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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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AML

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Mitoxantrone
* Drug: Etoposide
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologic evidence of high risk acute myeloid leukemia defined as one of the following: 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. Relapsed non-M3 AML 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus and MEC<br>Sirolimus and MEC (Mitoxantrone, Etoposide, and Cytarabine) | Drug: Sirolimus<br>* Sirolimus, by mouth, will be given as a 12mg loading dose followed by 8 daily doses of 4mg/day.<br>* Other names: Rapamycin;Drug: Mitoxantrone<br>* Mitoxantrone 8mg/m2/day IV<br>* Other names: Novantrone;Drug: Etoposide<br>* 100 mg/m2/day IV<br>* Other names: Etopophos;Drug: Cytarabine<br>* 1000mg/m2/day IV every 24 hours for 5 days<br>* Other names: ara-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Percent change compared between response groups (responder vs nonresponder). This outcome measure only includes patients who survived to outcome assessment. | From pre- to post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response | 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 | Within one week of peripheral count recovery but no later than day 42 | 
| Complete Response in the Absence of Platelet Recovery | 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) | Within one week of peripheral count recovery but no later than day 42 | 
| Partial Response | 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 | Within one week of peripheral count recovery but no later than day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, mTOR, rapamycin