Safety of 24-hour Infusion of ON 01910.Na in Combination With Gemcitabine in Advanced Solid Tumors

The order of infusion will be gemcitabine first, immediately followed by ON 01910.Na (with
the only exception being the first infusion for those patients undergoing PK sampling; where
the ON 01910.Na infusion will be given first on this occasion). The dose of gemcitabine will
be fixed at 1000 mg/m2 i.v. as a 30 minutes infusion on days 1, 8, and 15 every 28 days. As
of Amendment 2, the starting dose of ON 01910.Na is 250 mg/m2 as a 24 hour intravenous
(i.v.) infusion on days 1, 8 and 15 of a 28-day course. The dose of ON 01910.Na will be
escalated in increments in successive cohorts (dose level (DL) 1 = 250 mg/m2, DL 2 = 650
mg/m2, DL 3 = 1050 mg/m2, DL 4= 1350 mg/m2) of new patients. A course is defined as 4 weeks
in length. Toxicity will be graded according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE v3.0). A minimum of three new patients
will be treated at each dose level with a minimum of a 1 week stagger between the dosing of
the first and remaining patients in each new dose cohort. In exceptional circumstances (e.g.
where there is one slot available in a cohort and two eligible patients have been screened),
the Sponsor may allow four patients to enter a cohort (or seven patients to enter an
expanded cohort). A DL -1A (ON 01910.Na = 125 mg/m2) is set in case dose de-escalation is
required with the starting dose due to ON 01910.Na-related toxicity. A DL -1A gemcitabine =
750 mg/m2 and DL - 1B at 500 mg/m2 are set in case dose de-escalation is required with the
starting and subsequent doses due to gemcitabine-related toxicity. If DLT is not observed in
the first three patients, then the dose of ON 01910.Na will be increased to the next level.
If DLT occurs in any of the first three new patients in the first course, at least three
additional new patients will be treated. If no further DLT is encountered, dose escalation
will proceed. Alternately, if DLT is noted in one or more of three additional patients, dose
escalation will be terminated and the MTD will be defined as the highest dose level at which
none of the first three patients or no more than one of six patients experienced DLT in
course 1. All patients receiving doses exceeding the confirmed MTD will have their dose
reduced to the MTD; even if apparently tolerating their current dose. Intra-patient dose
escalation of ON 01910.Na will be permitted. There will be no limit to the number of courses
that could be administered to a patient who is both tolerating and benefiting from therapy.

Escalation to the next dose level will occur only after the third evaluable patient (or
sixth, if an expanded cohort), on the previous dose level has been observed for 4 weeks.
Dose escalation decisions will be made by a Cohort Review Committee (CRC). Intra-patient
dose escalation of ON 01910.Na will be allowed after the third evaluable patient on the next
dose level has been observed for 4 weeks with acceptable tolerability.

Once the MTD has been defined, an expanded cohort of 9 to 12 additional patients (depending
if 3 or 6 patients were enrolled on the previous cohort) will be enrolled at the MTD dose
level in order to further define the safety and tolerability of this regimen, and
characterize the pharmacokinetics of ON 01910.Na alone and after gemcitabine, and perform a
tumor biomarker study.

Inclusion Criteria:

- Patients with histologically confirmed solid malignancy for which standard curative
or palliative measures do not exist or are no longer effective; or patients with a
clinical rationale for a gemcitabine-based therapy.

- The last radiotherapy/chemotherapy dose must have been given ≥4 weeks prior to study
drug initiation; with any acute or chronic adverse events of prior radiotherapy or
chemotherapy having resolved to
- Patients must have a life expectancy of at least 12 weeks and an ECOG performance
status of <1 (Appendix I).

- Patients must be >18 years of age.

- Patients must have evaluable disease, either with informative tumor markers or with
measurable disease on imaging by RECIST (Response Evaluation Criteria in Solid
Tumors) criteria (Appendix II).

- Patients must have adequate liver and renal function as defined by serum creatinine
no greater than 2.0 times the institution's upper normal limits (or a 24 hour
creatinine clearance of >50 ml/min) and total bilirubin level no greater than 2.0
times the institution's upper normal limits and transaminase levels no higher than
3.0 times the institution's upper normal limits. (Note that patients with primary
liver cancer or hepatic metastases may have transaminase levels of up to 5.0 times
the limit of normal).

- Patients must have adequate bone marrow function as defined by a granulocyte count of
>1,500/mm3, platelet count of >100,000/mm3, and hemoglobin >9 g/dl.

- Patients at the expanded phase at the MTD must be willing and able to undergo blood
sampling for pharmacokinetic studies in Course 1.

- For patients in the expanded phase at the MTD, tumor amenable to a single tumor
biopsy, and willingness to undergo a baseline tumor biopsy.

- Patients must sign an informed consent form indicating that they are aware of the
investigational nature of this study and in keeping with the policies of the
institution.

Exclusion Criteria:

- Patients will be excluded if they have evidence of active heart disease including
myocardial infarction within the previous 3 months; symptomatic coronary
insufficiency or heart block; uncontrolled congestive heart failure; moderate or
severe pulmonary dysfunction.

- Patients will be excluded if they have an active infectious process.

- Patients will be excluded if they have active central nervous system metastases.

- Patients will be excluded if they have received prior radiotherapy administered to
more than 30% of marrow-bearing bone mass.

- Patients will be excluded if they have ascites requiring active medical management
including paracentesis for more than twice a month or hyponatremia (defined as serum
sodium value of <134 Meq/L).

- Patients will be excluded if they are women who are pregnant or lactating.

- Patients will be excluded if they are male patients with female sexual partners who
are unwilling to follow the strict contraception requirements described in this
protocol.

- Patients will be excluded if they have had major surgery without full recovery or
major surgery within 3 weeks of ON 01910.Na treatment start.