Conditions: Leukemia Myelofibrosis Anemia Splenomegaly
Keywords: Leukemia Myelofibrosis MF Anemia Splenomegaly Post-polycythemia vera MF post-PV post-essential thrombocythemia MF post-ET Rigosertib ON 01910.Na Questionnaire Survey
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if rigosertib can help to control MF in patients with anemia. The safety of this drug will also be studied.

This is an investigational study. Rigosertib is not FDA-approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work.

Up to 35 participants will be enrolled in this study. All will be enrolled at MD Anderson.

Detailed description:
Study Drug Administration:

If participant is found to be eligible to take part in this study, participant will take rigosertib capsules by mouth 2 times each day (1 morning dose, 1 afternoon dose) for 48 weeks. Participant will take participant's morning dose on an empty stomach. Participant's afternoon dose should be taken at about 3:00 pm (±1 hour), at least 2 hours after lunch. Participant should drink at least a ½ gallon of water each day. Rigosertib should be refrigerated.

Participant will also be given a study drug diary. Participant should write down each dose of study drug that participant takes, when participant takes it, and if participant misses or vomit any doses. If participant misses or vomits a dose of rigosertib, participant should not make up the dose. Participant should take the next scheduled dose as planned. Every 4 weeks for 12 weeks, then every 8 weeks thereafter, participant should bring any leftover rigosertib capsules and participant's study drug diary with participant to the clinic.

Study Visits:

On Cycle 1 Day 1:

* Participant will have a physical exam.
* Blood (about 2-3 teaspoons) and urine will be collected for routine tests.
* Blood (about 2 teaspoons) will be drawn for pharmacokinetic (PK) testing about 1 hour after participant's dose of study drug. PK testing measures the amount of study drug in the body at different time points.
* Participant will complete a questionnaire about participant's quality of life. It should take about 10-15 minutes.
* If the doctor thinks it is needed, participant will have a computed tomography (CT) or magnetic resonance imaging (MRI) scan to check the status of the disease.

Each week, blood (about 2-3 teaspoons) will be drawn for routine tests. If the study doctor approves it, participant may have these weekly blood draws at a local lab closer to participant's home. The results from these routine tests will be sent to the study doctor.

On Day 1 of Week 4, blood (about 2 teaspoons each time) will be drawn for PK testing before and 1 hour after participant's dose of study drug.

At Weeks 24 and 48 (± 1 week):

* Participant will have a bone marrow aspirate/biopsy performed to check the status of the disease. This sample may also be used for cytogenetic testing.
* If participant had a CT/MRI scan performed during Week 1, participant will have another CT/MRI scan to check the status of the disease.
* If participant can become pregnant, urine will be collected for a pregnancy test.

Every 4 weeks until Week 12 and then every 8 weeks after that:

* Participant will have a physical exam.
* Blood (about 2-3 teaspoons) and urine will be collected for routine tests.
* Participant will complete a questionnaire about participant's quality of life.

Length of Study:

Participant may continue taking the study drug for up to 48 weeks. Participant will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if participant is unable to follow study directions.

If the doctor thinks it is in participant's best interest, participant may be able to continue taking the study drug after 48 weeks. The study doctor will discuss this with participant.

Participation on the study will be over after the end-of-study visit.

End-of-Study Visit:

About 4 weeks after participant's last dose of study drug, participant will have an end-of-study visit. At this visit:

* Participant will have a physical exam.
* Blood (about 2-3 teaspoons) and urine will be collected for routine tests. This routine blood and urine collection will also include a pregnancy test if participant can become pregnant.

Arms:
arm 1: Participants receive oral Rigosertib under fasting conditions twice a day on a continuous basis. Quality of life questionnaire completed on Day 1 of Cycle 1.

Interventions: intervention 1: Rigosertib intervention 2: Questionnaire
Intervention descriptions: intervention 1: Participants take 560 mg Rigosertib by mouth in the morning (two 280 mg capsules) and 560 mg Rigosertib in the afternoon. intervention 2: Quality of life questionnaire completed on Day 1 of Cycle 1. It should take about 10-15 minutes to complete.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Page
A Phase II Single-arm Study of the Efficacy and Safety of Oral Rigosertib in Patients 
with Myelofibrosis (MF) and Anemia
2014-0546
Core Protocol Information
Short Title 
Phase II - Rigosertib in MF
Study Chair: 
Jorge Cortes
Additional Contact:
Maria Rhona B. Pinsoy
Rachel R. Abramowicz
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-794-5783
Unit:
428
Full Title: 
A Phase II Single-arm Study of the Efficacy and Safety of Oral 
Rigosertib in Patients with Myelofibrosis (MF) and Anemia
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated 08/25/2017
Version:
08
Document Status:
Saved as "Final"
Submitted by:
Rachel R. Abramowicz--8/7/2017 2:47:00 PM
OPR Action:
Accepted by:  Elizabeth Orozco -- 8/15/2017 3:09:53 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
Development Phase:
II
Product:
rigosertib sodium (ON 01910.Na), oral capsules
Principal Investigator:
Jorge Cortes, MD 
Professor of Medicine, Department of Leukemia 
UT MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 428 
Houston, TX 77030 
Email: jcortes@mdanderson.org
  


 
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1 
 
CLINICAL STUDY PROTOCOL 
 
A Phase II Single-arm Study of the Efficacy and Safety of Oral 
Rigosertib in Patients with Myelofibrosis (MF) and Anemia  
 
 
 
 
 
 
Development Phase: 
II 
Product: 
rigosertib sodium (ON 01910.Na), oral capsules 
Principal Investigator: 
Jorge Cortes, MD  
Professor of Medicine, Department of Leukemia 
UT MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 428 
Houston, TX 77030 
Email: jcortes@mdanderson.org 
 
 
Supporter: 
Onconova Therapeutics Inc. 
73 Route 31 North 
Pennington, New Jersey 08534 (USA) 
 


 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ..................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................. 4 
1. 
INTRODUCTION ....................................................................................................................... 8 
1.1. 
Description of the Investigational Product .................................................................... 8 
1.2. 
Summary of Clinical Findings Relevant to the Trial .................................................... 8 
1.3. 
Summary of Potential Risks ........................................................................................ 12 
1.4. 
Study Rationale ........................................................................................................... 17 
2. 
STUDY OBJECTIVES .............................................................................................................. 17 
3. 
INVESTIGATIONAL PLAN ....................................................................................................... 17 
3.1. 
Study Design ............................................................................................................... 17 
3.2. 
Selection of Study Population ..................................................................................... 19 
3.2.1. Inclusion Criteria ............................................................................................ 19 
3.2.2. Exclusion Criteria ........................................................................................... 20 
3.3. 
Removal of Patients from the Study ............................................................................ 21 
3.4. 
Study Procedures ......................................................................................................... 21 
3.4.1. Efficacy Assessments ...................................................................................... 22 
3.4.1.1. 
Efficacy Outcomes ........................................................................ 22 
3.4.1.2. 
Bone Marrow Examination and Cytogenetics .............................. 22 
3.4.1.3. 
Exploratory Genomics/Molecular Evaluation in Peripheral Blood 
Samples ......................................................................................... 23 
3.4.2. Safety Assessments ......................................................................................... 23 
3.5. 
Treatments ................................................................................................................... 24 
3.5.1. Method of Assigning Patients to Treatment Groups ....................................... 24 
3.5.2. Treatments Administered ................................................................................ 24 
3.5.3. Management of Clinical Supplies ................................................................... 25 
3.5.4. Rigosertib Dosing Adjustments ...................................................................... 26 
3.5.4.1. 
Hematologic Toxicity ................................................................... 26 
3.5.4.2. 
Non-hematologic Toxicity - Hyponatremia .................................. 26 
3.5.4.2.1. Treatment-related Urinary Symptoms .............................. 26 
3.5.4.2.2. Treatment-related ≥Grade 2 Toxicity other than Urinary 
Symptoms ......................................................................... 27 
3.5.5. Treatment Compliance .................................................................................... 27 
3.5.6. Management of Urinary Symptoms ................................................................ 28 
3.5.7. Concomitant Therapy...................................................................................... 28 


 
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3.6. 
Statistical Methods ...................................................................................................... 28 
3.6.1. Sample Size Considerations ............................................................................ 28 
3.6.2. Analysis Populations ....................................................................................... 29 
3.6.3. Final Analyses ................................................................................................. 29 
3.6.3.1. 
Efficacy Analyses ......................................................................... 29 
3.6.3.2. 
Safety Analyses ............................................................................. 30 
3.6.3.3. 
Additional Analyses ...................................................................... 30 
4. 
INVESTIGATOR’S OBLIGATIONS ........................................................................................... 31 
4.1. 
Reporting Adverse Events ........................................................................................... 31 
4.1.1. Serious Adverse Event Reporting ................................................................... 31 
4.1.2 Reporting Forms ............................................................................................. 29 
 
4.2 
Investigator Communications with Onconova……………………………………….29 
 
4.3 
Pregnancies…………………………………………………………………………..29 
5. 
REFERENCE LIST .................................................................................................................. 33 
6. 
APPENDICES .......................................................................................................................... 35 
Appendix 1: WHO Criteria for Diagnosis of Primary Myelofibrosis, Essential 
Thrombocythemia, and Polycythemia Vera .......................................................................... 36 
Appendix 2: 2008 IWG-MRT Diagnosis Criteria for Post-Polycythemia Vera and Post-
Essential Thrombocythemia Myelofibrosis ........................................................................... 38 
Appendix 3: Eastern Cooperative Oncology Group (ECOG) Performance Status ............... 40 
Appendix 4: 2013 IWG-MRT Revised Response Criteria for Myelofibrosis ....................... 41 
Appendix 5: Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score (MPN-SAF TSS) ......................................................................................................... 44 
Appendix 6: Schedule of Events and Procedures .................................................................. 44 
Appendix 7: List of Clinical Laboratory Tests ...................................................................... 47 
Appendix 8: List of Potential Substrates of CYP 2C8 and 2C9 ............................................ 48 
Appendix 9: List of Potential Inhibitors of P-gp ................................................................... 49 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
 
Definition 
ADL 
 
Activities of daily living 
ADR 
 
Adverse drug reaction 
AE 
 
Adverse event 
AKT 
 
Serine-threonine kinase 
ALT 
 
Alanine transaminase 
AML 
 
Acute myeloid leukemia 
ANC 
 
Absolute neutrophil count 
ASH 
 
American Society of Hematology 
AST 
 
Aspartate transaminase 
AUC0-∞ 
 
Area under the plasma concentration-time curve from 0 to infinity 
AZA 
 
Azacitidine 
BID 
 
Twice daily 
BM 
 
Bone marrow 
BMBL 
 
Bone marrow blast 
BMCR 
 
Bone marrow complete response 
BUN 
 
Blood urea nitrogen 
C1D1, C2D1 
 
Cycle 1 Day 1, Cycle 2 Day 1 
Cmax 
 
Maximum plasma concentration 
CBC 
 
Complete blood count 
CDC25 
 
Cell division cycle 25 
CDK 
 
Cyclin-dependent kinase 
CFR 
 
Code of Federal Regulations 
CI 
 
Clinical improvement 
CIV 
 
Continuous intravenous 
CRO 
 
Contract research organization 
CSR 
 
Clinical study report 
CT 
 
Computed tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events 


 
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Abbreviation 
 
Definition 
CYP 
 
Cytochrome P450 
DLT 
 
Dose-limiting toxicity 
ECG 
 
Electrocardiogram 
ECOG 
 
Eastern Cooperative Oncology Group 
eCRF 
 
Electronic case report form 
EMH 
 
Extramedullar hematopoiesis 
EOS 
 
End of study 
EPO 
 
Erythropoietin 
ER 
 
Erythroid response 
ERES 
 
Electronic Records/Electronic Signatures 
ERK 
 
Extracellular signal-regulated kinase 
ESA 
 
Erythropoiesis-stimulating agent 
ET 
 
Essential thrombocythemia 
FAS 
 
Full analysis set 
FDA 
 
Food & Drug Administration 
FISH 
 
Fluorescent in-situ hybridization 
GCP 
 
Good clinical practice 
G-CSF 
 
Granulocyte colony-stimulating factor 
GI 
 
Gastrointestinal 
GM-CSF 
 
Granulocyte-macrophage colony-stimulating factor  
Hgb 
 
Hemoglobin 
HIV 
 
Human immunodeficiency virus 
HMA 
 
Hypomethylating agent 
hr 
 
Hour 
IB 
 
Investigator's brochure 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonisation 
Int-1 
 
Intermediate-1  
IPSS 
 
International Prognostic Scoring System 


 
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Abbreviation 
 
Definition 
IRAE 
 
Immediately Reportable Adverse Event 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous 
IWG-MRT 
 
International Working Group for Myelofibrosis Research and 
Treatment 
JAK2 
 
Janus kinase 2 
LCM 
 
Left coastal margin  
LDH 
 
Lactate dehydrogenase 
MAPK 
 
Mitogen-activated protein kinase 
MDS 
 
Myelodysplastic syndromes 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MF 
 
Myelofibrosis 
MFSAF 
 
Myelofibrosis self assessment form 
MRI 
 
Magnetic resonance imaging 
MTD 
 
Maximum tolerated dose 
NCI 
 
National Cancer Institute 
NHLBI 
 
National Heart Lung and Blood Institute 
ON 01910.Na 
 
rigosertib sodium (rigosertib); sodium salt of (E)-2,4,6-
trimethoxystyryl-3-carboxymethylamino-4-methoxybenzyl 
sulfone 
OS 
 
Overall survival 
PB 
 
Peripheral blood 
PD 
 
Progressive disease 
P-gp 
 
P-glycoprotein 
PI3K 
 
Phosphatidylinositol-3 kinase 
PK 
 
Pharmacokinetic 
PLK 
 
Polo-like kinase  
PLT 
 
Platelet 
PMF 
 
Primary myelofibrosis 


 
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Abbreviation 
 
Definition 
PP 
 
Per protocol 
PRBC 
 
Packed red blood cells 
PT 
 
Preferred Term (MedDRA) 
PV 
 
Polycythemia vera 
Q3W  
 
Every 3 weeks 
Q6W 
 
Every 6 weeks 
QC 
 
Quality control 
QOL 
 
Quality of life 
QW 
 
Every week 
RAEB, -1, -2 
 
Refractory anemia with excess blasts, -type 1, -type 2 
RBC 
 
Red blood cell 
RBD 
 
Ras binding domain 
RPTD 
 
Recommended Phase II dose 
SADR 
 
Serious adverse drug reaction 
SAE 
 
Serious adverse event 
SC 
 
Subcutaneous(ly) 
SOC 
 
System Organ Class (MedDRA) 
SUSAR 
 
Suspected unexpected serious adverse reaction 
Tmax 
 
Time to maximum plasma concentration 
TEAE 
 
Treatment-emergent adverse event 
TI 
 
Transfusion independence 
ULN 
 
Upper limit of normal 
US 
 
United States 
UTI 
 
Urinary tract infection 
WBC 
 
White blood cell 
WHO 
 
World Health Organization 


 
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1. 
INTRODUCTION 
1.1. 
Description of the Investigational Product 
Rigosertib 
sodium 
(ON 01910.Na; 
rigosertib 
hereafter) 
is 
a 
first-in-class 
dual 
phosphatidylinositol 3-kinase (PI3K)/polo-like kinase (PLK) pathway inhibitor that targets critical 
signals involved in the growth and survival of cancer cells. At the molecular level, rigosertib acts 
by selectively targeting 2 of the PI3K subunits (α and β), while also inhibiting downstream signals 
in the pathway such as the phosphorylation of serine-threonine kinase (AKT) and translation of 
cyclin D1 (Prasad 2009, Olnes 2012). Rigosertib also acts by inhibiting the PLK pathway, leading 
to a reduction in the activity of pro-mitotic proteins such as cell division cycle 25 (CDC25) and 
cyclin-dependent kinase (CDK)/cyclin B (Jimeno 2010). The dual molecular mechanism of action 
of rigosertib results in induction of multiple centrosomes during cell division, leading to multi-
polar spindle formation (Reddy 2008), total disorganization of the mitotic apparatus causing 
chromosomal catastrophe (Reddy 2008), and modulation of the extracellular signal-regulated 
kinase (ERK)/mitogen-activated protein kinase (MAPK) (growth) and AKT (survival) pathways, 
promoting cell death (apoptosis) in cancer cells (Chapman 2012). Recent data suggest that 
rigosertib binds to the Ras binding domain (RBD) of Ras effector proteins (ie, PI3K and Raf), 
thereby leading to their inactivation (data on file). This novel mechanism may help explain the 
multi-faceted effects of rigosertib, such as inhibition of the PI3K and PLK pathways. 
 
Rigosertib was granted orphan drug status for the treatment of MDS by the Office of Orphan 
Products Development (HF-35) at the Food & Drug Administration (FDA) on September 3, 2009 
(designation request #09-2894).  
 
1.2. 
Summary of Clinical Findings Relevant to the Trial 
 
Two formulations of rigosertib are currently being studied: intravenous (IV) and oral. At the time 
of the latest compilation of information (Investigator's Brochure [IB] edition 21; Rigosertib IB), 
1176 patients with either MDS or other hematologic malignancies (N = 661) or advanced cancer 
and solid tumors (N = 515) were enrolled in 26 Phase I-III clinical studies of IV (N = 839) and 
oral (N = 337) rigosertib conducted by Onconova. Six other Phase I studies of rigosertib in a 
total of 51 patients with MDS and other hematologic malignancies were completed or are being 
conducted by other Sponsors (NHLBI and SymBio Pharmaceuticals) under different INDs..  
 
In Phase I/II studies of IV rigosertib in adult patients with MDS and acute myeloid leukemia 
(AML), rigosertib was administered as 2- to 6-day continuous intravenous (CIV) infusions. 
Overall, rigosertib was reasonably well tolerated (see Rigosertib IB). Significant activity in 
reducing bone marrow blasts (BMBL) was found to be correlated to overall survival (OS).  
 
 
 


 
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A Phase I dose escalation study of oral rigosertib in MDS patients was completed at Moffitt Cancer 
Center and Columbia University Medical Center (#09-01). The study was divided into 3 parts: 
Part I evaluated the bioavailability and tolerability of single oral doses (70 mg, 140 mg, 280 mg, 
560 mg, and 700 mg) administered weekly for 5 weeks. Part II (maximum tolerated dose [MTD] 
evaluation) assessed the tolerability of the same oral escalating doses (ie, 70 mg, 140 mg, 280 mg, 
560 mg, and 700 mg), administered twice daily (BID) for 14 days of a 21-day cycle. Part III was 
a confirmation of the recommended Phase II dose (RPTD) with absolute bioavailability and food 
effect studies. Eligibility criteria included any International Prognostic Scoring System (IPSS) 
MDS risk group with at least 1 cytopenia; failure to respond to at least 1 prior standard treatment; 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; and adequate kidney and 
liver functions. Key exclusion criteria included hypoplastic MDS (< 10% cellularity), ascites, 
history of seizures, uncontrolled hypertension, and history of human immunodeficiency virus 
(HIV) infection. Dose-limiting toxicity (DLT) was defined as ≥ Grade 3 non-hematologic drug-
related toxicity (based on National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE]) or delay in recovery of blood counts to Baseline levels for more than 
30 days in the absence of response. A total of 37 MDS patients were enrolled. Pharmacokinetic 
(PK) dose proportionality was established in the 70 mg to 700 mg single-dose range in the first 
3 patients enrolled, and pharmacodynamically active concentrations were reached. During the 
subsequent escalation phase, the RPTD was identified as 560 mg BID.  
 
Overall rigosertib capsules were reasonably well tolerated, with dysuria as the most frequent 
treatment-emergent adverse event (TEAE). One patient on 700 mg experienced 2 DLTs (dysuria 
and shortness of breath) during the first 3-week cycle. Another patient on 700 mg experienced 
Grade 3 dysuria during Cycle 2.  
 
Twelve patients in the confirming cohort underwent full PK evaluation (absolute bioavailability 
vs. the IV formulation, and food effect). Following a single fasting dose, oral rigosertib was rapidly 
absorbed (time to maximum plasma concentration [Tmax] ~ 1 hr). Systemic exposure, as 
determined by maximum plasma concentration (Cmax) and the area under the plasma concentration-
time from 0 to infinity (AUC0-∞), increased in a linear and dose-proportional manner over the dose 
range of 70 mg to 700 mg. The plasma concentration-time profile exhibited a rapid distribution 
phase followed by a slower elimination phase. The elimination half-life from plasma after oral 
rigosertib dosing was comparable to estimates obtained after IV dosing. The absolute 
bioavailability of rigosertib (560 mg dose) was 35%. Food significantly reduced the rate and extent 
of rigosertib absorption. Oral administration of rigosertib after a meal decreased Cmax and AUC0-
∞ by 77% and 61%, respectively, compared to fasting conditions, with an estimated bioavailability 
of 14%.  
 
Encouraging signs of activity were observed. Two bone marrow complete responses (BMCR) were 
observed in refractory anemia with excess blasts type 1 (RAEB-1) patients previously treated with 
azacitidine (AZA) at the 140 mg and 560 mg dose levels. In addition, transitions to transfusion 


 
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independence (TI) and erythroid response (ER) were observed in a subgroup of 16 patients with 
Low/intermediate-1 (Int-1) transfusion-dependent MDS patients in the 560 mg and 700 mg 
cohorts. Of the 12 evaluable patients treated for at least 8 weeks (of which 10 were in the 560 mg 
group), TI (defined as no red blood cell [RBC] transfusions needed over a period of 8 consecutive 
weeks) occurred in 4 patients, all in the 560 mg cohort. Erythropoiesis-stimulating agents (ESA) 
were administered before or after the onset of TI, suggesting a possible synergy between rigosertib 
and ESA for patients receiving ESA before the onset of TI. Duration of TI varied from 8 weeks to 
more than 47 weeks, with an onset of TI between Week 3 and Week 10. One additional patient in 
the 560 mg cohort had an ER, defined as reduction of at least 4 units of transfused RBC over 
8 weeks.   
 
The Phase II trial (09-05) is designed to evaluate oral rigosertib as a single agent in transfusion-
dependent, lower-risk MDS patients. This trial is a randomized, 2-arm study of oral rigosertib, 
which was administered initially as 560 mg BID continuously. The 560 mg BID continuous 
regimen was changed to an intermittent 2-weeks on/1-week off regimen after 9 patients were 
enrolled, due to an excess of urinary side effects. The 560 mg BID intermittent regimen was further 
reduced to 560 mg in the morning and 280 mg in the afternoon to try and further minimize adverse 
urinary effects. This intermittent reduced regimen resulted in a much improved urinary tolerability, 
particularly the absence of Grade 3 urinary toxicity. The study was then amended to a 
560 mg/280 mg continuous regimen. In the study, transfusion-dependent patients must have 
received at least 4 units of RBC transfusions over 8 weeks before randomization and can receive 
transfusions and ESA while on study.  
 
Enrollment of 57 patients from 5 clinical sites in Study 09-05 was completed on November 5, 
2013. Interim results are available and were reported during the annual meeting of the American 
Society of Hematology (ASH) in New Orleans in December 2013 (Raza 2013).  
 
Of the 36 evaluable patients on intermittent dosing (of which 35 were receiving the original 
560 mg BID regimen and 1 the reduced 560/280 mg regimen) treated for at least 8 consecutive 
weeks, 14 (39%) achieved TI (no RBC transfusion for at least 8 consecutive weeks) lasting from 
8 weeks to 73 weeks (median not reached) (see Figure 1). Of the 9 patients who received 
continuous dosing, of which 8 were treated for at least 8 weeks, 2 achieved TI, the first for 
10 weeks and the second for more than 18 weeks. In addition, 4 patients with ≥ Grade 3 
neutropenia at Baseline (absolute neutrophil count [ANC] values < 1.0 K/µL) had neutrophil 
improvement for at least 8 weeks. One patient achieved a minor ER (transfusion decrease of 4 units 
RBC over 8 weeks).  
 


 
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Figure 1 
Transfusion Independence in 14 of 36 Evaluable Patients (39%) Treated for at Least  
8 Weeks with Intermittent Rigosertib Regimen (Original or Reduced) 
 
 
Overall oral rigosertib was reasonably well tolerated with the exception of urinary side effects. 
The most frequent adverse events (AEs) in the 560 mg BID continuous dosing arm (≥ 20% of 
patients) were nausea, dysuria, pollakiuria, and urinary tract infection (UTI) (33% each), and 
cystitis, hematuria, micturition urgency, diarrhea, oedema peripheral, and pyrexia (22% each). The 
most frequent AEs in the 560 mg BID intermittent dosing arm (≥ 20% of patients) were pollakiuria 
(51%), fatigue (40%), micturition urgency and urinary tract pain (34% each), hematuria and 
dysuria (31% each), constipation (26%), nausea and UTI (23% each), and diarrhea (20%). There 
was a clinically significant reduction of urinary events in patients receiving the 560/280 mg 
intermittent regimen: the most frequent AE to date in this arm (≥ 20% of patients) is fatigue (31%). 
The following urinary events were observed in 1 patient each: nocturia, pollakiuria and UTI.  
 
In the group receiving the continuous regimen, 2 patients (22%) developed Grade 3 cystitis, 
1 patient each (11%) developed Grade 3 hematuria and Grade 3 UTI. The incidence of Grade 3 
urinary events seemed to be reduced when patients were administered the original intermittent 
regimen (6% of patients each with Grade 3 cystitis, Grade 3 UTI and Grade 3 urinary tract pain, 
and 11% of patients with hematuria). No patients receiving the reduced intermittent regimen 
developed Grade 3 urinary events to date. The only Grade 3 AE in that group was progression to 
AML in 1 patient. 
 
The causality of urinary side effects is being investigated. Since no nephrotoxicity was evident and 
significant urinary excretion of unmetabolized drug was noted, it was hypothesized that the 
residence time of rigosertib in the urinary bladder was a mitigating factor in causing irritation or 
inflammation of the bladder epithelia. Limited cystoscopy and other observations supported this 
hypothesis and lead to an improvement program based on hydration, bicarbonate tablets as needed, 
and judicious dose reduction. In general, symptoms can be relieved or reduced by these 
approaches.  
 


 
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Final study results are pending. 
 
1.3. 
Summary of Potential Risks 
The Reference Safety Information for this study is in the latest Rigosertib's IB   A summary of 
expected drug-related treatment-emergent adverse events (AEs) in studies of oral rigosertib is 
presented below (Table 1). 
 


 
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Table 1  
Reference Safety Information (RSI) 
Summary of Expected Drug-related Treatment-emergent Adverse Events by Preferred Term, Sorted by Frequency, in Studies of Oral Rigosertib 
Safety-Evaluable (N=337) 
Rigosertib Integrated Analysis 
MedDRA Preferred Term [1][2] 
Any Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Dysuria 
 103 (30.6%) 
  35 (10.4%) 
  61 (18.1%) 
   7 (2.1%) 
  0 
  0 
Pollakiuria 
  67 (19.9%) 
  25 (7.4%) 
  42 (12.5%) 
  0 
  0 
  0 
Haematuria 
  62 (18.4%) 
  27 (8.0%) 
  25 (7.4%) 
  10 (3.0%) 
  0 
  0 
Micturition urgency 
  43 (12.8%) 
  20 (5.9%) 
  22 (6.5%) 
   1 (0.3%) 
  0 
  0 
Fatigue 
  40 (11.9%) 
  18 (5.3%) 
  19 (5.6%) 
   3 (0.9%) 
  0 
  0 
Nausea 
  39 (11.6%) 
  27 (8.0%) 
   9 (2.7%) 
   3 (0.9%) 
  0 
  0 
Urinary tract pain 
  31 (9.2%) 
  11 (3.3%) 
  18 (5.3%) 
   2 (0.6%) 
  0 
  0 
Diarrhoea 
  28 (8.3%) 
  19 (5.6%) 
   8 (2.4%) 
   1 (0.3%) 
  0 
  0 
Urinary tract infection 
  27 (8.0%) 
   3 (0.9%) 
  21 (6.2%) 
   3 (0.9%) 
  0 
  0 
Decreased appetite 
  18 (5.3%) 
  15 (4.5%) 
   2 (0.6%) 
   1 (0.3%) 
  0 
  0 
Cystitis 
  17 (5.0%) 
   2 (0.6%) 
   8 (2.4%) 
   7 (2.1%) 
  0 
  0 
Constipation 
  13 (3.9%) 
  11 (3.3%) 
   2 (0.6%) 
  0 
  0 
  0 
Neutropenia 
  10 (3.0%) 
  0 
   1 (0.3%) 
   1 (0.3%) 
   8 (2.4%) 
  0 
Vomiting 
  10 (3.0%) 
   8 (2.4%) 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
Nocturia 
   9 (2.7%) 
   3 (0.9%) 
   6 (1.8%) 
  0 
  0 
  0 
Abdominal pain 
   8 (2.4%) 
   7 (2.1%) 
   1 (0.3%) 
  0 
  0 
  0 
Hyponatraemia 
   8 (2.4%) 
   4 (1.2%) 
  0 
   4 (1.2%) 
  0 
  0 
Proteinuria 
   8 (2.4%) 
   2 (0.6%) 
   4 (1.2%) 
   2 (0.6%) 
  0 
  0 
Thrombocytopenia 
   8 (2.4%) 
   1 (0.3%) 
  0 
   2 (0.6%) 
   5 (1.5%) 
  0 
Dyspepsia 
   7 (2.1%) 
   6 (1.8%) 
   1 (0.3%) 
  0 
  0 
  0 
Headache 
   7 (2.1%) 
   5 (1.5%) 
   2 (0.6%) 
  0 
  0 
  0 
Urinary incontinence 
   7 (2.1%) 
  0 
   7 (2.1%) 
  0 
  0 
  0 
Neutrophil count decreased 
   6 (1.8%) 
  0 
  0 
  0 
   6 (1.8%) 
  0 


 
2014-0546 
August 7, 2017 
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Table 1  
Reference Safety Information (RSI) 
Summary of Expected Drug-related Treatment-emergent Adverse Events by Preferred Term, Sorted by Frequency, in Studies of Oral Rigosertib 
Safety-Evaluable (N=337) 
Rigosertib Integrated Analysis 
MedDRA Preferred Term [1][2] 
Any Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Abdominal discomfort 
   5 (1.5%) 
   3 (0.9%) 
   2 (0.6%) 
  0 
  0 
  0 
Anaemia 
   5 (1.5%) 
   3 (0.9%) 
  0 
   2 (0.6%) 
  0 
  0 
Cystitis noninfective 
   5 (1.5%) 
   3 (0.9%) 
   2 (0.6%) 
  0 
  0 
  0 
Dysgeusia 
   5 (1.5%) 
   5 (1.5%) 
  0 
  0 
  0 
  0 
Aspartate aminotransferase increased 
   4 (1.2%) 
   4 (1.2%) 
  0 
  0 
  0 
  0 
Chromaturia 
   4 (1.2%) 
   4 (1.2%) 
  0 
  0 
  0 
  0 
Flatulence 
   4 (1.2%) 
   4 (1.2%) 
  0 
  0 
  0 
  0 
Abdominal distension 
   3 (0.9%) 
   2 (0.6%) 
   1 (0.3%) 
  0 
  0 
  0 
Abdominal pain upper 
   3 (0.9%) 
   1 (0.3%) 
   2 (0.6%) 
  0 
  0 
  0 
Alanine aminotransferase increased 
   3 (0.9%) 
   1 (0.3%) 
   2 (0.6%) 
  0 
  0 
  0 
Blood bilirubin increased 
   3 (0.9%) 
   3 (0.9%) 
  0 
  0 
  0 
  0 
Platelet count decreased 
   3 (0.9%) 
  0 
  0 
   1 (0.3%) 
   2 (0.6%) 
  0 
Urinary hesitation 
   3 (0.9%) 
  0 
   3 (0.9%) 
  0 
  0 
  0 
Urinary retention 
   3 (0.9%) 
   3 (0.9%) 
  0 
  0 
  0 
  0 
Bladder irritation 
   2 (0.6%) 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
Bladder spasm 
   2 (0.6%) 
   2 (0.6%) 
  0 
  0 
  0 
  0 
Blood urine present 
   2 (0.6%) 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
Confusional state 
   2 (0.6%) 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
Frequent bowel movements 
   2 (0.6%) 
   2 (0.6%) 
  0 
  0 
  0 
  0 
Leukopenia 
   2 (0.6%) 
  0 
  0 
   1 (0.3%) 
   1 (0.3%) 
  0 
Lymphocyte count decreased 
   2 (0.6%) 
   2 (0.6%) 
  0 
  0 
  0 
  0 
Malaise 
   2 (0.6%) 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
White blood cell count decreased 
   2 (0.6%) 
   1 (0.3%) 
  0 
   1 (0.3%) 
  0 
  0 
Bladder pain 
   1 (0.3%) 
  0 
   1 (0.3%) 
  0 
  0 
  0 


 
2014-0546 
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Table 1  
Reference Safety Information (RSI) 
Summary of Expected Drug-related Treatment-emergent Adverse Events by Preferred Term, Sorted by Frequency, in Studies of Oral Rigosertib 
Safety-Evaluable (N=337) 
Rigosertib Integrated Analysis 
MedDRA Preferred Term [1][2] 
Any Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Bowel movement irregularity 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Leukocyturia 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Liver function test abnormal 
   1 (0.3%) 
  0 
  0 
   1 (0.3%) 
  0 
  0 
Lymphopenia 
   1 (0.3%) 
  0 
  0 
   1 (0.3%) 
  0 
  0 
Mental status changes 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Neutropenic sepsis 
   1 (0.3%) 
  0 
  0 
   1 (0.3%) 
  0 
  0 
Polyuria 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Red blood cells urine 
   1 (0.3%) 
  0 
   1 (0.3%) 
  0 
  0 
  0 
Red blood cells urine positive 
   1 (0.3%) 
  0 
   1 (0.3%) 
  0 
  0 
  0 
Urethral pain 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Urge incontinence 
   1 (0.3%) 
  0 
   1 (0.3%) 
  0 
  0 
  0 
Urine analysis abnormal 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Urine flow decreased 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
Urine output decreased 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
White blood cells urine positive 
   1 (0.3%) 
   1 (0.3%) 
  0 
  0 
  0 
  0 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple TEAEs were only counted once within a summary category: preferred term, maximum grade, or relationship to treatment. Treatment-Emergent Adverse 
Events (TEAEs) were defined as all AEs that occurred after the first dose of study medication or within 30 day post-treatment period. MedDRA version 17.0. 
Studies include 09-01, 09-02, 09-03, 09-04, 09-05, 09-07, 09-08, 09-09 and 09-12. 
 
 
 
 


 
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Based on nonclinical studies, the following effects could potentially be observed:  
 Decrease in spleen or thymus weight;  
 In men, reduction in sperm cell count and/or decrease of testicles’ weight that could lead 
to infertility, and/or a decrease in the size of the prostate gland; these effects were 
partially or completely reversible in animals. 
 Fetotoxicity (lower fetal weight) and teratogenicity (increased incidence of primarily 
craniofacial malformations); no maternal toxicity was observed in animals; 
 Rigosertib was found to be an inhibitor or a substrate of the following transporters, which 
has the potential to lead to drug-drug interactions. Caution should be exercised and dose 
adjustments of the concomitant substrate or inhibitor drugs should be considered when 
dosing concurrently with rigosertib (see list of drugs that are substrates or inhibitors of 
these transporters at: FDA Guidance DDI).  
o Inhibition of CYP isoform 2C9 in vitro at clinically relevant concentrations. 
Additional in vitro studies to determine the effect of plasma protein binding 
showed that, when rigosertib was incubated with cryopreserved human 
hepatocytes in 100% human plasma to determine its potential for inhibition of 
CYP2C9, the potency of rigosertib decreased by 2.74-fold (12.5 µM) relative to 
that measured in the absence of protein. Based on these data, rigosertib has the 
potential for drug-drug interaction (DDI) with CYP2C9;  
o Time-dependent inhibition of CYP isoform 2C8. However, additional in vitro 
studies to determine the effect of plasma protein binding showed that, in the 
presence of plasma, the potency of rigosertib to inhibit CYP2C8 was very low 
(IC50 > 300 µM). Based on these data, rigosertib does not have the potential for 
DDI with CYP2C8;  
o Inhibition of OAT3, OATP1B1, and OATP1B3 at clinically relevant 
concentrations. Rigosertib could impair the excretion of co-medications that are 
known substrates of these transporters;  
o Rigosertib was found to be a substrate (but not an inhibitor) of P-gp and BCRP. 
Co-medications that are known inhibitors of these transporters should be taken 
with caution, as they could impair the hepatic excretion of rigosertib 
o Rigosertib is 98% protein bound and should be administered with caution to 
patients who are taking concomitant medications that are also highly protein 
bound (eg, warfarin). 
 There was no evidence of ocular or cutaneous phototoxicity in female pigmented rats 
after 3 consecutive daily IV administrations of rigosertib with single solar-simulated 
ultraviolet radiation exposure simultaneously during the final administration.  
 
Based on all clinical and nonclinical data available to date, and evaluating the frequency of 
reported events, the following are considered potential risks: Urinary disorders; Hyponatremia; 
pulmonary alveolar haemorrhage/respiratory distress;  Hepatic effects; Central nervous system 


 
2014-0546 
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(CNS) effects; Effects on spermatogenesis; Thymus involution; Teratogenicity/fetotoxicity; 
Potential carcinogenicity; and Retroperitoneal fibrosis have been identified as potentially 
important risks. The risk of phototoxicity was ruled out based on lack of evidence in animal 
studies but ongoing monitoring via routine proactive pharmacovigilance continues. Informed 
consents are being revised as needed to incorporate all the new potentially important risks. After 
evaluating the evidence in animal studies and the frequency of reporting in the clinical studies, 
the following AEs were deleted from this list: gallbladder hyperplasia, diabeltes insipidus, and 
phototoxicity. These events occurred in less than 0.1% of exposed patients and are unlikely to be 
risks associated with Rigosertib. 
 
1.4. 
Study Rationale 
Strong erythroid activity of oral rigosertib has been observed in lower-risk transfusion-dependent 
MDS patients (Section 1.2) treated with oral rigosertib. As 45% of patients receiving ruxolitinib 
experience Grade 3 or 4 anemia, it is hypothetized that oral rigosertib may improve anemia post-
ruxolitinib.  
 
In addition, Janus kinase 2 (JAK2) allelic reduction has been described in 1 patient in Study 04-05 
conducted at Mount Sinai School of Medicine. This patient had MDS with evidence of 
myelofibrosis (MF) treated initially with AZA for 4 years. Splenomegaly, which was present at 
the outset of treatment, resolved completely. The patient was positive for presence of the 
JAK2 V617F mutation prior to the start of IV rigosertib. The JAK 2-positive allele burden was 
reduced by 41% between Cycle 2 and Cycle 4, suggesting that rigosertib could have activity in MF. 
 
2. 
STUDY OBJECTIVES 
The primary objective of this study is to assess, in patients with myelofibrosis and anemia, the 
efficacy of oral rigosertib in improving anemia and symptoms, and in decreasing the spleen size 
of those patients with splenomegaly.  
 
This study will also assess the safety and tolerability of oral rigosertib in this patient population. 
 
3. 
INVESTIGATIONAL PLAN 
 
3.1. 
Study Design 
This is planned as a Phase II, 2-stage, single-arm study. Up to 35 evaluable patients with MF and 
anemia will receive oral rigosertib BID daily, on a continuous basis (see Study Design in Figure 2). 
Patients will take 560 mg rigosertib (two 280 mg capsules) twice daily in fasting conditions (see 
fasting instructions in Section 3.5.2). To be evaluable, patients need to be treated for at least 
24 weeks with oral rigosertib. 
 


 
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In the first stage, a total of 18 evaluable patients will be enrolled. If 2 or fewer responses are 
observed in the first 18 evaluable patients, the trial may terminate for futility. Otherwise, an 
additional 17 evaluable patients will be enrolled in the second stage.  A summary of the composite 
response (as defined in Section 3.6.1) of the first 18 subjects should be submitted to the IND 
Medical Monitor before moving to the second phase of enrollment. 
 
At least 7 responses in 35 evaluable patients treated for at least 24 weeks with oral rigosertib are 
required to confirm a 30% target response rate at a significance level of 0.05 (see Section 3.6.1, 
Sample Size Considerations).  
 
 
Figure 2 
2014-0546 Design 
 
 
 
All study participants will be allowed, as medically justified, access to RBC and platelet (PLT) 
transfusions, and to filgrastim (granulocyte colony-stimulating factor, [G-CSF]). Rigosertib dosing 
adjustment policies are described in Section 3.5.4. 
 
Patients will remain treated on study for 48 weeks or until progressive disease (PD) criteria 
according to 2013 revised International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT) response criteria (Appendix 4) are met, unacceptable toxicity is observed, 
intercurrent illness or a change in the patient’s condition prevents further administration of study 
drug treatment, or until death from any cause occurs, whichever comes first. Patients who have 
decreased 
splenomegaly 
and/or 
improvement 
of 
anemia 
and/or 
improvement 
in 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF 
   Screening                   Treatment for up to 48 weeks 
Patients with 
MF + anemia 
 N=35 
evaluable 
 
Oral rigosertib, fasting conditions 
560 mg morning/560 mg afternoon, 
continuously 
Endpoints: 
•
Anemia 
response 
•
Symptoms 
response 
•
Spleen 
response 


 
2014-0546 
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TSS) scoring of at least 50% (see Appendix 5) may continue to be treated in the study beyond 
48 weeks until progression or until death from any cause, whichever comes first. 
 
3.2. 
Selection of Study Population 
The diagnosis of MF will be based on bone marrow (BM) aspirate and/or biopsy performed within 
6 weeks prior to Screening. Measurement of JAK2 V617F allele burden in BM samples, if not 
done within 6 months prior to Screening, must be provided with the Screening BM biopsy/aspirate 
report. 
 
3.2.1. 
Inclusion Criteria 
Male and female patients who meet all of the following criteria are eligible for enrollment in the 
trial: 
 
a. ≥18 years of age;  
b. Diagnosis of primary myelofibrosis (PMF) or post-polycythemia vera (post-PV) MF or 
post-essential thrombocythemia (post-ET) MF based on the World Health Organization 
(WHO) criteria (Appendix 1) or the IWG-MRT criteria (Appendix 2), which must be 
confirmed by BM aspirate and/or biopsy within 6 weeks prior to Screening. Measurement 
of JAK2 V617F allele burden in BM samples, if not done within 6 months prior to 
Screening, must be provided with the Screening BM biopsy/aspirate report (patients are 
eligible regardless of JAK2 mutation status); 
c. Anemia or RBC-transfusion dependence defined as follows:   
a. Anemia:  defined for the purpose of this protocol as 1) a hemoglobin level <10 g/L 
on every determination over 84 days before study-entry, without RBC-transfusions, 
or 2) a hemoglobin level <10 g/L on a patient that is receiving RBC-transfusions 
periodically but not meeting criteria for transfusion-dependent patient as defined 
below.  The baseline hemoglobin value for these subjects is the lowest hemoglobin 
level during the antecedent 84 days. 
b. RBC-transfusion-dependence:  RBC-transfusion-frequency of >/=2 units PRBC/28 
days averaged over 84 days immediately pre-study-entry.  There must not be any 
consecutive 42 days without an RBC-transfusion during this interval. 
d. ECOG performance status of 0, 1 or 2 (see Appendix 3); 
e. Willing to adhere to the prohibitions and restrictions specified in this protocol (Notation:  
the subject’s willingness to adhere to prohibitions and restrictions must be clearly 
communicated in the on-study note.); 
f. The patient must signed an informed consent form (ICF) indicating that s/he understands 
the purpose of, and procedures required for, the study and is willing to participate. 
 


 
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3.2.2. 
Exclusion Criteria 
Patients with any of the following will not be enrolled in the study: 
a. Ongoing clinically significant anemia due to factors such as known iron, vitamin B12, or 
folate deficiencies, auto-immune or hereditary hemolysis, or gastrointestinal (GI) bleeding; 
b. Serum ferritin < 50 ng/mL; 
c. Any active malignancy within the past year, except basal cell or squamous cell skin cancer 
or carcinoma in situ of the cervix or breast; patients with history of prior malignancies 
should be free of disease for at least 3 years to be eligible for this study; 
d. Uncontrolled intercurrent illness, including, but not limited to symptomatic congestive 
heart failure, unstable angina pectoris, or cardiac arrhythmia; 
e. Active infection not adequately responding to appropriate therapy; 
f. Direct bilirubin ≥ 2.0 mg/dL not related to hemolysis or Gilbert’s disease; 
g. Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2.5 x the upper limit of 
normal (ULN);  
h. Serum creatinine ≥ 2.5 mg/dL;  
i. Ascites requiring active medical management including paracentesis;  
j. Hyponatremia (defined as serum sodium level < 130 mEq/L); 
k. Female patients who are pregnant or lactating;  
l. Patients of childbearing potential (ie, women of childbearing potential and men with female 
partners of childbearing potential) who are unwilling to follow strict contraception 
requirements (including 2 reliable methods in combination: 1 non-hormonal, highly-
reliable method [diaphragm, condoms with spermicidal foam or jelly, or sterilization] plus 
1 additional reliable method [birth control pills, intrauterine device, contraceptive 
injections, or contraceptive patches]) before entry and throughout the study, up to and 
including the 30-day non-treatment follow-up period;  
m. Female patients of childbearing potential who have a positive blood or urine pregnancy test 
at Screening; 
n. Major surgery without full recovery or major surgery within 3 weeks of Screening; 
o. Uncontrolled hypertension (defined as a sustained systolic pressure ≥ 160 mmHg and/or a 
diastolic pressure ≥ 110 mmHg); 
p. New onset seizures (within 3 months prior to Screening) or poorly controlled seizures; 
q. Any other concurrent investigational agent or chemotherapy, radiotherapy, or 
immunotherapy; 
r. Chronic use (˃ 2 weeks) of corticosteroids (prednisone ˃/= 10 mg/24 hr equivalent) within 
4 weeks of Screening; 
s. Investigational therapy within 2 weeks of Screening; 


 
2014-0546 
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t. Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or 
comply with study requirements. 
 
3.3. 
Removal of Patients from the Study 
Patients will be discontinued in the following circumstances: 
a. The patient dies; 
b. There is evidence of clinically significant PD according to 2013 revised IWG-MRT criteria 
(Appendix 4); 
c. There is no clinical improvement (CI) or anemia response per 2013 revised IWG-MRT 
criteria (Appendix 4) after 48 weeks of treatment; 
d. The Investigator decides that the patient should be withdrawn from the study. If this 
decision is due to a serious adverse event (SAE) or a clinically significant abnormal 
laboratory value, the study drug must be discontinued and appropriate measures taken. The 
MD Anderson IND Office must be notified immediately;  
e. The patient or attending physician requests that the patient be withdrawn from the study;  
f. The MD Anderson IND Office, the supporter or a regulatory agency for any reason, 
terminates the study;  
g. The patient develops unstable ascites requiring medical management including 
paracentesis; 
h. The patient has bilateral Grade 4 edema (per CTCAE) with 10% increase in body weight; 
i. The drug exhibits unacceptable toxicity;  
j. The patient becomes pregnant or fails to use adequate birth control (for those patients of 
childbearing potential);  
k. Non-compliance to condom use for male patients; 
l. The patient exhibits a pattern of non-compliance with study procedures;  
m. The patient is lost to follow-up. In such a case, every possible effort must be made by the 
study site personnel to contact the patient and determine the reason for discontinuation. 
The measures taken to contact the patient must be documented. 
 
3.4. 
Study Procedures 
The schedule of events and study procedures is detailed in tabular form in Appendix 6. 
 
Each study procedure should be performed on the day dictated by the patient's dosing schedule. 
However, if a patient is unable to have a study procedure performed on the scheduled day, the 
procedure must be performed within the particular visit window; otherwise it will be considered a 


 
2014-0546 
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missed procedure. Since significant failure to comply may result in the patient’s being withdrawn 
from the study, repeated deviations from visit windows should be discussed with theMD Anderson 
IND Office. 
 
3.4.2. 
Efficacy Assessments 
 
3.4.2.1. Efficacy Outcomes 
The following outcomes will be assessed: 
 Symptoms response, as determined by change in QOL score before Week 48, using the 
MPN-SAF TSS (Appendix 5); 
 Spleen response at Week 24 and Week 48 (defined as ≥ 35% spleen volume reduction from 
Baseline, which must be confirmed by MRI or CT measurement; see 2013 revised 
IWG-MRT response criteria for MF in Appendix 4); 
 Duration of spleen response; 
 Anemia response (see 2013 revised IWG-MRT response criteria for MF in Appendix 4) 
including change in Hgb and PRBC units transfusion requirements;  
 Change in PLT count and PLT transfusion requirements;  
 BM aspirate and/or biopsy at Week 24 and Week 48 to assess MF and measure 
JAK2 V617F allele burden; 
 OS at Week 48. 
 
3.4.2.2. Bone Marrow Examination and Cytogenetics 
The percentage of BMBL will be quantified by morphology assessment of a specimen of BM 
aspirated smear (Wright-Giemsa stained) and/or biopsy (Hematoxylin-Eosin stained). If the 
proportion of BMBL is estimated as an interval (eg, 5% to 10% BMBL), then the interval mean 
value (ie, 7.5% in this example) will be used for BMBL evaluation. Automated quantification of 
CD34+ blasts by flow cytometry method will not routinely be used for quantification of BMBL. 
However, if the BM is too fibrotic to get a satisfactory BM aspirate, then quantification of BMBL 
using CD34 immunostaining on BM biopsy may be performed. 
 
Cytogenetic analysis will be performed using the fluorescent in-situ hybridization (FISH) 
technique or the conventional G-banding technique (20-metaphases method). 
 
Optional exploratory evaluations of genomics and proteomics exploring pathways potentially 
involved in the pathogenesis of MF and response to treatment will be carried out in BM samples 
collected before and during treatment.  
 


 
2014-0546 
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Leftover blood and BM samples will be used for this testing.  No additional samples will be 
collected. 
 
3.4.2.3. Exploratory Genomics/Molecular Evaluation in Peripheral Blood 
Samples 
Optional genomic and molecular evaluations exploring pathways potentially involved in the 
pathogenesis of MF and response to treatment may be carried out in aliquots of peripheral blood 
(PB) samples, which will be refrigerated and processed.  
 
Leftover blood and BM samples will be used for this testing.  No additional samples will be 
collected. 
 
3.4.3. 
Safety Assessments 
Specific safety parameters and procedures will include recording of medical history, medication 
history, and concomitant medications, physical examination, measurement of vital signs (blood 
pressure, temperature, respiration rate, and pulse), weight, standard 12-lead ECG at Screening, 
laboratory evaluations, and toxicity and AE assessments. Adverse events will be graded according 
to the NCI Common Terminology Criteria Version 4 (CTCAE v4).  Adverse events will be 
recorded from the time of the first protocol-specific intervention up to 30 days after last dose of 
rigosertib. 
 
Safety assessments will include the collection of AEs reported by the patient or observed by the 
Investigator or study site personnel. Questions should be of a general nature and should not suggest 
symptoms. Patients should be asked whether, since the time of the last observation or visit, any of 
the following occurred: 
 They experienced any changes in well-being; 
 They used any new medications;  
 They changed medication regimens (both prescription and over-the-counter); 
 They were hospitalized or had any accidents.   
 
When an AE is suspected, all relevant evaluations will be carried out and appropriate treatment 
provided. Additional follow-up will be performed as necessary and recorded in the patient’s source 
documents, with the results provided to theMD Anderson IND Office. Patients who experience 
any clinically significant AEs will remain under medical supervision until the Investigator or the 
MD Anderson IND Office deems the AE to be resolved, stabilized, or no longer serious enough to 
warrant follow-up. Laboratory values that are abnormal and not assessed as AEs may be followed 
at the discretion of the Investigator or the MD Anderson IND Office until resolved or stabilized. 
 
For AE definitions and reporting requirements, refer to Section 4.1. 


 
2014-0546 
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3.5. 
Treatments 
 
3.5.1. 
Method of Assigning Patients to Treatment Groups 
This is a Phase II, 2-stage, single-arm study. Up to 35 evaluable patients with MF and anemia will 
be enrolled. To be evaluable, patients need to be treated for at least 24 weeks with oral rigosertib.   
 
Outside Physician Participation During Treatment 
 
1. MDACC Physician communication with the outside physician is required prior to the 
patient returning to the local physician. This will be documented in the patient record 
 
2. A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to supervise the patient's care (Appendix E) 
 
3. Protocol required evaluations outside MDACC will be documented by fax. Faxed 
evaluations will be dated and signed by the MDACC physician/investigator indicating that 
they have reviewed it.  
 
4. A copy of the informed consent, protocol abstract, treatment schema and evaluation 
during treatment will be provided to the local physician. 
 
5. Documentation to be provided by the local physician will include progress notes, 
reports of protocol required laboratory and diagnostic studies and documentation of any 
hospitalizations. 
 
6. The home physician will be requested to report to the MDACC physician/investigator 
all life threatening events within 24 hours of documented occurrence. 
 
7. 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. 
 
 
3.5.2. 
Treatments Administered 
Rigosertib will be supplied as 280 mg and 70 mg capsules by Onconova. Study drug must be stored 
between 2°C and 8°C (ie, refrigerated), protected from light, whether at the patient's home or at 
the institution.  
 
Rigosertib will be administered daily, continuously, on an outpatient basis. Patients will take 
560 mg rigosertib in the morning (two 280 mg capsules) and 560 mg rigosertib in the afternoon. 


 
2014-0546 
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See Section 3.5.4 for adjusted rigosertib dose regimens.   Treatments should be started within 2 
weeks of completion of screening and meeting eligibility criteria. 
 
Patients should be instructed to take rigosertib in a fasting state BID as follows: 
 The morning dose should be taken after an overnight fast, on an empty stomach, and 
patients should wait 1 hr after dosing to have breakfast.  
 The afternoon dose should be taken at approximately 3 PM (±1 hr) at least 2 hr after lunch, 
on an empty stomach, and patients should wait 1 hr before the next meal.  
 
Water is permitted during the fasting period. Any vomited dose will be reported as a missed dose. 
Good hydration (ie, at least 2 liters of water per day) is recommended for all patients.   
 
3.5.3. 
Management of Clinical Supplies 
The Investigator will have overall responsibility for the use of the study medication. Under no 
circumstances will the Investigator allow rigosertib to be used other than as directed by this 
protocol. The Investigator or designee will provide a signed acknowledgment for receipt of the 
study medications and a signed acknowledgment for return of study medication containers and 
unused study medication at the end of the study. An accurate record of the dispensing of all study 
medication must be maintained. Upon completion or termination of the study, remaining study 
drug will be returned to Onconova, unless otherwise instructed by the MD Anderson IND Office 
or Onconova. 
 
Qualified study center personnel must receive study drug deliveries, record the receipt, and assure 
that the study drug is handled and stored safely and properly. The packing list must be reconciled 
against the bottles received. Any extra/damaged drug product containers will be destroyed at the 
site according to local procedures, or sent to Onconova for destruction, as instructed and 
documented by Onconova. 
 
Study drug must be stored between 2°C and 8°C (ie, refrigerated), protected from light, whether 
at the patient's home or at the institution.   
 
Copies of all dispensing records for the study drug must be kept at the study center as part of 
required study documentation. At the end of the study, the study center must be able to reconcile 
delivery records with records of study drug received, dispensed, and returned. The Investigator 
must account for any discrepancies. 
 
Rigosertib may not be relabeled or reassigned for use. Rigosertib may not be used for any purposes 
other than what is outlined in this protocol, including other human studies, animal investigations, 
or in vitro testing. 
 


 
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3.5.4. 
Rigosertib Dosing Adjustments  
The number of capsules to be taken as a function of adjusted dose is presented in Table 2.  
 
Table 2  
Rigosertib Dosing Adjustments 
 
Original Dose 
First Dose 
Reduction 
Second Dose 
Reduction 
Third Dose Reduction 
Morning dose 
560 mg  
(Two 280 mg 
capsules) 
560 mg  
(Two 280 mg 
capsules) 
420 mg  
(One 280 mg + two 
70 mg capsules) 
280 mg  
(One 280 mg capsule) 
Afternoon 
dose 
560 mg  
(Two 280 mg 
capsules) 
280 mg  
(One 280 mg 
capsule) 
210 mg  
(Three 70 mg 
capsules) 
140 mg  
(Two 70 mg capsules) 
 
3.5.4.1. Hematologic Toxicity 
If ANC and/or PLT nadir are decreased by  50% from Baseline count and to > Grade 3 levels  
unrelated to disease, comorbidities or concomitant medications, the next rigosertib dose may be 
delayed until the ANC has increased to > 1 x 109/L and the PLT count has increased to 
> 75 x 109/L. If the next dose has to be delayed by more than 14 days after the last dose, rigosertib 
will be restarted at the next lower dose level (see Table 2).  If the delay is ≤ 14 days after the last 
dose, rigosertib may be restarted at 100% of scheduled dose.  Patients who experience  treatment-
related neutropenia and/or thrombocytopenia of 6 weeks duration or more (consecutive) in more 
than two occasions may continue on study (after appropriate dose adjustments as per Table 2) only 
after discussion with the IND office to justify the appropriateness of continued therapy. 
 
3.5.4.2. Non-hematologic Toxicity - Hyponatremia 
If a patient develops ≥ Grade 3 hyponatremia, rigosertib will not be administered until resolution 
to Grade 2 and serum and urine osmolality, serum albumin, BUN, serum creatinine, and serum 
and urinary sodium will be measured to assist in the medical management of hyponatremia. 
Additional tests may be carried out as clinically warranted. 
 
3.5.4.2.1. Treatment-related Urinary Symptoms 
If any treatment-related urinary symptoms of Grade 2 or higher in severity that are at least 1 grade 
higher than Baseline, develop during the treatment period, treatment will be withheld until 
resolution to ≤ Grade 1 or Baseline status and resumed using the schedule displayed in Table 3.  
 


 
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Table 3  
Oral Rigosertib Step-by-step Dose Reductions for Urinary Toxicity 
Episodes of 
Urinary Toxicity 
Starting Dose 
Dose Adjustment 
Morning 
Afternoon 
Morning 
Afternoon 
1 
560 mg 
560 mg 
560 mg 
280 mg 
2 
560 mg 
280 mg 
420 mg 
280 mg 
3 
420 mg 
280 mg 
420 mg 
210 mg 
4 
420 mg 
210 mg 
280 mg 
210 mg 
5 
280 mg 
210 mg 
280 mg 
140 mg 
6 
280 mg 
140 mg 
140 mg 
140 mg 
7 
140 mg 
140 mg 
140 mg 
70 mg 
8 
140 mg 
70 mg 
70 mg 
70 mg 
9 
70 mg 
70 mg 
140 mg every other day 
0 mg 
 
Should a further episode of urinary toxicity occur, the patient will be withdrawn from the trial and 
followed.  
 
3.5.4.2.2. Treatment-related ≥Grade 3 Toxicity other than Urinary Symptoms 
If any treatment-related non-hematologic toxicity of Grade 3 or higher is present on the day of 
administration of rigosertib:  
1. Rigosertib treatment will be withheld until resolution to ≤ Grade 1 or Baseline toxicity 
grading, whichever is greater, then dosing will be resumed at full dose;   
2. If the same treatment-related toxicity of Grade 2 or higher reoccurs, rigosertib dosing will 
be reduced (see Table 2) at the next administration;   
3. If the same treatment-related non-hematologic toxicity of ≥ Grade 2 reoccurs, rigosertib 
dose will be reduced further (see Table 2) after resolution to ≤ Grade 1 or Baseline status;  
4. If the same toxicity persists and is not tolerable, the patient will be withdrawn from the 
study. 
 
3.5.5. 
Treatment Compliance 
Each dose of rigosertib should be administered on the day dictated by the patient’s dosing schedule. 
Patients should not take missed doses.  Patients will be given a diary to document compliance with 
study drug. 
 


 
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3.5.6. 
Management of Urinary Symptoms 
Good hydration (ie, at least 2 liters of water per day) is recommended for all patients. If dysuria 
develops, the following therapies may be prescribed: 
 Sodium bicarbonate tablets if the patient is not on a sodium-restricted diet: 650 mg tablets 
given BID with two 8-ounce glasses of water 1 hr after rigosertib administration; 
 Pyridium if the patient has a normal creatinine value and is not allergic to phenazopyridine: 
100 mg 3 times daily orally, taken with a full glass of water and food; pyridium should not 
be taken for more than 2 days. 
 
Please refer to Section 3.5.4.2.1 for dosing adjustments in case of ≥ Grade 2 urinary toxicity. 
 
3.5.7. 
Concomitant Therapy 
All concomitant medications (including non-prescription drugs and herbal therapies) received 
from 30 days prior to study entry until the end of study will be recorded in the patient’s chart. The 
information should include the name of the drug, indication, daily dose with units, and the start 
and stop date(s) of administration.  
 
All patients may be transfused when judged to be medically necessary by the Investigator. The 
date and type of transfusion, the Hgb and/or PLT values prior to transfusion (obtained at the time 
of type/cross match), and the number of units transfused must be recorded on the eCRF. The reason 
for transfusion should also be documented. 
 
Recombinant G-CSF or granulocyte-monocyte colony stimulating factor (GM-CSF) can be used 
as clinically indicated (e.g., for Grade 3 or 4 neutropenia with recurrent or resistant bacterial 
infections). Recommended dosage for G-CSF is 5 µg/kg subcutaneous (SC) daily (NCCN 2011). 
 
Based on findings from nonclinical studies, rigosertib inhibits CYP isoforms 2C9 and 2C8 in vitro 
at clinically relevant concentrations. Caution should be exercised and dose reduction of the 
concomitant substrate drugs should be considered when dosing rigosertib concurrently with 
medications with narrow therapeutic range that are substrates of CYP2C9 or CYP2C8 (see 
Appendix 8). In addition, rigosertib was found to be a P-gp substrate, but not a P-gp inhibitor (see 
list of potential P-gp inhibitors in Appendix 9). 
 
3.6. 
Statistical Methods 
This study is a Phase II, proof-of-concept, single-arm study of the efficacy and safety of oral 
rigosertib in patients with MF and anemia.  
 
3.6.1. 
Sample Size Considerations 
The primary endpoint will be the proportion of patients achieving spleen response by Week 24 or 
Week 48 (defined as ≥ 35% spleen volume reduction from Baseline, which requires confirmation 


 
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by MRI or CT; see 2013 revised IWG-MRT criteria in Appendix 4) and/or anemia response by 
Week 24 or Week 48 (defined as the proportion of transfusion-independent patients with Hgb 
increase of at least 2 g/dL from Baseline or the proportion of transfusion-dependent patients 
becoming transfusion independent for at least 12 weeks as defined in 2013 IWG-MRT criteria; 
Appendix 4) and/or symptoms response (defined as the proportion of patients achieving ≥ 50% 
reduction in the MPN-SAF TSS score; see Appendix 5) at any time before Week 48.  These 
response criteria will be referred to as “composite response”. 
 
A response rate (composite response described above) of 30% or more is considered clinically 
meaningful, against a minimal or "uninteresting" response rate of 10% or less. A Simon 2-stage 
optimal design is used in order to minimize the expected sample size if the regimen has low 
activity. If there are 2 or fewer responses in the first 18 evaluable patients, the trial may terminate 
for futility. Otherwise, 17 more evaluable patients will be enrolled, for a total of 35 evaluable 
patients. At least 7 responses in 35 evaluable patients are required to confirm the 30% target 
response rate at a significance level of 0.05, assuming a power of 0.90. Probability of termination 
at Stage 1 is 73% and 6% for underlying responses rates of ≤ 10% and ≥ 30%, respectively.  
 
Descriptive statistics (mean, standard deviation, and coefficient of variation, median, minimum 
and maximum) will be calculated for safety and efficacy parameters.  
 
3.6.2. 
Analysis Populations 
The analyses will be done on the 3 following populations: 
 The full analysis set (FAS) population will include all patients enrolled and treated.   
 The per-protocol (PP) population will include all patients who complete the study without 
major protocol violations and are treated for a minimum of 24 weeks.  
 The safety population will include all patients who received at least 1 dose of rigosertib. It 
is identical to the FAS population.  
 
3.6.3. 
Final Analyses 
 
3.6.3.1. Efficacy Analyses 
Analyses of the primary and secondary efficacy outcomes will be performed on the FAS and PP 
populations.  
 
The primary endpoint will be the proportion of patients with splenomegaly at Baseline achieving 
spleen response at Week 24 or Week 48 (defined as ≥ 35% spleen volume reduction from Baseline, 
which requires confirmation by MRI or CT; see 2013 revised IWG-MRT criteria in Appendix 4) 
and/or anemia response at Week 24 or Week 48 (defined as the proportion of transfusion-
independent patients with Hgb increase of at least 2 g/dL from Baseline or the proportion of 


 
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transfusion-dependent patients becoming transfusion independent for at least 12 weeks as defined 
in 2013 IWG-MRT criteria; Appendix 4) and/or symptoms response (defined as the proportion of 
patients achieving ≥ 50% reduction in the MPN-SAF TSS score; see Appendix 5) at any time 
before Week 48. 
 
3.6.3.2. Safety Analyses 
Safety analyses will be performed on the safety population. Safety definitions are found in 
Section 4.1. 
 
Adverse Events: 
Adverse events will be coded using the most recent version of the Common Terminology Criteria 
for Adverse Events v4 (CTCAE). Adverse events will be summarized by patient, not by event. 
Investigators will be asked to assess the relationship of AEs to study drug. The relationship of each 
AE to study drug will be categorized as not related, unlikely related, possibly related, probably 
related, or definitely related to study drug.   
 
Disease progression will not be considered an AE. 
 
A listing of all AEs will be provided using the most recent version of CTCAE and will include 
(but will not be limited to) onset and resolution dates, seriousness, severity, relationship, action 
taken with study drug, and outcome.  Adverse Events (AEs) will be evaluated according to 
current CTC version in each protocol. Only unexpected and related AEs will be recorded in 
the Case Report Form (CRF). Appendix D “Leukemia Specific AE Recording Guidelines” will 
be followed. 
 
Deaths: 
The number of patients who died will be summarized. A by-patient listing of deaths including 
death date, cause of death, number of days from first and last dose of rigosertib, and relationship 
to study drug will also be provided. 
 
Laboratory Assessments: 
Laboratory test data may be analyzed using summary statistics on changes from Baseline or 
distributions of worst on-study laboratory values based on CTCAE grade.  
 
Vital Signs: 
Vital signs may be analyzed using summary statistics on changes from Baseline or distribution of 
worst on-study values based on CTCAE grade.  
 
3.6.3.3. Additional Analyses 
 


 
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ECOG Performance Status:  
 
ECOG performance status has integer values from 0 (fully active) to 4 (completely disabled) (see 
Appendix 3). The number and percentage of patients with each result for the latest pre-enrollment 
examination will be summarized. For each patient, the best post-screening ECOG performance 
status (lowest score) will be summarized over the entire time on study. A shift table will be 
presented indicating the change from baseline ECOG status to maximum ECOG for the entire time 
on study. Graphical displays may be generated if appropriate. 
 
Population Pharmacokinetics: 
Blood samples for measurement of rigosertib will be taken in all patients 1 hr after rigosertib 
administration on Baseline/C1D1 visit (morning dose), and at predose and 1 hr after rigosertib 
administration on Day 28 (+/-5 days) (morning dose). Population PK analyses will consider 
relationships between mean blood levels of rigosertib and the efficacy outcomes. 
 
4. 
INVESTIGATOR’S OBLIGATIONS 
 
4.1. 
Reporting Adverse Events 
 
4.1.1. 
  Serious Adverse Event Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience 
as it occurred. It does not include an adverse experience that, had it occurred in a more 
severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 


 
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 Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting 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). 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB for participants enrolled at MDACC. 
 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.   
 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. 
 
Reporting to FDA: 
 Serious adverse events will be forwarded to FDA by the Investigator at UT MD Anderson 
Cancer Center (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,  UT MD Anderson Cancer Center, and Institutional Review Board policy. 
 
4.1.2 Case Report Form 
In this study all AEs will be reported electronically via the AE Recording Form (PDMS/CORe). 
 
4.2 
Investigator Communications with Onconova 
Adverse Event Reporting to Supporting Company: 
SAEs must be reported to Onconova within 24 hours of the study center’s knowledge of the AE.  
SAEs are to be emailed to USDrugSafety@onconova.us. 
.   
 
4.3 
Pregnancies 
In pregnant rats, rigosertib was found to be fetotoxic (as evidenced by lower fetal weights) and 
teratogenic (increased incidence of primarily craniofacial malformations). No maternal toxicity 
was observed (see Rigosertib IB). Pregnancies occurring between the signing of the ICF up to 


 
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30 days after the last dose of study drug must be reported on the Pregnancy Notification Form by 
the investigational staff within 24 hr of their knowledge of the event. Any patient who becomes 
pregnant during participation in this study must be promptly withdrawn from the study. These 
patients will be asked to consent to allow their treating physician to provide Onconova with follow-
up information on the pregnancy itself and its outcome. Follow-up information regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant will be required. 
 
5. 
REFERENCE LIST 
Barosi G, Mesa RA, Thiele J, et al. Proposed criteria for the diagnosis of post-polycythemia vera 
and post-thrombocythemia myelofibrosis: a consensus statement from the international working 
group for myelofibrosis research and treatment. Leukemia. 2008; 22:437-8 
Chapman CM, Sun X, Roschewski M, et al. ON 01910.Na is selectively cytotoxic for chronic 
lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition 
and induction of oxydative stress. Clin Cancer Res. 2012; 18:1979-91. 
Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom 
assessment form total symptom score: prospective international assessment of an abbreviated 
symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012; 30:4098-4103 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed 
2013/02/04. 
Food & Drug Administration. Drug development and drug interactions: table of substrates, 
inhibitors 
and 
inducers. 
http://www.fda.gov/drugs/developmentapprovalprocess/ 
developmentresources/druginteractionslabeling/ucm093664.htm#PgpTransport  
Jimeno A, Rubio-Viqueira B, Rajeshkumar NV, Chan A, Solomon A, Hidalgo M. A fine-needle 
aspirate-based vulnerability assay identifies polo-like kinase 1 as a mediator of gemcitabine 
resistance in pancreatic cancer. Mol Cancer Ther. 2010; 9:311-8. 
Manoharan A, Horsley R, Pitney WR. The reticulin content of bone marrow in acute leukemia 
in adults. Br J Haematol. 1979; 43:185-90. 
Mesa RA, Gotlib JR, Gupta V et al. Results using the modified myelofibrosis Symptom 
Assessment Form (MFSAF v2.0) in Comfort I: a randomized, double-blind, phase III trial of 
Jak ½ inhibitor ruxolitinib vs. Placebo in myelofibrosis. Poster 912; 16th Congress EHA; June 
2011 
NCCN clinical practice guidelines in oncology (NCCN Guidelines™). Myelodysplastic 
syndromes. Version 2.2011. 


 
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Page 34 of 49 
 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-55. 
Olnes MJ, Shenoy A, Weinstein B et al. Directed therapy for patients with myelodysplastic 
syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na. Leukemia Res. 2012; 
36:982-9. 
Prasad A, Park IW, Allen H, et al. Styryl sulfonyl compounds inhibit translation of cyclin D1 in 
mantle cell lymphoma cells. Oncogene. 2009; 28:1518–28. 
Raza A, Tycko B, Sangmin L, et al. Oral rigosertib (ON 01910.Na) treatment produces an 
encouraging rate of transfusion independence in lower risk myelodysplastic syndrome (MDS) 
patients; a genomic methylation profile is associated with responses. ASH 2013, New Orleans, 
LA. Abstract #2745. 
Reddy MV, Mallireddigari MR, Cosenza SC, et al. Design, synthesis, and biological evaluation 
of (E)-styrylbenzylsulfones as novel anticancer agents. J Med Chem. 2008; 51: 86-100. 
Rigosertib (ON 01910.Na) Investigator's Brochure. Edition 19, November 20, 2013. 
Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health 
Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary 
myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007; 
110:1092-7. 
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;122:1395-8. 
Thiele J, Kvasnicka HM, Facchetti F, Franco V, Ven der Walt J, Orazi A. et al. European 
consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 
2005; 90:1128. 
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revisions of the World Health Organization 
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important 
changes. Blood. 2009;114:937-51. 
 


 
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6. 
APPENDICES 


 
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Appendix 1: WHO Criteria for Diagnosis of Primary Myelofibrosis, Essential Thrombocythemia, and 
Polycythemia Vera 
 
Reference: Vardiman 2009 
 
Criteria for Primary Myelofibrosis(PMF) 
Diagnosis requires meeting all 3 major criteria and 2 minor criteria. 
Major Criteria 
1. Presence of megakaryocyte proliferation and atypia,(a) usually accompanied by either reticulin or 
collagen fibrosis  
or, 
in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an 
increased bone marrow cellularity characterized by granulocytic proliferation and often decreased 
erythropoiesis (ie, prefibrotic cellular-phase disease) 
2. Not meeting WHO criteria for polycythemia vera,(b) BCR-ABL1–positive chronic myelogenous 
leukemia,(c) myelodysplastic syndrome,(d) or other myeloid disorders 
3. Demonstration of JAK2 V617F or other clonal marker (eg, MPLW515K/L),  
or, 
in the absence of the above clonal markers, no evidence that bone marrow fibrosis is secondary to 
infection, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or 
other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies(e) 
Minor criteria 
1. Leukoerythroblastosis(f) 
2. Increase in serum lactate dehydrogenase level(f) 
3. Anemia(f) 
4. Palpable splenomegaly(f) 
(a) 
Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or irregularly 
folded nuclei and dense clustering. 
(b) 
Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the 
presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels. 
Red cell mass measurement is not required. 
(c) 
Requires the absence of BCR-ABL1. 
(d) 
Requires the absence of dyserythropoiesis and dysgranulopoiesis. 
(e) 
It should be noted that patients with conditions associated with reactive myelofibrosis are not immune to primary 
myelofibrosis, and the diagnosis should be considered in such cases if other criteria are met. 
(f) 
Degree of abnormality could be borderline or marked. 
 
 


 
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Criteria for Essential Thrombocythemia (ET) 
Diagnosis requires meeting all 4 criteria  
1. Sustained platelet count ≥ 450 x 109/L(a) 
2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with 
increased numbers of enlarged, mature megakaryocytes. No significant increase or left-shift of 
neutrophil granulopoiesis or erythropoiesis. 
3. Not meeting WHO criteria for polycythemia vera,(b) primary myelofibrosis,(c) BCR-ABL1–positive 
CML,(d) or myelodysplastic syndrome,(e) or other myeloid neoplasm. 
4. Demonstration of JAK2 V617F or other clonal marker, or in the absence of JAK2 V617F, no evidence 
of reactive thrombocytosis(f) 
ET = essential thrombocythemia; BM = bone marrow; WHO = World Health Organization; CML = chronic myelogenous 
leukemia. 
(a) 
Sustained during the work-up process. 
(b) 
Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range in the 
presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels, 
and red cell mass measurement is not required. 
(c) 
Requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral blood leukoerythroblastosis, or  
markedly hypercellular marrow accompanied by megakaryocyte morphology that is typical for primary 
myelofibrosis—small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, 
bulbous, or irregularly folded nuclei and dense clustering. 
(d) 
Requires the absence of BCR-ABL1. 
(e) 
Requires the absence of dyserythropoiesis and dysgranulopoiesis. 
(f) 
Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, 
connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, the presence of a 
condition associated with reactive thrombocytosis does not exclude the possibility of ET if other criteria are met. 
 
Criteria for Polycythemia Vera (PV) 
Diagnosis requires the presence of both major criteria and 1 minor criterion or the presence of the first 
major criterion together with 2 minor criteria 
Major Criteria 
1. Hemoglobin > 18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume* 
2. Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation 
Minor criteria 
1. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with 
prominent erythroid, granulocytic, and megakaryocytic proliferation 
2. Serum erythropoietin level below the reference range for normal 
3. Endogenous erythroid colony formation in vitro 
*Hemoglobin or hematocrit > 99th percentile of method-specific reference range for age, sex, altitude of residence or  
hemoglobin > 17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL 
from a person’s baseline value that cannot be attributed to correction of iron deficiency or elevated red cell mass > 25% 
above mean normal predicted value. 


 
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Appendix 2: 2008 IWG-MRT Diagnosis Criteria for Post-Polycythemia Vera and Post-Essential 
Thrombocythemia Myelofibrosis 
 
Reference: Barosi 2008 
 
IWG-MRT Recommended Criteria for Post-Polycythemia Vera (PV) Myelofibrosis (MF) and 
Post-Essential Thrombocythemia (ET) MF 
Criteria for Post-PV MF 
Required Criteria: 
1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria 
(Tefferi 2007 and Error! Reference source not found.) 
2. Bone marrow fibrosis grade 2-3 (on a 0-3 scale) (Thiele 2005)(a) or grade 3-4 (on a 0-4 scale) 
(Manoharan 1979)(a) 
Additional Criteria (two are required): 
1. Anemia(b) or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive 
therapy) or cytoreductive treatment for erythrocytosis 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable 
splenomegaly 
4. Development of ≥ 1 of 3 constitutional symptoms: > 10% weight loss in 6 months, night sweats, 
unexplained fever (> 37.50C) 
 
Criteria for Post-ET MF 
Required Criteria: 
1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO 
criteria (Tefferi 2007) 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale) (Thiele 2005)(a) or grade 3–4 (on 0–4 scale) 
(Manoharan 1979(a) 
Additional Criteria (2 are required): 
1. Anemia(b) and a ≥ 2 mg/mL (Tefferi 2007) decrease from baseline hemoglobin level 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥ 5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable 
splenomegaly 
4. Increased lactate dehydrogenase (LDH) (above reference level) 


 
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IWG-MRT Recommended Criteria for Post-Polycythemia Vera (PV) Myelofibrosis (MF) and 
Post-Essential Thrombocythemia (ET) MF 
5. Development of ≥ 1 of 3 constitutional symptoms: > 10% weight loss in 6 months, night sweats, 
unexplained fever (> 37.50C) 
IWG-MRT = International Working Group for Myelofibrosis Research and Treatment; LDH = lactate 
dehydrogenase;  
(a) 
Grade 2-3 according to the European classification: diffuse, often coarse fiber network with no evidence 
of collagenization (negative trichrome  stain) or diffuse, coarse fiber network with areas of 
collagenization (positive trichrome stain). Grade 3–4 according to the standard classification: diffuse and 
dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen 
and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with 
coarse bundles of collagen, often associated with significant osteosclerosis 
(b) 
Below the reference range for appropriate age, sex, gender and altitude considerations
 


 
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Appendix 3: Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
The ECOG toxicity and response criteria are summarized below (Oken 1982). 
 
ECOG Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


 
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Appendix 4: 2013 IWG-MRT Revised Response Criteria for Myelofibrosis 
 
Reference: Tefferi 2013 
 
Revised IWG-MRT and ELN Response Criteria for Myelofibrosis 
 
Response Categories 
Required Criteria (For all response categories, benefit must last for 
≥ 12 weeks to qualify as a response) 
Complete response (CR) 
Bone marrow(1): Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 
MF(2) and  
Peripheral blood: Hemoglobin ≥ 100 g/L and < ULN; neutrophil count 
≥ 1 x 109/L and < ULN; platelet count ≥ 100 x 109/L and < ULN; < 2% 
immature myeloid cells(3) and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
Partial response (PR) 
Peripheral blood: Hemoglobin ≥ 100 g/L and < ULN; neutrophil count 
≥ 1 x 109/L and < UNL; platelet count ≥ 100 x 109/L and < ULN; < 2% 
immature myeloid cells(3) and 
Clinical: resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH or 
Bone marrow(1): Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 
MF(2) and peripheral blood: Hemoglobin ≥ 85 but < 100 g/L and < ULN; 
neutrophil count ≥ 1 x 109/L and < ULN; platelet count ≥ 50, but 
< 100 x 109/L and < ULN; < 2% immature myeloid cells(3) 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(4) 
Anemia response 
 Anemia response  is a composite endpoint defined as an increase in 
hemoglobin (hemoglobin response; defined below) in a subject with anemia 
(5) OR becoming RBC-transfusion-independent in a subject who is RBC-
transfusion-dependent (6) defined as follows: 
o 
Hemoglobin-response is defined as an increase in hemoglobin level of 
≥1.5 g/L (compared to baseline) on every determination consecutively 
for a ≥84 d interval, without RBC-transfusions. 
o 
RBC-transfusion-independence is defined as no RBC-transfusion in 
any “rolling” 84 day interval during the treatment period, in patients 
who were RBC-transfusion dependent at enrollment. 
Spleen response(7) 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, 
becomes not palpable(8) 
A baseline splenomegaly that is palpable at > 10 cm, below the LCM, 
decreases by ≥ 50%(8) 
A baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not 


 
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Revised IWG-MRT and ELN Response Criteria for Myelofibrosis 
eligible for spleen response  
A spleen response requires confirmation by MRI or computed tomography 
showing ≥ 35% spleen volume reduction 
Symptoms response 
A ≥ 50% reduction in the MPN-SAF TSS(9) 
Progressive disease (PD)(10) 
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 x 109/L that lasts for at least 2 weeks 
Stable disease (SD) 
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 a 6-months 
window 
CR: eradication of a preexisting abnormality 
PR: ≥ 50% reduction in abnormal metaphases (PR applies only to patients 
with at least 10 abnormal metaphases at baseline) 
Molecular remission 
Molecular response evaluation must be analyzed in peripheral blood 
granulocytes and requires confirmation by repeat testing within 6 months 
window 
CR: Eradication of a pre-existing abnormality 
PR: ≥ 50% decrease in allele burden (PR 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 = extramedullar hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-proven 
nonhepatosplenic EMH); LCM = left costal margin; ULN = upper limit of normal; MPN-SAF TSS = myeloproliferative 
neoplasm symptom assessment form total symptom score;. 
(1) 
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. 
(2) 
Grading of MF is according to the European classification (Thiele 2005). It is underscored that the consensus 
definition of a CR bone marrow is to be used in only those patients in whom 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. 
(3) 
Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood cells. 
In splenectomized patients, < 5% immature myeloid cells is allowed. 


 
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Revised IWG-MRT and ELN Response Criteria for Myelofibrosis 
(4) 
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 x 109/L and absolute neutrophil count of ≥ 0.5 x 109/L. 
(5) 
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. 
(6) 
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. 
(7) 
In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
(8) 
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. 
(9) 
Symptoms are evaluated by the MPN-SAF TSS (Emanuel 2012). 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. 
(10) Progressive disease assignment for splenomegaly requires confirmation by MRI or CT 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 post-treatment measurements. 
 
 
 


 
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Appendix 5:   Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-
SAF TSS) 
 
MRN _______________ 
 
Name _________________________________ 
 
 
Symptom 
1 to 10 (0 if absent) ranking 
1 is most favorable and 10 least favorable 
Please rate your fatigue (weariness, 
tiredness) by circling the one number 
that best describes your WORST level 
of fatigue during the past 24 hours 
(No fatigue) 0   1   2   3   4   5   6   7   8   9   10  (Worst Imaginable) 
 
 
Circle the one number that describes how, during the past week, much  
difficulty you have had with each of the following symptoms 
Numbess/Tingling in hands and feet 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Night Sweats 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Itching (pruritus) 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Bone Pain 
(Diffuse – not joint pain or arthritis) 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Fever (>100 F) 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Unintentional weight loss last 6 
months 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Filling up quickly when you eat 
(Early satiety) 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Abdominal Discomfort 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Inactivity 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
Problems with concentration – 
compared to prior to my MPD 
(Absent)  0    1    2    3    4   5    6    7    8    9    10  (Worst Imaginable) 
 
 
 
 
 
 


 
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Appendix 6: Schedule of Events and Procedures  
 
Schedule of Events and Procedures  
 
 
 
Tests/Evaluations 
 
 
 
Screeninga 
 
 
Baseline/ 
C1D1b 
 
 
 
QWb 
Q4W for 
12 Wk 
then 
Q8Wb 
 
Week 24 
and 
Week 48b 
 
End-of-study/ 
Early 
Withdrawalc 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Medical historyd 
X 
X 
 
 
 
 
Prior & current therapyd 
X 
X 
 
 
 
 
Concomitant medications 
 
X 
 
X 
 
X 
Transfusion historye 
X 
X 
 
X 
 
X 
Physical examination 
X 
Xf 
 
X 
 
X 
ECOG performance status 
X 
Xf 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
Height and weightg 
X 
X 
 
X 
 
X 
12-lead ECG 
X 
 
 
 
 
 
CBC with differentialh 
X 
Xf 
X 
 
 
X 
Serum chemistry paneli 
X 
Xf 
X 
 
 
X 
Serum erythropoietin 
X 
 
 
 
 
 
Serum ferritin 
X 
 
 
 
 
 
Blood/urine pregnancy testj 
X 
 
 
 
X 
X 
Urinalysisk 
X 
Xf 
 
X 
 
X 
BM aspirate and/or biopsy 
and cytogeneticsl 
X 
 
 
 
X 
 
QOL questionnaire  
(MPN-SAF-TSS) 
 
X 
 
X 
 
 
Spleen volume (MRI or CT) 
in patients with palpable 
splenomegaly at baseline 
 
X 
 
 
X 
 
Blood PK samplesm 
 
X 
 
Xm 
 
 
Study drug dispensing 
 
X 
 
X 
 
 
Assessment of compliance 
 
 
 
X 
 
 


 
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Schedule of Events and Procedures  
 
 
 
Tests/Evaluations 
 
 
 
Screeninga 
 
 
Baseline/ 
C1D1b 
 
 
 
QWb 
Q4W for 
12 Wk 
then 
Q8Wb 
 
Week 24 
and 
Week 48b 
 
End-of-study/ 
Early 
Withdrawalc 
Adverse eventsn 
X 
X 
X 
 
 
 
a Screening procedures will occur up to 14 days before Baseline/C1D1 visit, except for urine pregnancy test (to be done 
within 7 days prior to Baseline/C1D1 visit). Bone marrow aspirates and biopsies performed up to 6 weeks before 
Baseline/C1D1 visit do not need to be repeated. JAK2V617F allele burden measurement in BM samples, if not done 
within 6 months prior to Screening, must be provided with the Screening BM biopsy/aspirate report. 
b A 2-day window is allowed for Baseline/C1D1 and QW; a 5-day window for Q4W and Q8W visits. A 1-week window is 
allowed for Weeks 24 and 48 visits. 
c The end-of-study/early withdrawal procedures should be performed 30 days after study completion. If a study procedure 
cannot be performed on the scheduled day, the procedure must be performed within 1 week. 
d Includes date and diagnosis of MF and JAK2V617F status. The last available karyotype report prior to Screening should 
be collected. Prior treatment with ruxolitinib if applicable needs to be documented. Medical and medication history should 
be updated at Baseline/C1D1 visit. 
e This includes number and dates of PRBC and PLT units administered within the past 12 weeks prior to enrollment, and 
Hgb and PLT values prior to transfusion. 
f 
Does not need to be repeated at Baseline/C1D1 visit if Screening took place within 72 hours. 
g Height measured at Screening only. 
h Automated and/or manual differential per institution’s standard; the method should be consistent throughout the study. 
i 
Includes serum albumin, total protein, total bilirubin, direct bilirubin (if total bilirubin > ULN), ALT, AST, LDH, alkaline 
phosphatase, bicarbonate, sodium, potassium, chloride, serum creatinine, BUN, calcium, phosphorus, uric acid, and 
glucose. Note: If a patient develops ≥Grade 3 hyponatremia, rigosertib will not be administered and serum and urine 
osmolality, serum albumin, BUN, creatinine, and serum and urinary sodium will be measured to assist in the medical 
management of hyponatremia. Additional tests may be carried out as clinically warranted. 
j 
Blood or urine pregnancy test in female patients of childbearing potential only; must be completed within 7 days prior to 
Baseline/C1D1 visit. Pregnancy tests must have sufficient sensitivity (ie, at least 25 mIU/mL) to guarantee positive 
identification of pregnancy. 
k Includes glucose, protein, white blood cells (WBC), blood/occult blood, ketone, pH and specific gravity, and crystals. 
l 
Bone marrow aspirate and/or biopsy and cytogenetics must be performed within 6 weeks prior to Screening visit; 
JAK2 V617F allele burden measurement in BM samples, if not done within 6 months prior to Screening, must be provided 
with the Screening BM biopsy/aspirate report. BM aspirate and/or biopsy will be performed every 12 weeks only in 
patients with more than 5% pre-treatment BMBL.  
m Blood samples for Population PK analysis will be obtained in all patients at Baseline/C1D1 visit 1 hr after rigosertib 
administration (morning dose), and on Day 28 (+/- 5 days) from start of therapy at predose and 1 hr after administration of 
rigosertib (morning dose). 
n AEs will be monitored from the time of the first protocol-specific intervention  up to 30 days after the last dose of 
rigosertib. 


 
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Appendix 7: List of Clinical Laboratory Tests 
 
Serum Chemistry Panel : 
Complete Blood Count with Differential: 
Serum albumin 
Total protein 
Total bilirubin 
Direct bilirubin (if total bilirubin > ULN only) 
Aspartate transaminase (AST) 
Alanine transaminase (ALT) 
Lactate dehydrogenase (LDH) 
Alkaline phosphatase 
Bicarbonate 
Sodium 
Potassium 
Chloride 
Serum creatinine 
BUN 
Glucose 
Calcium 
Phosphorus 
Uric acid 
White blood cells (WBC) 
Neutrophils (absolute count) 
Lymphocytes (absolute count) 
Monocytes (absolute count) 
Basophils (absolute count) 
Eosinophils (absolute count) 
Red blood cells (RBC) 
Hematocrit 
Hemoglobin (Hgb) 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Platelets (PLT) 
Mean platelet volume 
Hyponatremia Panel (if ≥ Grade 3 Hyponatremia): 
Urinalysis: 
Serum osmolality 
Urine osmolality 
Serum albumin 
BUN 
Serum creatinine 
Serum sodium 
Urinary sodium 
pH 
Specific gravity 
Protein 
Glucose 
WBC 
Blood/occult blood 
Ketone 
Crystals (microscopic analysis) 
Other Serum Laboratory Tests: 
Pregnancy test (if childbearing potential): 
 
 
Serum endogenous erythropoietin  
Serum ferritin 
Blood or urine pregnancy tests  
 


 
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Appendix 8: List of Potential Substrates of CYP 2C8 and 2C9 
 
Reference: Flockhart 2007 
 
Substrates of CYP 2C8 and 2C9 include, but are not limited to, drugs below: 
 
2C8 Substrates 
2C9 Substrates 
amodiaquine 
cerivastatin 
paclitaxel 
repaglinide 
sorafenib 
torsemide 
NSAIDs: 
diclofenac 
ibuprofen 
lornoxicam 
meloxicam 
S-naproxen→Nor 
piroxicam 
suprofen 
 
Oral Hypoglycemic Agents: 
tolbutamide 
glipizide 
 
Angiotensin II Blockers: 
losartan 
irbesartan 
 
Sulfonylureas: 
glyburide 
glibenclamide 
glipizide 
glimepiride 
tolbutamide 
 
Others: 
amitriptyline 
celecoxib 
fluoxetine 
fluvastatin 
glyburide 
nateglinide 
phenytoin-4-OH2 
rosiglitazone 
tamoxifen 
torsemide 
S-warfarin 
Sulfamethoxazole 
 
 
 


 
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Appendix 9: List of Potential Inhibitors of P-gp 
 
Reference: FDA Guidance 
 
Examples of In Vivo Inhibitors of Human Transporter P-gP (MDR1) 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporine 
Diltiazem 
Dronedarone 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lopinavir & Ritonavir  
Quercetin 
Quinidine 
Ranolazine 
Ticagrelor 
Verapamil