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

Study Overview
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Brief Summary
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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.

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

Official Title
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A Pilot, Pharmacodynamic Correlate Trial of Sirolimus in Combination With Chemotherapy (Idarubicin, Cytarabine) for the Treatment of Newly Diagnosed Acute Myelogenous Leukemia

Conditions
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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

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Idarubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Subjects must be 18 years of age and <= 60 Subjects must have an ECOG performance status of 2 or less. (see attachment 1). Subjects must have a life expectancy of at least 4 weeks. Subjects must be able to consume oral medication. 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. 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 APL - FAB M3 (t(15;17)(q22;q21)[PML-RAR] are not eligible 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). 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) 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 who require HIV protease inhibitors or those with 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 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. 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.

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: Treatment (sirolimus, idarubicin, cytarabine)<br>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<br>* Given PO<br>* Other names: Rapamune;Drug: Idarubicin<br>* Given IV<br>* Other names: Idamycin;Drug: Cytarabine<br>* Given IV<br>* Other names: Arabinofuranosyl Cytidine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in measurement of mTOR activation paired with mTOR target inhibition | 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. | Baseline to day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | 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. | 1 year, 2 years, 5 years | 
| Progression free survival | 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. | 1 year, 2 years, 5 years | 
| Incidence of toxicities, graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) 4.0 guidelines | Safety data analysis is descriptive. All estimates of adverse events rates will be presented with corresponding confidence intervals using the exact method. | Up to 45 days | 
| Response defined as patients achieving a complete remission (CR), complete response in absence of total platelet recovery (CRp), or partial remission (PR) | 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. | Up to 5 years |