Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy

PRIMARY OBJECTIVE:

I. To characterize the rate of response to azacitidine and sirolimus in adults with high-risk
myelodysplastic syndrome (MDS), or relapsed or refractory acute myeloid leukemia (AML) or
those unable or unwilling to tolerate high dose chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the pharmacodynamic effect of sirolimus on inhibition of mammalian target of
rapamycin (mTOR) signaling in adults with high-risk MDS, or relapsed or refractory AML or
those unable or unwilling to tolerate high dose chemotherapy.

II. To determine the safety and tolerability of sirolimus and azacitidine in adults with
high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high
dose chemotherapy.

III. To determine the progression free survival and overall survival in adults with high-risk
MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose
chemotherapy.

IV. To determine if the quality of life of patients is improved with the combination of
azacitidine and sirolimus when compared to historical controls of azacitidine alone.

OUTLINE:

Patients receive sirolimus orally (PO) on days 1-10 or 1-12 and azacitidine intravenously
(IV) on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

1. Patients must have a diagnosis of one of the following:

- MDS (Arm A): High-risk MDS defined as: >5% blasts in bone marrow and/or the
following cytogenetic categories: presence of inv(3)/t(3q)/del(3q), -7/del(7q),
complex cytogenetics (3 or more abnormalities)

- AML (Arm B): Relapsed/refractory/unable to tolerate conventional chemotherapy

- MDS or AML as above BUT with prior therapy with Azacitibine (Arm C): Patients who
meet criteria for either Arm A or Arm B but have been treated or are currently
treated with Azacitibine

2. Patients must be ≥ 18 years old

3. Patients must have an ECOG performance status of <= 2 (see Attachment 1).

4. Patients must have a life expectancy of at least 4 weeks.

5. Patients must be able to consume oral medication.

6. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2
weeks for local palliative XRT (small port).

7. Patients must have recovered from the toxic effects of any prior chemotherapy to <
Grade 2 (except for alopecia).

8. Required initial laboratory values: Creatinine≤ 2.0mg/dL; total or direct bilirubin ≤
1.5mg/dL (if not due to the leukemia itself or known Gilbert's Syndrome);(as
documented by treating physician) SGPT(ALT) ≤ 3xULN; glucose <200 mg/dL, negative
pregnancy test for women of child-bearing potential.

9. Patients must be able to sign consent and be willing and able to comply with scheduled
visits, treatment plan and laboratory testing.

10. Patients may have had a prior stem cell transplant (autologous or allogeneic), however
they may not have active GvHD, nor be on any immunosuppression

Exclusion Criteria:

1. Patients must not be receiving any chemotherapy agents (except Hydroxyurea)

- Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not
systemic and only isolated to the central nervous system).

- Patients can not have received more than 3 prior lines of therapy for their
hematologic malignancy.

- Patients who meet all other study criteria but have either previously been
treated or are currently undergoing treatment with azacitibine shall be evaluated
in Arm C

2. Patients must not be receiving growth factors.

3. Patients with a current second malignancy requiring systemic therapy, other than
non-melanoma skin cancers, are not eligible. If a patient has had a prior second
malignancy that is not currently requiring active treatment, the patient will be
considered eligible.

4. Patients with uncontrolled high blood pressure, unstable angina, symptomatic
congestive heart failure, myocardial infarction within the past 6 months or serious
uncontrolled cardiac arrhythmia are not eligible.

5. Patients may not take any of the following medications while on study, but will be
considered eligible if medication is discontinued 72 hrs prior to first dose of
Sirolimus:

- Carbamazepine (e.g. Tegretol)

- Rifabutin (e.g. Mycobutin)

- Rifampin (e.g. Rifadin)

- Rifapentine (e.g. Priftin)

- St. John's Wort- may decrease effects of sirolimus by decreasing the amount of
sirolimus in the body

- Clarithromycin (e.g. Biaxin)

- Cyclosporin e.g. (Neoral or Sandimmune)

- Diltiazem (e.g. Cardizem)

- Erythromycin (e.g. Akne-Mycin, Ery-Tab)

- Itraconazole (e.g. Sporanox)

- Fluconazole (e.g. Diflucan)

- Ketoconazole (e.g. Nizoral)

- Telithromycin (e.g. Ketek)

- Verapamil (e.g. Calan SR, Isoptin, Verelan)

- Voriconazole (e.g. VFEND) - May increase the effects of sirolimus by increasing
the amount of this medicine in the body. Can take 72 hours after last dose of
Sirolimus

- Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or serious side
effects in patients on sirolimus.

6. Patients with known HIV positivity or AIDS-related illness are not eligible.

7. Patients with other severe concurrent disease which in the judgment of the
investigator would make the patient inappropriate for entry into this study are
ineligible.

8. Patients must not have received any investigational agents within 21days of study
entry.

9. Patients must not be pregnant or breastfeeding. Pregnancy tests must be obtained for
all females of child-bearing potential. Pregnant or lactating patients are ineligible
for this study due to the unknown human fetal or teratogenic toxicities of rapamycin.
Males or females of reproductive age may not participate unless they have agreed to
use an effective contraceptive method.

10. Patients who have uncontrolled infection are not eligible. Patients must have any
active infections under control. Fungal disease must be stable for at least 2 weeks
before study entry. Patients with bacteremia must have documented negative blood
cultures prior to study entry.