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

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.

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