Phase II Part 2 Expansion of Oral Rigosertib in Combination With Azacitidine

This will be a Phase I/II open-label, single-arm, dose-escalating, multicenter study, in
three parts: Phase I Dose Escalation, Phase II, Part 1 RPTD Cohort, and Phase II, Part 2
Expansion, in which patients with myelodysplastic syndrome (MDS), acute myeloid leukemia
(AML), or chronic myelomonocytic leukemia (CMML) will receive subcutaneous (SC) or
intravenous (IV) azacitidine per approved label in combination with oral rigosertib. The
first two parts of the study have been completed.

The Phase II Part 2 Expansion will enroll up to 40 patients, randomized 1:1 into 2 cohorts of
up to 20 patients each, to receive 1120 mg of rigosertib over 24 hours: either 560 mg in the
morning and 560 mg in the afternoon, or 840 mg in the morning and 280 mg in the afternoon.
The afternoon dose in both cohorts must be administered at 3 PM (±1 hr) at least 2 hr after
lunch. In the Phase II, Part 2 Expansion patients with RAEB t/non-proliferative AML will be
eligible, however patients with CMML will not.

Inclusion Criteria:

- Diagnosis of MDS, CMML, or RAEB-t/non-proliferative AML (as defined by 20-30% BMBL,
WBC ≤ 25,000 x 10^9/L and stable for at least 4 weeks without intervention) according
to World Health Organization (WHO) criteria or French American British (FAB)
classification either previously treated or previously untreated. The diagnosis must
be confirmed via BM aspirate and/or biopsy within 6 weeks prior to Screening. Note:
patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ≤ 25,000 x
10^9/L and stable for at least 4 weeks without intervention) are not eligible for the
Phase II Part 1 RPTD component of the study and patients with CMML will not be
eligible for Phase II Part 2 Expansion of the study.

- If the patient has been diagnosed with MDS, disease of patient must be classified as
Int-1, Intermediate-2 (Int-2) or High-risk, according to International Prognosis
Scoring System (IPSS) classification. Note: Only Int-2 or High-risk patients will be
enrolled at French site.

- Off all other treatments for MDS, CMML, or AML including an erythropoiesis-stimulating
agent (ESA), for at least 4 weeks prior to Screening. Filgrastim (G-CSF) is allowed
before and during the study, as clinically indicated.

- For AML patients, no more than 1 prior salvage therapy.

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

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

- The patient must signed an informed consent form indicating that she/he understands
the purpose of and procedures required for the study and is willing to participate in
the study.

Exclusion Criteria:

- Prior treatment with rigosertib;

- Anemia due to factors other than MDS, CMML, or AML (including hemolysis or
gastrointestinal bleeding).

- 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 Gilbert's disease or hemolysis.

- Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x 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 who are pregnant or lactating.

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

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

- 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 Screening) or poorly controlled seizures.

- Any other investigational agent or chemotherapy, radiotherapy, or immunotherapy
administered within 4 weeks prior to Screening.

- Chronic use (˃ 2 weeks) of corticosteroids (˃ 10 mg/24 hr equivalent prednisone)
within 4 weeks of Baseline/First Dose.

- 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.

- Patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ≤ 25,000 x
10^9/L and stable for at least 4 weeks without intervention) are not eligible to
participate in the Phase II Part 1 RPTD component of the study and patients with CMML
will not be eligible for Phase II Part 2 of the study.