Clinical Trials /

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

NCT01822015

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Sirolimus, Idarubicin, and Cytarabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
  • Official Title: A Pilot, Pharmacodynamic Correlate Trial of Sirolimus in Combination With Chemotherapy (Idarubicin, Cytarabine) for the Treatment of Newly Diagnosed Acute Myelogenous Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 12D.588
  • SECONDARY ID: 2012-55
  • NCT ID: NCT01822015

Conditions

  • 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

Interventions

DrugSynonymsArms
Sirolimusrapamycin, RapamuneTreatment (sirolimus, idarubicin, cytarabine)
Idarubicin4-demethoxydaunorubicin, Zavedos, IdamycinTreatment (sirolimus, idarubicin, cytarabine)
Cytarabinecytosine arabinoside, Cytosar-U, Depocyt, Ara-C, Arabinofuranosyl CytidineTreatment (sirolimus, idarubicin, cytarabine)

Purpose

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

      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:

        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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sirolimus, idarubicin, cytarabine)ExperimentalPatients 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.
  • Sirolimus
  • Idarubicin
  • Cytarabine

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in measurement of mTOR activation paired with mTOR target inhibition
Time Frame:Baseline to day 4
Safety Issue:
Description: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

Measure:Overall survival
Time Frame:1 year, 2 years, 5 years
Safety Issue:
Description: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.
Measure:Progression free survival
Time Frame:1 year, 2 years, 5 years
Safety Issue:
Description: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.
Measure:Incidence of toxicities, graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) 4.0 guidelines
Time Frame:Up to 45 days
Safety Issue:
Description:Safety data analysis is descriptive. All estimates of adverse events rates will be presented with corresponding confidence intervals using the exact method.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Sidney Kimmel Cancer Center at Thomas Jefferson University

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