A Phase III, International, Randomized, Controlled Study of Rigosertib versus Physician*s Choice of Treatment in Patients with Myelodysplastic Syndrome after Failure of a Hypomethylating Agent

Patients with higher-risk MDS failing HMA treatment have no approved
alternative therapy and a short life expectancy (approximately 4-6 months). We
propose to enroll patients with MDS who have excess blasts (5% to 30% BM
blasts), and have progressed during, failed to respond to, are intolerant of,
or relapsed after AZA or DAC treatment. Patients* MDS must be classified as
RAEB-1 and RAEB-2 by World Health Organization (WHO) criteria or refractory
anemia with excess blasts in transformation (RAEB-t) based on the
French-American-British (FAB) classification.
Rigosertib will be administered at a dose of 1800 mg/24 hr as 72-hr CIV
infusions on Days 1, 2, and 3 of a 2-week cycle for the first 8 cycles, and on
Days 1, 2, and 3 of a 4-week cycle thereafter.
The rationale for the proposed dose regimen is as follows:
1. Overall, in the 6 MDS/AML studies conducted to date, patients receiving
3-day infusions of rigosertib every other week (Q2W) achieved better BMBL
responses than patients receiving 2-day infusions weekly for 3 weeks of a
4-week cycle. Extending infusion duration beyond 3 days did not result in
further improvements of the rate of BMBL responses. In addition, initial BMBL
response was highly correlated to survival benefit in these patients.
2. The selected dose of 1800 mg/24 hr rigosertib administered as 72-hr CIV
infusions Q2W has been the most frequently administered dose in our studies
conducted to date, including in the Phase III Study 04-21 in 299 patients with
MDS; 199 of whom received rigosertib. No improvement in efficacy was noted in
the patients receiving higher doses of rigosertib compared to those who
received the selected dose for this study and no increased safety risk was
observed at the 1800 mg/24 hr dose.

Primary:
• To compare the overall survival (OS) of patients in the rigosertib group vs
the Physician*s Choice group, in all patients and in a subgroup of patients
with IPSS-R very high risk
Secondary efficacy
• To compare rigosertib to Physician*s Choice with regard to the following:
o Overall survival of patients with monosomy 7 chromosomal aberrations
o Overall survival of patients with trisomy 8 chromosomal aberrations
o Overall response according to 2006 International Working Group (IWG) criteria
o Quality-of-life (QoL) scores using the EuroQol EQ-5D Questionnaire
o Overall bone marrow blast response according to 2006 IWG criteria
o Hematologic improvement (HI) (erythroid, platelet or neutrophil response)
according to 2006 IWG criteria
Exploratory: Evaluation of the following:
• Bone marrow genomic mutational status
• Transformation time to AML (defined as a bone marrow or peripheral blood
blast percentage >30%)
Safety objectives: Evaluation of the following:
• Safety and tolerability of rigosertib administered as 72-hour CIV infusions
versus PC.
• Rigosertib population pharmacokinetics (PK)

Design: Phase III, open-label, randomized (2:1), controlled, international study
Patient population: Patients with MDS classified as RAEB-1, RAEB-2 or RAEB-t
after failure of treatment with azacitidine (AZA) or decitabine (DAC)
Treatment regimens:
• Rigosertib 1800 mg/24 hr administered as a 72-hr CIV infusion on Days 1, 2,
and 3 of a 2-week cycle (N ~150 patients) for the first eight 2-week cycles,
then on Days 1, 2, and 3 of a 4-week cycle thereafter
• Physician*s choice of alternative treatment (N ~75 patients), which may
include any approved or standard-of-care therapy, based on frequently used
treatment for MDS after failure of treatment with HMAs. Experimental therapies
are not allowed.
If a patient requires a change to a different PC treatment, that patient must
be discontinued from the study treatment, with AEs followed for 30 days after
discontinuation of the initial study treatment.
Stratified prior to random assignment by IPSS-R classification of very high
risk (VHR) vs non-VHR, and by geographic region (North America vs Europe vs
Asia) (for the purpose of this study, Australia, New Zealand and Israel will be
included in the Europe group).
Duration of treatment: Until disease progression per 2006 IWG criteria (ie, 50%
increase of BM blasts or worsening of cytopenias) or onset of an unacceptable
toxicity or intolerance. All patients will be followed for survival until death.
Concomitant therapy allowed in both treatment groups: Red blood cell (RBC) and
platelet transfusions, growth factors (erythropoietin, granulocyte
colony-stimulating factor [G-CSF], thrombopoietin [TPO]). Once a patient*s MDS
has progressed and the patient has discontinued from study treatment on either
arm, other therapies (except for rigosertib) are allowed at the discretion of
the investigator.
Data Monitoring Committee (DMC): An independent DMC will be established for the
purpose of reviewing patient safety and the results of the interim analysis.
The DMC will review the interim analysis results and may recommend stopping the
study for futility, or continuing the trial as initially planned. The DMC may
also recommend increasing the sample size using an adaptive design algorithm.

Study Treatments, Dose and Mode of Administration:
• Rigosertib sodium is supplied by Onconova Therapeutics, Inc., as a sterile
concentrated solution that must be stored between 2°C and 8°C, and should be
diluted in 0.9% sodium chloride for injection just prior to dosing.
Reconstituted rigosertib must be kept at room temperature and administration
must start within 6 hr of reconstitution, through a port or central line using
an infusion pump with an in-line filter. Infusion bags must be changed every 24
hours.
• Rigosertib dose: 1800 mg/24 hr as 72-hr CIV infusion every other week for the
first eight 2-week cycles (ie, 16 weeks, if no dose delays), then every 4 weeks
afterward.
• Dosing adjustments of rigosertib are based on hematologic and non-hematologic
toxicities.
• Physician*s Choice of treatment (approved or standard-of-care therapy, based
on frequently used regimens for MDS treatment after receipt of HMAs).The drugs
used in the Physician's Choice arm should be used according to the
recommendations, if clinically appropriate (eg, dosing regimen and
administration scheme) provided in the corresponding Summary of Product
Characteristics (SmPC) and Prescribing Information of these drugs. Experimental
therapies are not allowed.
• All patients will receive, as clinically indicated, transfusions of RBC
and/or platelets and growth factors.

This study places additional burdens on patients as they will be required to
attend visits more frequently than they would for standard of care. This is
required in order for the participants to be closely monitored. The study drug
will also be given over 72 hours via a catheter and the participants will be
required to either stay each time in the clinic for 72 hours or go home but
come in to the study centre after each 24 hour period of the 3 day infusion to
change the bag. Participants will also be exposed to risks and side effects
that they perhaps wouldn't normally be exposed to following standard treatment.
Although additional risks and burdens are being placed on participants,
patients with higher risk MDS failing hypomethylating agent treatments have no
approved alternative therapy and have a short life expectancy (46 months).
Information on the risks associated with the investigational drug is provided
in the Investigator*s Brochure version 21.1 . Also, risks and discomforts
associated with the investigational drug and study procedures are described in
the ICF. Risk-benefit analysis is described in the document *Summary/Update
Risk Benefit Profile*.
The potential risks identified in association with rigosertib are considered
justified by the anticipated benefits that may be afforded to patients with
myelodysplastic syndrome or hematologic malignancies and patients with advanced
cancer and solid tumors. Continued close monitoring to determine whether there
is an increase in frequency and or severity of these events and to detect other
potential safety signals will help to monitor patient safety and minimize the
risk to patients participating in ongoing and future studies.