
(partial response applies only to 
patients with at least ten abnormal 
metaphases at baseline) 
 
 
Molecular remission 
Molecular response evaluation must 
be 
analyzed 
in 
peripheral 
blood 
granulocytes and 


Page 26 of 33 
 
requires confirmation by repeat testing 
within 6 months window 
CR: Eradication of a pre-existing 
abnormality 
PR: ≥50% decrease in allele burden 
(partial response applies only to 
patients with at least 20% mutant 
allele burden at baseline) 
 
 
Cytogenetic/molecular relapse 
Re-emergence 
of 
a 
pre-existing 
cytogenetic or molecular abnormality 
that is confirmed by repeat testing 
 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or 
imaging study-proven nonhepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit.  
*Baseline and post treatment bone marrow slides are to be interpreted at one sitting by a central 
review process. Cytogenetic and molecular responses are not required for CR assignment.  
†Grading of MF is according to the European classification: Thiele et al. European consensus on 
grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90:1128. It is 
underscored that the consensus definition of a CR bone marrow is to be used only in those 
patients in which all other criteria are met, including resolution of leukoerythroblastosis. It should 
also be noted that it was a particularly difficult task for the working group to reach a consensus 
regarding what represents a complete histologic remission.  
‡Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + 
nucleated red blood cells. In splenectomized patients, <5% immature myeloid cells is allowed.  
§See above for definitions of anemia response, spleen response, and progressive disease. 
Increase in severity of anemia constitutes the occurrence of new transfusion dependency or a ≥20 
g/L decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. 
Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from 
pretreatment baseline, in platelet count or absolute neutrophil count, according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to CI 
requires a minimum platelet count of ≥25 000 × 10(9)/L and absolute neutrophil count of ≥0.5 × 
10(9)/L.  
||Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict 
criteria for transfusion dependency at the time of study enrollment (see as follows), but have 
received transfusions within the previous month, the pretransfusion hemoglobin level should be 
used as the baseline.  
¶Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of 
packed red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of 
<85 g/L, in the absence of bleeding or treatment-induced anemia. In addition, the most recent 
transfusion episode must have occurred in the 28 days prior to study enrollment. Response in 
transfusion-dependent patients requires absence of any PRBC transfusions during any 
consecutive “rolling” 12-week interval during the treatment phase, capped by a hemoglobin level of 
≥85 g/L.  


Page 27 of 33 
 
#In splenectomized patients, palpable hepatomegaly is substituted with the same measurement 
strategy.  
 **Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in 
spleen volume, as assessed by MRI or CT, is required. Furthermore, a ≥35% volume reduction in 
the spleen or liver, by MRI or CT, constitutes a response regardless of what is reported with 
physical examination.  
††Symptoms are evaluated by the MPN-SAF TSS.17 The MPN-SAF TSS is assessed by the 
patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, 
itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as 
good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS 
is the summation of all the individual scores (0-100 scale). Symptoms response requires ≥50% 
reduction in the MPN-SAF TSS.  
 
‡‡Progressive disease assignment for splenomegaly requires confirmation by MRI or 
 
computed tomography showing a ≥25% increase in spleen volume from baseline. Baseline 
 
values for both physical examination and imaging studies refer to pretreatment baseline  and not 
 
to posttreatment measurements.  
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.1  Adverse Event Reporting for MD Anderson-Sponsored IND Protocols 
 
All adverse events that are possible, probably or definitely related to the study treatment 
will be captured on the case report form. Any grade 3 or higher adverse event that is 
considered unrelated or unlikely related to the study treatment will also be recorded. 
Adverse events will be defined using NCI CTCAE version 4.0. 
 
All adverse events occurring between the time the subject is consented and begins 
study drug will be considered a baseline event and recorded. Baseline adverse events will 
be recorded in the case report form in prior medical history. All baseline adverse events that 
increase in severity during the course of treatment will be captured as an adverse 
event in the case report form. 
 
Any adverse event that occurs during the study period (up through 30 days after the last 
day drug is administered) will be followed until clinical recovery is complete and 
laboratory tests have returned to normal, until progression of the event has been 
stabilized, or until the PI determines there has been acceptable resolution of the 
event. 
 
7.2  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: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from the 


Page 28 of 33 
 
adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND 
Office. 
 
 All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures as per “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 IRB, regardless of 
attribution (within 5 working days of knowledge of the event). 
 
 All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to and MDACC IRB.  
 
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression 
of the event has stabilized, or there has been acceptable resolution of the event. 
 
 Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 


Page 29 of 33 
 
 
Reporting to FDA: 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. It is the responsibility of the PI and 
the research team to ensure serious adverse events are reported according to the Code 
of Federal Regulations, Good Clinical Practices, the protocol guidelines, the sponsor’s 
guidelines, and Institutional Review Board policy. 
  
7.2 
Expedited reporting by investigator to Helsinn Healthcare SA 
 
Serious adverse events (SAE) are defined above.  The investigator will inform Helsinn 
Healthcare SA of any SAE within 24 hours of being aware of the event via email and/or 
fax.  
 
All pregnancies will also be reported.  
 
The following SAEs are not subject to expedited reporting, but will be included in the 
annual report via the SAE log. 
a.        Infection or cytopenias leading to hospitalization or prolongation of 
hospitalization; disease progression leading to death; life-threating AE, hospitalization or 
prolongation of hospitalization, or disability. 
 
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. This form must be completed and supplied to Helsinn 
Healthcare SA 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 30 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 Helsinn Healthcare SA 
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 30 of 33 
 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
This is a single-center phase II trial designed to assess the effect of ruxolitinib in 
combination with pracinostat in subjects with Primary, Post Polycythemia Vera, or Post 
Essential Thrombocythemia Myelofibrosis (PMF, post-PV MF, or post-ET MF).  
The primary objective is to assess efficacy in terms of the objective response rate (i.e., 
complete and partial response, and clinical improvement by IWG-MRT) in patients with 
MF.  Secondary objective is to determine the safety of the combination therapy in this 
population. 
Primary Endpoint is the objective response rate (ORR), defined as a clinical 
improvement (CI), partial remission (PR), and complete remission (CR) according to the 
International Working Group (IWG) Criteria. All subjects meeting the eligibility criteria 
that have signed a consent form and have begun treatment will be evaluable for 
response. 
A total of 25 patients will be enrolled from MDACC and patients will be registered 
through the Clinical Oncology Research System (CORE). The estimated accrual rate is 
2-3 patients per month. Initially patients will receive ruxolitinib alone for the first 3 cycles, 
where 1 cycle is 28 days (i.e., 4 weeks). Then, starting from cycle #4, patients will 
receive the combination therapy of ruxolitinib with pracinostat.  
The method of Thall, Simon and Estey [1995] will be used for futility and toxicity 
monitoring for this study. For futility monitoring, the primary endpoint of interest is the 
objective response (OR) rate at the end of 6 treatment cycles. Patients who drop off the 
study early due to any reason will be counted as failures (i.e., non-responders).  The 
target response rate is 50% and the following futility stopping rule will be applied 
prob{p(OR)<0.5)>0.95, where p(OR) denotes the objective response rate, with a beta 
(1,1) prior distribution. That is, the treatment will be stopped if during the study we 
determine that there is more than 95% chance that the OR rate is less than 50%.   
For toxicity monitoring, we denote the probability of toxicity by p (T), where toxicity is 
defined as Grade 3-4 clinically relevant non-hematologic toxicity or a serious adverse 
event that is at least possibly related to the study drug (Common Terminology Criteria 
for Adverse Events CTCAE version 4.0). We assume as a priori, p (T) ~ beta (0.4, 1.6).  
We will stop treating patients if Pr (p (T)> 0.20 | data) >0.87. That is, we will stop the trial 
for new patient enrollment if at any time during the study we determine that there is 
more than 87% chance that the toxicity rate is more than 20%. The OR rate and the 
toxicity will be monitored simultaneously using Bayesian stopping boundaries (Table 1) 
calculated based on beta-binomial distribution. Independence is assumed between OR 
and toxicity. Patients will be monitored in cohort size of 5, starting from the 5th patient. 
Multc Lean Desktop (version 2.1) was used to generate the futility/toxicity stopping 
boundaries and the operating characteristics table (Table 2). 
 
Table 1: Stopping boundaries for OR and toxicity 
Number of patients Stop the trial if 
Stop the trial if 


Page 31 of 33 
 
evaluated 
there are this 
many OR patients  
there are this 
many patients with 
toxicities 
5 
0 
3-5 
10 
0-2 
4-10 
15 
0-4 
6-15 
20 
0-6 
7-20 
 
 
Table 2: Operating characteristics of the Bayesian futility and toxicity monitoring 
 
True OR Rate 
True toxicity 
Rate 
Prob (stop the trial early) 
Average sample size 
0.3 
0.1 
0.69 
15.7 
  
0.2 
0.74 
14.6 
  
0.3 
0.84 
12.4 
  
0.4 
0.94 
9.8 
0.4 
0.1 
0.35 
20.3 
  
0.2 
0.46 
18.6 
  
0.3 
0.67 
15.1 
  
0.4 
0.88 
11.3 
0.5 
0.1 
0.13 
23.1 
  
0.2 
0.27 
21.1 
  
0.3 
0.56 
16.8 
  
0.4 
0.83 
12.1 
0.6 
0.1 
0.04 
24.3 
  
0.2 
0.2 
22.1 
  
0.3 
0.52 
17.5 
  
0.4 
0.82 
12.5 
 
 
Statistical Analysis Plan  
 
Summary statistics will be provided for continuous variables.  Frequency tables will be 
used to summarize categorical variables.  The objective response rate (ORR) will be 
estimated along with the Bayesian 95% credible interval. Data from all subjects who 
receive any study drug will be included in the safety analyses. 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. Safety data will be summarized 
by category, severity and frequency. The proportion of patients with AEs will be 
estimated, along with the Bayesian 95% credible intervals.  


Page 32 of 33 
 
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 of 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 allele burden from baseline to each 
visit where it is measured. 
Correlative Studies: Descriptive statistics will be applied to the analysis of these 
findings. 
 
9.0 
REFERENCES 
1. 
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of 
ruxolitinib for myelofibrosis. The New England journal of medicine. 2012;366(9):799-
807. 
2. 
Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK Inhibition with Ruxolitinib versus 
Best Available Therapy for Myelofibrosis. New England Journal of Medicine. 
2012;366(9):787-798. 
3. 
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. 
4. 
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. 
5. 
Verstovsek S, Kantarjian HM, Estrov Z, et al. Long term outcomes of 107 
patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage 
in comparison to matched historical controls. Blood. 2012. 
6. 
Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with 
ruxolitinib treatment in patients with myelofibrosis: results of a median 2-year follow-up 
of COMFORT-I. Haematologica. 2013. 


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7. 
Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and 
survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best 
available therapy for myelofibrosis. Blood. 2013;122(25):4047-4053. 
8. 
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: 
International Working Group-Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 
2013;122(8):1395-1398.