Three Dosing Schedules of Oral Rigosertib in MDS Patients

This will be a Phase I, randomized, 3-treatment arm, single-center study in
transfusion-dependent Myelodysplastic Syndrome (MDS) patients classified as Low- or
Intermediate-1 (Int-1) or Intermediate-2 (Int-2) risk by the International Prognostic Scoring
System (IPSS). Initially, 18 patients (6 per treatment arm) will be randomized in a 1:1:1
ratio to 1 of 3 oral rigosertib dosing regimens, each of which is a cycle consisting of 14
consecutive days of dosing followed by 7 days off drug.

Treatment with erythropoiesis-stimulating agent (ESA) is prohibited for the first 15 weeks (5
cycles). After 15 weeks of dosing (5 cycles), ESA treatment will be initiated if the patient
still needs red blood cell (RBC) transfusions and if the pre-transfusion hemoglobin (Hgb)
value is ≤ 9 g/dL, unless the clinical judgment of the Investigator determines ESA
administration to a patient with a Hgb level > 9 g/dL is warranted.

All study participants will be allowed, as medically justified, access to RBC and platelet
(PLT) transfusions, and to filgrastim. Rigosertib dosing adjustment policies are described.

After all 18 patients have completed 3 cycles, a risk/benefit analysis will be completed
assessing the distribution of adverse events (AEs) and serious adverse events (SAEs) and the
number of transfusions among the 3 treatment arms. This analysis will select 1 of the 3
dosing regimens as having the best risk/benefit profile and an additional 12 to 18 patients
will be enrolled at this dosing regimen. Eligibility criteria may be modified by protocol
amendments to enroll patients with different characteristics. All patients will be treated
for 48 weeks or until 2006 International Working Group (IWG) progression criteria 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 continued hematologic response at 48
weeks may continue to be treated in the study beyond 48 weeks until 2006 IWG progression
criteria are met or until death from any cause, whichever comes first.

Inclusion Criteria:

- Diagnosis of MDS according to World Health Organization (WHO) criteria or
French-American-British (FAB) classification that must be confirmed by bone marrow
(BM) aspirate and/or biopsy within 6 weeks prior to Screening.

- MDS classified as Low-risk or Int-1 risk or Int-2 risk according to International
Prognostic Scoring System (IPSS) classification; in addition, patients should never
have been classified as High-risk since their MDS was diagnosed.

- Transfusion dependency defined by transfusion of at least 4 units of RBC (red blood
cells) within 8 weeks before Screening; pre-transfusion Hgb (hemoglobin) values must
be ≤ 9 g/dL to be taken into account.

- Refractory to 8- to 12-week course of ESA (erythropoiesis stimulating agent)
administered within the past 2 years before enrollment, or erythropoietin (EPO) level
˃ 500 mU/mL and off ESA for at least 8 weeks before Screening.

- Off all other treatments for MDS for at least 2 weeks prior to Screening.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

- Willing to adhere to the prohibitions and restrictions specified in the protocol.

- The patient must signed an informed consent form (ICF).

Exclusion Criteria:

- Ongoing clinically significant anemia due to factors such as iron, vitamin B12, or
folate deficiencies, auto-immune or hereditary hemolysis, or gastrointestinal
bleeding.

- Serum ferritin < 50 ng/mL.

- Hypoplastic MDS (cellularity < 10%).

- Any active malignancy within the past year, except basal cell or squamous cell skin
cancer or carcinoma in situ of the cervix or breast.

- Uncontrolled intercurrent illness.

- Active infection not adequately responding to appropriate therapy.

- Total bilirubin ≥ 2.0 mg/dL not related to hemolysis or Gilbert's disease.

- Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2.5 x the upper limit of
normal (ULN).

- Serum creatinine ≥ 2.0 mg/dL.

- Ascites requiring active medical management including paracentesis.

- Hyponatremia (defined as serum sodium value of < 130 mEq/L).

- Female patients of child-bearing potential or male patients with partners of
child-bearing potential who are unwilling to follow strict contraception requirements
before entry and throughout the study, up to and including the 30-day non-treatment
follow-up period.

- Female patients with reproductive potential who do not have a negative blood or urine
pregnancy test at Screening or who are lactating.

- Major surgery without full recovery or major surgery within 3 weeks of Screening.

- Uncontrolled hypertension (defined as a systolic pressure ≥ 160 mmHg and/or a
diastolic pressure ≥ 110 mmHg).

- New onset seizures (within 3 months prior to the first dose of rigosertib) or poorly
controlled seizures.

- Any other concurrent chemotherapy, radiotherapy, or immunotherapy.

- Chronic use (˃ 2 weeks) of corticosteroids (˃ 10 mg/24 hour equivalent prednisone)
within 4 weeks of Baseline/Cycle 1 Day 1 visit.

- Investigational therapy within 4 weeks of Screening.

- Psychiatric illness or social situation that would limit the patient's ability to
tolerate and/or comply with study requirements.