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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


N/A
18 Years
N/A
Open (Enrolling)
Both
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

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Trial Information

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


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.


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; 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).

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 have evidence of cerebellar dysfunction at baseline.

11. 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.

12. 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.

13. Subjects with bacteremia must have documented negative blood cultures prior to study
entry.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in measurement of mTOR activation paired with mTOR target inhibition

Outcome 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.

Outcome Time Frame:

Baseline to day 4

Safety Issue:

No

Principal Investigator

Margaret Kasner, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Thomas Jefferson University

Authority:

United States: Institutional Review Board

Study ID:

12D.588

NCT ID:

NCT01822015

Start Date:

March 2013

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic

Name

Location

Thomas Jefferson UniversityPhiladelphia, Pennsylvania  19107-6541