Trial Information

A Phase 1/2, Single Arm Study To Assess the Efficacy and Safety of Rigosertib (ON 01910.Na) Administered as 72-Hour and 120-Hour Continuous Intravenous Infusions Every Other Week for Two Cycles Then as Twice Daily Oral Capsules Given Continuously in Patients With Relapsed/Refractory Acute Myeloid or Lymphocytic Leukemia or Transformed Myeloproliferative Neoplasms

This is a single center, open-label, phase 1/2 study in which 2 to 34 patients with
refractory acute myeloid or lymphocytic leukemia or transformed myeloproliferative neoplasms
(MPNs)who meet all other inclusion/exclusion criteria will be administered a daily dose of
2400 mg ON 01910.Na dose as a intravenous continuous infusion (IVCI) over 24 hours for 72 to
120 consecutive hours every 2 weeks for the first 4 weeks then will receive oral rigosertib
at a 560 mg twice-daily dose as capsules taken continuously.

In the phase 1 component of the trial, a standard dose escalation scheme will be followed
with the enrolment of at least three patients treated with a daily dose of 2400 mg ON
01910.Na IVCI over 24 hours for 72 hours. The dose escalation scheme will follow a
traditional dose escalation rule, also known as the "3+3" rule:

If none of the initial three patients treated in the 72-hour cohort experience dose-limiting
toxicity (DLT), during the first two 2-week cycles, then a new cohort of three patients will
be treated at the same 2400 mg/24h daily dose but for an increased 120 hours duration.

DLT is defined as an adverse event possibly related to ON 01910.Na that is:

- Grade ≥ 3 non-hematological toxicity other than nausea, vomiting, diarrhea, fever,
esophagitis/dysphagia

- Grade ≥ 3 nausea and vomiting uncontrolled by antiemetics; grade ≥ 3 diarrhea
uncontrolled by antidiarrheal agents; grade ≥ 3 drug-induced fever uncontrolled by
antipyretics; grade ≥3 metabolic abnormalities that are not controlled by optimal
supportive care measures

- Grade ≥ 3 stomatitis and/or esophagitis/dysphagia lasting > 3 days

- Marrow cellularity <5% on day 42 or later (6 weeks) from start of therapy without
evidence of leukemia

If one of the three patients in the 72-hour cohort experiences a DLT during the first two
cycles, then three additional patients will be treated for the same 72 hours duration.
Escalation to the 120-hour cohort will proceed only if no more than one of the six patients
treated in the 72-hour cohort experiences a DLT.

If two or more patients in the 72-hour cohort experience DLT during the first two cycles,
then the maximum tolerated dose (MTD) will have been exceeded, no further dosing extension
will occur, and a full safety review will determine if further enrollment of patients will
proceed.

If none of the initial three patients in the 120-hour cohort experiences DLT during the
first two cycles, this regimen will be confirmed as the Maximum Tolerated Dose (MTD) and no
further dose escalation will occur.

If one of the three patients in the 120-hour cohort experiences DLT during the first two
cycles, then three additional patients will be treated for the same duration. If no more
than one patient experiences a DLT, the 120-hour regimen will be confirmed as the Maximum
Tolerated Dose (MTD) and no further dose escalation will occur.

If two or more patients in the 120 hours cohort experience DLT during the first two cycles,
then the maximum tolerated dose (MTD) will be determined to be 2400 mg/24h administered for
72 hours every other week.

Once the phase 1 portion of the study is completed, accrual to the phase 2 portion will
begin. Patients treated at the MTD during the phase 1 portion will be included in the phase
2 component and will be evaluated for response and secondary end points.

The total study duration is 30 weeks, which includes a 2-week screening phase, a 24-week
dosing phase (4-week rigosertib CIV administration, followed by 20 weeks of oral rigosertib
administration), and a 4-week follow-up phase that begins after the last dose of rigosertib.
Beginning at week 5, patients will be assessed for response every time a complete blood
count (CBC) is performed and followed up.

Patients who achieve by week 24 a response or stabilization of their disease are eligible to
receive an additional 24 weeks of rigosertib at the same dose and will be followed up.