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Azacitidine and Sirolimus in Treating Patients with High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That Is Relapsed or Refractory or Not Eligible for Intensive Chemotherapy

Trial Status: Closed to Accrual

This phase II trial studies how well azacitidine and sirolimus work in treating patients with myelodysplastic syndrome that is likely to come back or spread (high-risk) or acute myeloid leukemia that has come back (relapsed) or is not responding to treatment (refractory) or is not eligible for intensive chemotherapy. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine with sirolimus may kill more cancer cells.

Inclusion Criteria

  • 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 clinical diagnosis with prior therapy with azacitidine (Arm C) ** Note: As of July 2018, only high-risk MDS patients will be eligible as Arm B is closed. As of October 2017, those patients with MDS who have received prior treatment will now be enrolled on Arm A as Arm C is closed
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Patients must have a life expectancy of at least 4 weeks
  • Patients must be able to consume oral medication
  • Patients must have completed any radiotherapy four weeks prior to study entry, 0-2 weeks for local palliative radiotherapy (XRT) (small port)
  • Patients must have recovered from the toxic effects of any prior chemotherapy to < grade 2 (except for alopecia)
  • Creatinine =< 2.0 mg/dL
  • Total or direct bilirubin =< 1.5 mg/dL (if not due to the leukemia itself or known Gilbert’s syndrome) (as documented by treating physician)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN)
  • Glucose < 200 mg/dL
  • Negative pregnancy test for women of child-bearing potential
  • Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing
  • Patients may have had a prior stem cell transplant (autologous or allogeneic), however they may not have active graft-vs-host disease (GvHD), nor be on any immunosuppression

Exclusion Criteria

  • Patients must not be currently receiving any chemotherapy agents (except hydroxyurea) * Intrathecal cytarabine (ARA-C) and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system) * Patients cannot have received more than 3 prior lines of therapy for their hematologic malignancy; patient may have previously had azacitidine or decitabine will be eligible to enroll on Arm A (MDS)
  • Patients must not be receiving growth factors
  • 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
  • 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
  • Patients may not take any of the following medications while on study, but will be considered eligible if medication is discontinued 72 hours 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) * Cyclosporine 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
  • Patients with known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness are not eligible
  • 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
  • Patients must not have received any investigational agents within 21 days of study entry
  • 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. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method.
  • 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


Thomas Jefferson University Hospital
Contact: Neil David Palmisiano
Phone: 215-955-8874


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.


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.


Patients receive sirolimus orally (PO) on days 1-10 or 1-12 and azacitidine intravenously (IV) over 10-40 minutes or subcutaneously (SC) on days 4-8, 11, and 12 or days 4-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Thomas Jefferson University Hospital

Principal Investigator
Neil David Palmisiano

  • Primary ID 12D.587
  • Secondary IDs NCI-2013-01004, 2012-50
  • ID NCT01869114