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

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 thefollowing 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): Patientswho meet criteria for either Arm A or Arm B but have been treated or arecurrently treated with Azacitibine *Note: As of July 2018, only high risk MDSpatients will be eligible as Arm B is closed. As of October 2017, thosepatients with MDS who have received prior treatment will now be enrolled in ArmA as Arm C is closed.

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, 0-2weeks 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);(asdocumented by treating physician) SGPT(ALT) ≤ 3xULN; glucose <200 mg/dL, negativepregnancy test for women of child-bearing potential.

9. Patients must be able to sign consent and be willing and able to comply withscheduled 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 notsystemic and only isolated to the central nervous system).

• Patients can not have received more than 3 prior lines of therapy for theirhematologic malignancy. Patient may have previously had azacitidine ordecitabine will be eligible to enroll on Arm A (MDS)

2. Patients must not be receiving growth factors.

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

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

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

• 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 ofsirolimus 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 increasingthe amount of this medicine in the body. Can take 72 hours after last dose ofSirolimus

• Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or seriousside 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 theinvestigator would make the patient inappropriate for entry into this study areineligible.

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

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

10. Patients who have uncontrolled infection are not eligible. Patients must have anyactive infections under control. Fungal disease must be stable for at least 2 weeksbefore study entry. Patients with bacteremia must have documented negative bloodcultures prior to study entry.