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Pilot Trial of Sirolimus/MEC in High Risk Acute Myelogenous Leukemia (AML)

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: NCT01184898
Recruitment Status : Completed
First Posted : August 19, 2010
Results First Posted : August 27, 2014
Last Update Posted : November 29, 2016
University of Pennsylvania
Information provided by (Responsible Party):
Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University )

Brief Summary:
The purpose of this study is to evaluate the addition of Sirolimus (rapamycin) to standard chemotherapy for the treatment of patients with high risk acute myelogenous leukemia (AML). Cancer cells taken from the patients will be studied in the laboratory to see if rapamycin is affecting the mTOR pathway in the cells and if this effect is correlated with how well patients respond to the therapy.

Condition or disease Intervention/treatment Phase
AML Drug: Sirolimus Drug: Mitoxantrone Drug: Etoposide Drug: Cytarabine Not Applicable

Detailed Description:

Recent improvements in our understanding of leukemia biology have led to the introduction of highly effective, molecularly targeted therapies. This is exemplified by the development of BCR-ABL tyrosine kinase inhibitors such as imatinib as monotherapy for chronic myeloid leukemia (CML) and in combination with chemotherapy for BCR-ABL+ acute lymphoblastic leukemia (ALL). Imatinib mesylate blocks the protein made by the BCR-ABL oncogene.

The PI3K (phosphatidylinositol 3-kinases) signaling is critical to leukemia cell survival and can be targeted. Growth and survival stimulating signal transduction pathways are abnormally and universally activated in AML (Acute Myeloid Leukemia). This signal cascade is thought to contribute to survival and growth in tumor cells via downstream effects upon target proteins AKT/Protein kinase B and mammalian target of rapamycin (mTOR) a protein that helps control several cell functions.

In AML, we and others have shown that PI3K signaling is constitutively activated in over 85% of primary samples and that the small molecule PI3K inhibitor LY294002 is cytotoxic in vitro to virtually all samples tested. As LY294002 is poorly suited for drug development, we have concentrated upon other ways to inhibit signal transduction through this pathway. Mammalian target of rapamycin (mTOR) emerged as a reasonable target due to the availability of clinically available, highly specific inhibitors with favorable safety profiles. Mammalian target of rapamycin (mTOR) plays a central but complex role in cancer cells' metabolic regulation and survival. This serine/threonine kinase coordinates several important cellular functions and its activity is modulated in response to amino acid, glucose, oxygen, and ATP availability as well as extracellular growth factor ligation. Mammalian target of rapamycin (mTOR) activity regulates protein translation, nutrient and amino acid uptake, mitochondrial respiration, glycolysis, cell size regulation, cell cycle entry and progression, ribosome biogenesis, and autophagy. Constitutive mammalian target of rapamycin (mTOR) activation is commonly seen in cancer cells and is thought to promote survival in the setting of a wide variety of cellular insults. Importantly, mTOR opening may cause chemotherapy resistance. Although regulation of mTOR signaling in leukemia occurs through by several inputs, mTOR activity in AML is thought to be primarily regulated by PI3K signaling through AKT via the agent tumor suppressor tuberous sclerosis complex (TSC1& 2) and its target rheb GTPase.

Taken together, mammalian target of rapamycin mTOR is a smart target for molecularly targeted therapy in AML due to its importance in the growth and survival of AML cells, its necessity for AML cell survival in certain contexts, and its probable role in chemotherapy resistance and relapse.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Pharmacodynamic Correlate, Multi-Institutional Trial of Sirolimus in Combination With Chemotherapy (Mitoxantrone, Etoposide, Cytarabine) for the Treatment of High Risk, Acute Myelogenous Leukemia
Study Start Date : July 2010
Actual Primary Completion Date : January 2012
Actual Study Completion Date : February 2016

Arm Intervention/treatment
Experimental: Sirolimus and MEC
Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine)
Drug: Sirolimus
Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day.
Other Name: Rapamycin

Drug: Mitoxantrone
Mitoxantrone 8mg/m2/day IV
Other Names:
  • Mitozantrone
  • Novantrone

Drug: Etoposide
100 mg/m2/day IV
Other Names:
  • Etoposide phosphate
  • VP-16
  • Etopophos

Drug: Cytarabine
1000mg/m2/day IV every 24 hours for 5 days
Other Names:
  • Cytosine arabinoside
  • Cytosar-U
  • Depocyt
  • ara-C

Primary Outcome Measures :
  1. Association Between the Magnitude of mTOR Target Inhibition Post-treatment in Leukemic Blasts and Clinical Response in Patients With High Risk AML Treated With Sirolimus MEC [ Time Frame: From pre- to post-treatment ]

    Percent change compared between response groups (responder vs nonresponder).

    This outcome measure only includes patients who survived to outcome assessment.

Secondary Outcome Measures :
  1. Complete Response [ Time Frame: Within one week of peripheral count recovery but no later than day 42 ]

    Complete response is defined as:

    • Peripheral Blood Counts -Neutrophil count >1 x 109/L.
    • Platelet count ≥ 100 x 109/L.
    • Reduced hemoglobin concentration or hematocrit has no bearing on remission status.
    • Leukemic blasts must not be present in the peripheral blood.
    • Cellularity of bone marrow biopsy must be > 20% with maturation of all cell lines with < 5% blasts and no Auer rods.
    • Extramedullary leukemia, such as CNS or soft tissue involvement, must not be present

  2. Complete Response in the Absence of Platelet Recovery [ Time Frame: Within one week of peripheral count recovery but no later than day 42 ]

    Complete response in the absence of platelet recovery is defined as:

    - Bone marrow (<5% blasts) with adequate bone marrow cellularity, no evidence of circulating blasts or extramedullary disease and normalization of peripheral blood counts except for platelets (neutrophil count =1,000/µL)

  3. Partial Response [ Time Frame: Within one week of peripheral count recovery but no later than day 42 ]

    Partial response is defined as:

    • Requires that all of the criteria for complete remission be satisfied except that the bone marrow may contain ≥ 5% blasts but < 25% blasts.
    • A marrow with <5% blasts that contain Auer rods will also be considered a PR

Information from the National Library of Medicine

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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:

  • Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following:

    1. Primary refractory non-M3 AML (i) Residual leukemia after a minimum of 2 prior courses of chemotherapy (Same or different) (ii) Evidence of leukemia after a nadir bone marrow biopsy demonstrates no evidence of residual leukemia.
    2. Relapsed non-M3 AML
    3. Any non-M3 AML age >60 with no evidence of favorable karyotype (stratum 2 ONLY), defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBF;MYH11] by cytogenetics, FISH, or RT-PCR
    4. Secondary AML (from antecedent hematologic malignancy or following therapy with radiation or chemotherapy for another disease) with no evidence of favorable karyotype (stratum 2 ONLY), defined by presence of t(8;21)(q22;q22) [AML1-ETO], inv16(p13;q22), or t(16;16)(p13;q22) [CBF;MYH11] by cytogenetics, FISH, or RT-PCR
  • Age > or = 18
  • ECOG = 0 or 1

Exclusion Criteria:

  • Subjects with FAB M3 (t(15;17)(q22;q21)[PML-RAR]) 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 SR, Isoptin, Verelan)
    • Voriconazole (e.g., VFEND)
    • Tacrolimus (e.g. Prograf)
  • 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.
  • 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

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): NCT01184898

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United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Thomas Jefferson University
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Sidney Kimmel Cancer Center at Thomas Jefferson University
University of Pennsylvania
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Principal Investigator: Margaret Kasner, MD Thomas Jefferson University
Additional Information:
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Responsible Party: Sidney Kimmel Cancer Center at Thomas Jefferson University Identifier: NCT01184898    
Other Study ID Numbers: 10D.21
2009-42 ( Other Identifier: CCRRC )
First Posted: August 19, 2010    Key Record Dates
Results First Posted: August 27, 2014
Last Update Posted: November 29, 2016
Last Verified: October 2016
Keywords provided by Thomas Jefferson University ( Sidney Kimmel Cancer Center at Thomas Jefferson University ):
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Etoposide phosphate
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antifungal Agents
Sensory System Agents
Peripheral Nervous System Agents