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Biomarkers in Predicting Treatment Response to Sirolimus and Combination Chemotherapy in Patients with High-Risk Acute Myeloid Leukemia

Trial Status: Complete

This phase II trial studies whether biomarkers (biological molecules) in bone marrow samples can predict treatment response to sirolimus and combination chemotherapy in patients with acute myeloid leukemia (AML) that is likely to come back or spread (high-risk). Sirolimus inhibits or blocks the pathway that causes cancer cells to grow. Drugs used in chemotherapy, such as mitoxantrone hydrochloride, etoposide, and cytarabine, 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. Adding sirolimus to combination chemotherapy may help improve patient response. Studying samples of bone marrow from patients treated with sirolimus in the laboratory may help doctors learn whether sirolimus reverses or turns off that pathway and whether changes in biomarker levels can predict how well patients will respond to treatment.

Inclusion Criteria

  • Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following: * Primary refractory non-M3 AML ** Residual leukemia after a minimum of 2 prior courses of chemotherapy (same or different) ** Evidence of leukemia recurrence after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia ** Evidence of leukemia after induction therapy which, in the opinion of the investigator, would be appropriate for reinduction with sirolimus/MEC therapy * Relapsed non-M3 AML * Previously untreated non-M3 AML age > 60 with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) [AML1-ETO], inversion (inv)16(p13;q22), or t(16;16)(p13;q22) [core-binding factor (CBF)beta; myosin, heavy chain (MYH)11] by cytogenetics, fluorescence in situ hybridization (FISH), or real time-polymerase chain reaction (RT-PCR) * Previously untreated secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBFbeta;MYH11] by cytogenetics, FISH, or RT-PCR
  • Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
  • Subjects must have a life expectancy of at least 4 weeks
  • Subjects must be able to consume oral medication
  • Subjects must have recovered from the toxic effects of any prior chemotherapy to < grade 1 (except alopecia)
  • Creatinine =< 2.0 mg/dL
  • Total or direct bilirubin =< 1.5 mg/dL
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (ULN)
  • Negative pregnancy test for women with 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
  • Subjects must have a left ventricular ejection fraction (LVEF) of >= 45%

Exclusion Criteria

  • Subjects with French American British (FAB) M3 (t (15; 17) (q22; q21) [promyelocytic leukemia (PML)-retinoic acid receptor (RAR) alpha]) are not eligible
  • Subjects must not be receiving any chemotherapy agents (except hydroxyurea) * Intrathecal methotrexate and cytarabine are permissible
  • Subjects must not be receiving growth factors, except for erythropoietin
  • Subjects with a “currently active” second malignancy, other than non-melanoma skin cancers are not eligible
  • Subjects 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
  • Subjects taking the following are not eligible: * Carbamazepine (e.g., Tegretol) * Rifabutin (e.g., Mycobutin) or * Rifampin (e.g., Rifadin) * Rifapentine (e.g., Priftin) * St. John's wort * 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) * Ketoconazole (e.g., Nizoral) * Telithromycin (e.g., Ketek) * Verapamil (e.g., Calan sustained release [SR], Isoptin, Verelan) * Voriconazole (e.g., VFEND) • Tacrolimus (e.g. Prograf)
  • Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and ketoconazole within 72 hours of study drug starting are not eligible; reinstitution of fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is permissible 72 hours after the last dose of sirolimus
  • Subjects who require human immunodeficiency virus (HIV) protease inhibitors or those with acquired immune deficiency syndrome (AIDS)-related illness
  • Subjects with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible
  • Subjects must not have evidence of cerebellar dysfunction at baseline or during prior cytarabine therapy
  • Subjects must not have received any investigational agents within 30 days of study entry
  • Subjects 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
  • Subjects 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
  • Subjects with bacteremia must have documented negative blood cultures prior to study entry


Thomas Jefferson University Hospital
Contact: Neil David Palmisiano
Phone: 215-955-0432


I. To test the association between biochemical response and clinical response.


I. To estimate complete response rate of sirolimus mitoxantrone (mitoxantrone hydrochloride) + etoposide + cytarabine (MEC) in patients with high risk AML.

II. To estimate progression free survival in this patient population.

III. To collect further information on the safety, tolerability, and efficacy of sirolimus in combination with MEC in patients with relapsed or refractory myeloid malignancies.


Patients undergo collection of bone marrow samples prior to sirolimus dosing on day 4 and within 1 week and no later than day 45 of hematologic recovery. Patients receive sirolimus orally (PO) on days 2-9 (loading dose on day 1 only), and standard MEC chemotherapy comprising mitoxantrone hydrochloride intravenously (IV) over 15 minutes, etoposide IV over 1 hour, and cytarabine IV over 1 hour every 24 hours on days 4-8.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Thomas Jefferson University Hospital

Principal Investigator
Neil David Palmisiano

  • Primary ID 15D.377
  • Secondary IDs NCI-2015-01507, 2013-087, JT#5530, JT#5530/CCRRC 2013-087
  • ID NCT02583893