Bortezomib and Doxil for the Treatment of Patients With Acute Myelogenous Leukemia

Acute myeloid leukemia (AML) remains largely incurable despite advances that have been made
in recent years into increasing the complete response (CR) rates. In elderly patients (over
the age of 60), CR rates are lower, 40 to 50%, and long term disease-free and overall
survival is less than 10%. The therapeutic options for relapsed/refractory AML are
significantly limited. Bortezomib has shown promising activity in patients with advanced
hematologic malignancies, including those with leukemia and non-Hodgkin's lymphoma.

Given the available data suggesting efficacy of bortezomib in combination with doxil in
patients with relapsed multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and Non
Hodgkin's lymphoma (NHL) as well as the known sensitivity of AML to anthracyclines and in
vitro data demonstrating the sensitivity of multiply resistant AML cells to bortezomib, we
are proposing the use of this combination in patients with relapsed/refractory AML or elderly
patients who are not candidates for standard induction therapy.

Using the subcutaneous formulation of bortezomib would provide patients with reduced
neurotoxicity and easier schedule due to decreased time in the infusion room and it would
decrease overall cost of care.

Inclusion Criteria:

- Written informed consent

- Female subjects must be either postmenopausal for at least 1 year before the screening
visit, is surgically sterilized or if they are of childbearing potential, agree to
practice 2 effective methods of contraception from the time of signing the informed
consent form through 30 days after the last dose of SQ VELCADE, or agree to completely
abstain from heterosexual intercourse.

- Male subjects, even if surgically sterilized must agree to 1 of the following:
practice effective barrier contraception during the entire study treatment period and
through a minimum of 30 days after the last dose of study drug, or completely abstain
from heterosexual intercourse.

- Adults (age 18 to 80) with AML, excluding the M3 subtype, that are not likely to
respond to conventional therapy

- Bone marrow and peripheral blood studies must be available for confirmation of
diagnosis.

- Performance status of 60% or greater by the Karnofsky scale

- A minimum of 4 weeks must have elapsed since the completion of prior chemotherapy.

- Patients may have had autologous transplant.

- There are no minimum hematological parameter requirements prior to the first two
cycles, as patients with AML and myelodysplastic syndrome (MDS) are understood to have
low absolute neutrophil count (ANC) and platelet counts when the disease is active.
However, patients with white blood cell count (WBC) greater than 30,000 will receive
hydroxyurea to reduce the WBC count to below 30,000 at which point they may begin
treatment.

- A pretreatment calculated creatinine clearance (absolute value) of ≥ 40 ml/minute or
serum creatinine of < 1.5 x upper limit of normal is required.

- Patients must have a serum bilirubin ≤1.5 mg/dl, serum glutamic-oxaloacetic
transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) ≤2.5 times the
institutional upper limits of normal.

Exclusion Criteria:

- There is no specific platelet and absolute neutrophil count that will exclude patients
from this study given the natural history of AML.

- Patient has greater than or equal to Grade 2 peripheral neuropathy

- Patient had myocardial infarction within 6 months prior to enrollment or has New York
Heart Association Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Prior to study entry, any ECG
abnormality at screening must be documented by the investigator as not medically
relevant. An left ventricular ejection fraction (LVEF) must be > 50

- Patient has hypersensitivity to VELCADE, boron, or mannitol.

- Female subject is pregnant or lactating.

- Female patients who are lactating or have a positive serum pregnancy test during the
screening period, or a positive urine pregnancy test on Day 1 before first dose of
study drug, if applicable.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

- Participation in clinical trials with other investigational agents not included in
this trial, within 14 days of the start of this trial and throughout the duration of
this trial.

- Radiation therapy within 3 weeks before randomization. Enrollment of subjects who
require concurrent radiotherapy (which must be localized in its field size) should be
deferred until the radiotherapy is completed and 3 weeks have elapsed since the last
date of therapy.

- Patients with active/uncontrolled central nervous system (CNS) leukemia

- Patients eligible, at the time of starting treatment, for curative therapeutic
approaches (such as allogeneic transplant) are not eligible for the trial.

- Patients may not receive any other anti-cancer therapy (cytotoxic, biologic,
radiation, or hormonal other than for replacement) while on this study other than
hydroxyurea for control of counts.

- Human Immunodeficiency Virus (HIV)-positive.