A Phase II Study of MS-275, in Combination With GM-CSF Treating Relapsed and Refractory Myeloid Malignancies

MDS is an abnormality of the bone marrow and blood cells that may develop into cancer.

AML is a cancer of the bone marrow and blood cells. Both result in problems making normal
blood cells. The cells in the bone marrow do not undergo the normal expected patterns of
growth or maturation that is called “differentiation.” Because of this, they do not work
very well. People with these problems often need blood transfusions and are at high risk for
infections and bleeding.

Treatment options for MDS and AML are often limited due to their side effects. We hope to
develop combinations of drugs that will help the bone marrow function better without many of
the side effects of traditional chemotherapy treatments.

Inclusion Criteria:

In general, patients with MDS and relapsed or refractory AML, who are not eligible for a
potentially curative myeloablative allogeneic stem cell transplant or who are considered
poor candidates for such a procedure due to age, medical co-morbidities, or lack of a
suitable donor, will be considered for participation in the proposed trial.

Disease Specific Inclusion Criteria:

- MDS

- Relapsed AML

- Untreated AML

Additional Criteria:

1. Age > 18.

2. JHOC confirmed and documented diagnosis of either AML or MDS within 12 weeks of trial
enrollment. Patients with MDS are restricted to those with IPSS of INT-2 or high
risk.

3. Patients must have relatively stable bone marrow function for more than seven days
prior to enrollment on the study. WBC count doubling within seven days of enrollment
or WBC greater than 10 x 103/dL would indicate unstable bone marrow function.

4. ECOG performance status of 0, 1, 2.

5. Patient or caregiver must be willing to perform subcutaneous injection.

6. Patients must have the following end organ function:

- Serum creatinine < 2.0 mg/dL

- Total serum bilirubin < 1.6 mg/dL, unless secondary to hemolysis.

- SGOT/SGPT each < 3 times the upper limit of normal unless disease related

- Hemoglobin should be at least 8 gm/dL at the time of protocol entry. Patients
may receive transfusions to achieve this level.

7. Patients must not have received treatment for their myeloid disorder within 2 weeks
of beginning the trial. Treatments include the use of chemotherapy, hematopoietic
growth factors, and biologic therapy such as monoclonal antibodies. The exception is
the use of hydroxyurea for patients with WBC > 30 x 103/μL. This duration of time
appears adequate for wash out due to the relatively short-acting nature of most
anti-leukemia agents.

8. Patients must have recovered from all toxicities (to grade 0 or 1) associated with
previous treatment.

9. Patients must not have any clinical symptoms of active CNS disease. If CNS disease is
suspected, patient must have LP with negative cytology.

10. All women of potential child bearing must have negative urine or serum B-HCG prior to
enrollment.

11. All women of potential child bearing must agree to use adequate birth control
throughout the trial period. All men must agree to use barrier contraceptive
throughout the trial period.

12. Patients must be able to provide informed consent and to return to clinic for
adequate follow up as required by the protocol.

Exclusion Criteria:

1. Diagnosis of RA with 5q- syndrome

2. Peripheral leukemia with blast count > 30 x 103/dL, uncontrolled with hydroxyurea.

3. Age < 18

4. ECOG performance status > 3

5. Patients with untreated or progressive infections

6. Patients with active CNS disease

7. Patients with a previous history of intolerance to GM-CSF

8. Pregnant or lactating women