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Sirolimus, Idarubicin, and Cytarabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01822015
Recruitment Status : Completed
First Posted : April 1, 2013
Last Update Posted : December 23, 2019
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

Brief Summary:
This pilot clinical trial studies sirolimus, idarubicin, and cytarabine in treating patients with newly diagnosed acute myeloid leukemia. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving sirolimus together with idarubicin and cytarabine may kill more cancer cells.

Condition or disease Intervention/treatment Phase
Adult Acute Megakaryoblastic Leukemia (M7) Adult Acute Monoblastic Leukemia (M5a) Adult Acute Monocytic Leukemia (M5b) Adult Acute Myeloblastic Leukemia With Maturation (M2) Adult Acute Myeloblastic Leukemia Without Maturation (M1) Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Adult Acute Myelomonocytic Leukemia (M4) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Untreated Adult Acute Myeloid Leukemia Drug: Sirolimus Drug: Idarubicin Drug: Cytarabine Early Phase 1

Detailed Description:


1) To determine whether there is an association between baseline mammalian target of rapamycin (mTOR) activation paired with mTOR target inhibition post-treatment in leukemic blasts and clinical response in patients with newly diagnosed acute myeloid leukemia (AML) treated with sirolimus idarubicin/cytarabine.


  1. To estimate the response rate of sirolimus idarubicin/cytarabine in patients with newly diagnosed AML compared to historical data using idarubicin/cytarabine alone.
  2. To determine the ability of oral sirolimus to inhibit mTOR in leukemic blasts.
  3. To assess if mTOR pathway inhibition correlates with clinical response.
  4. To collect further information on the safety, tolerability, and efficacy of sirolimus in combination with idarubicin/cytarabine in patients with newly diagnosed AML.
  5. To describe the progression-free survival and overall survival (1 year, 2 year and 5 year) of patients treated with sirolimus idarubicin/cytarabine.


Patients receive sirolimus orally (PO) once daily (QD) on days 1-10, idarubicin intravenously (IV) over 3-5 minutes on days 4-6, and cytarabine IV continuously over 24 hours on days 4-10.

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 55 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Pharmacodynamic Correlate Trial of Sirolimus in Combination With Chemotherapy (Idarubicin, Cytarabine) for the Treatment of Newly Diagnosed Acute Myelogenous Leukemia
Actual Study Start Date : March 15, 2013
Actual Primary Completion Date : December 12, 2019
Actual Study Completion Date : December 12, 2019

Arm Intervention/treatment
Experimental: Treatment (sirolimus, idarubicin, cytarabine)
Patients receive sirolimus PO QD on days 1-10, idarubicin IV over 3-5 minutes on days 4-6, and cytarabine IV continuously over 24 hours on days 4-10.
Drug: Sirolimus
Given PO
Other Names:
  • rapamycin
  • Rapamune

Drug: Idarubicin
Given IV
Other Names:
  • 4-demethoxydaunorubicin
  • Zavedos
  • Idamycin

Drug: Cytarabine
Given IV
Other Names:
  • cytosine arabinoside
  • Cytosar-U
  • Depocyt
  • Ara-C
  • Arabinofuranosyl Cytidine

Primary Outcome Measures :
  1. Change in measurement of mTOR activation paired with mTOR target inhibition [ Time Frame: Baseline to day 4 ]
    The association between mTOR response and clinical response (complete or partial response) will be evaluated using the two-sided Fisher's exact test with alpha 0.05.

Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 1 year, 2 years, 5 years ]
    Will be evaluated using the Kaplan-Meier method stratified by mTOR response. Log rank test will be used to compare the overall survival in patients with and without mTOR response. Based on the estimated survival curves, the 1-year, 2-year, and 5-year survival rates will be computed with the corresponding 95% confidence intervals.

  2. Progression free survival [ Time Frame: 1 year, 2 years, 5 years ]
    Based on the estimated survival curves, the 1-year, 2-year, and 5-year survival rates will be computed with the corresponding 95% confidence intervals.

  3. Incidence of toxicities, graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) 4.0 guidelines [ Time Frame: Up to 45 days ]
    Safety data analysis is descriptive. All estimates of adverse events rates will be presented with corresponding confidence intervals using the exact method.

  4. Response defined as patients achieving a complete remission (CR), complete response in absence of total platelet recovery (CRp), or partial remission (PR) [ Time Frame: Up to 5 years ]
    Proportions of complete response and partial response with be computed separately in patients with and without mTOR response and presented with corresponding exact binomial 95% confidence intervals.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Patients must have histologic evidence of newly diagnosed acute myeloid leukemia (non-M3 AML) as documented by the presence of >20% myeloid blasts in the bone marrow
  2. Subjects must be 18 years of age and <= 60
  3. Subjects must have an ECOG performance status of 2 or less. (see attachment 1).
  4. Subjects must have a life expectancy of at least 4 weeks.
  5. Subjects must be able to consume oral medication.
  6. Required initial laboratory values: Creatinine 2.0mg/dL; total or direct bilirubin 1.5mg/dL; SGPT(ALT) 3xULN (if not due to the leukemia itself); negative pregnancy test for women with child-bearing potential.
  7. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing.
  8. Subjects must have a left ventricular ejection fraction (LVEF) of >/= 45%.

Exclusion Criteria:

  1. Subjects with APL - FAB M3 (t(15;17)(q22;q21)[PML-RAR] are not eligible
  2. Subjects must not have received any chemotherapeutic agents for the AML (except Hydroxyurea). Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system).
  3. Subjects must not be receiving growth factors, except for erythropoietin.
  4. Subjects with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible.
  5. 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.
  6. Subjects taking the following are not eligible:

    1. Carbamazepine (e.g., Tegretol)
    2. Rifabutin (e.g., Mycobutin)
    3. Rifampin (e.g., Rifadin)
    4. Rifapentine (e.g., Priftin)
    5. St. John's wort
    6. Clarithromycin (e.g., Biaxin)
    7. Cyclosporine (e.g. Neoral or Sandimmune)
    8. Diltiazem (e.g., Cardizem)
    9. Erythromycin (e.g., Akne-Mycin, Ery-Tab)
    10. Itraconazole (e.g., Sporanox)
    11. Ketoconazole (e.g., Nizoral)
    12. Telithromycin (e.g., Ketek)
    13. Verapamil (e.g., Calan SR, Isoptin, Verelan)
    14. Voriconazole (e.g., VFEND)
    15. Tacrolimus (e.g. Prograf)
  7. Subjects taking fluconazole, voriconazole, itraconazole, posaconazole, and ketoconazole within 72 hours of study entry are not eligible. Reinstitution of fluconazole, voriconazole, itraconazole, posaconazole, ketoconazole and diltiazem is permissible 72 hours after the last dose of sirolimus.
  8. Subjects who require HIV protease inhibitors or those with AIDS-related illness
  9. 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.
  10. 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 due to the unknown human fetal or teratogenic toxicities of sirolimus. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method.
  11. 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.
  12. Subjects with bacteremia must have documented negative blood cultures prior to study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01822015

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United States, Pennsylvania
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
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Principal Investigator: Margaret Kasner, MD Thomas Jefferson University
Additional Information:
Chiarini F, Grimaldi C, Ricci F, et al. Temsirolimus, An Allosteric mTORC1 Inhibitor, Is Synergistic with Clofarabine in AML and AML Leukemia Initiating Cells. ASH Annual Meeting Abstracts;118:2596-.
Park S, Chapuis N, Marcoux FS, et al. RAD001: A Clinico-Biological Phase I GOELAMS trial of Everolimus Association with High Dose Chemotherapy in Late Relapsing AML Patients Under 65 Years of Age. ASH Annual Meeting Abstracts;118:945-.
Scott EC, Perl A, Luger SM, Carroll M, Kasner M. A Feasibility Study of Rapamycin with Hyper-CVAD Chemotherapy in Adults with Acute Lymphoblastic Leukemia (ALL) and Other Aggressive Lymphoid Malignancies and Evaluation of mTOR Signaling Using Phosphoflow. ASH Annual Meeting Abstracts;118:4245-.

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Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University Identifier: NCT01822015    
Other Study ID Numbers: 12D.588
2012-55 ( Other Identifier: CCRRC )
First Posted: April 1, 2013    Key Record Dates
Last Update Posted: December 23, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Monocytic, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Neoplasms by Histologic Type
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors