Bortezomib, Sorafenib Tosylate, and Decitabine in Treating Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To identify the biologically effective and tolerable dose (BETD) of the
bortezomib/sorafenib (sorafenib tosylate) combination in acute myeloid leukemia (AML) with
biological activity defined as the dose(s) that induce a 100% increase (i.e. a doubling) in
the level of microRNA-29b (miR-29b) in bone marrow (BM) after bortezomib/sorafenib treatment
from pretreatment levels in at least 5 out of 6 patients at a given dose levels.

II. To recommend a dose level for a Phase II study using this agent combination in patients
with AML.

III. To define the specific toxicities and the dose limiting toxicity (DLT) of bortezomib in
combination with sorafenib and decitabine.

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR) of this combination. II. To determine the
rate of complete remission (CR) of this combination. III. To conduct pharmacodynamic studies
by measuring the effect of this chemotherapy combination on the micronome, kinome and
epigenome.

OUTLINE: This is a dose-escalation study of bortezomib and sorafenib tosylate.

STEP A: Patients receive bortezomib subcutaneously (SC) on days 1 and 4, sorafenib tosylate
orally (PO) twice daily (BID) on days 1-14, and decitabine intravenously (IV) over 1 hour on
days 5-14.

STEP B: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib
tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 9-18 or 12-21.

STEP C: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib
tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14.

Treatment repeats every 28 days for up to 4 courses in the absence of unacceptable toxicity.
Patients achieving complete response (CR) or incomplete CR (CRi) receive maintenance therapy
comprising decitabine IV on days 1-5. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed acute myeloid leukemia
(AML) by World Health Organization (WHO) criteria in the blood and/or marrow AND age
>= 60 and not candidates/refuse standard induction treatment OR who have one of the
following: poor risk cytogenetics, AML following antecedent hematologic disorder, or
therapy-related AML

- Patients with relapsed or refractory AML age >= 18 years are also eligible for
treatment; patients may have been treated for antecedent hematologic disorder with
myeloid growth factors, recombinant erythropoietin, thalidomide, lenalidomide,
5-azacitidine or the 5 day schedule of decitabine; patients who have received the 10
day schedule of decitabine for treatment an antecedent hematologic disorder or AML are
not eligible

- If the patient has co-morbid medical illness, life expectancy attributed to this must
be greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin < 2.0 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transferase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transferase [SGPT]) <
2.5 X institutional upper limit of normal

- Creatinine < 2.0 mg/dL or creatinine clearance (CrCl) >= 60 mL/min

- Prothrombin time (PT)/international normalized ratio (INR) monitoring, < 1.5 x
institutional upper limits of normal

- Both women and men must agree to use adequate contraception (barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation;
if the patient does not agree, the patient is not eligible

- Ability to understand and willingness to sign the written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study; hydroxyurea may be
administered for count control both pre-treatment and during cycle 1 only

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 14 days of enrollment

- Patients with active central nervous system disease or with granulocytic sarcoma as
sole site of disease

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to sorafenib, bortezomib or decitabine that are not
easily managed

- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements; as infection is a common feature of AML, patients with active infection
are permitted to enroll provided that the infection is under control; myocardial
infarction within 6 months prior to enrollment or has New York Heart Association
(NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled hypertension,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities

- Patients with serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- Patients with pre-existing grade 2 or higher neuropathy or other serious neurologic
toxicity that would significantly increase risk of complications from bortezomib
therapy are excluded

- Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV)
infection who are taking chronic anti-retroviral therapy (HAART) are ineligible if
there is a potential for drug-drug interactions with the chemotherapeutic agents;
patients with a known confirmed diagnosis of HIV infection who meet standard
eligibility criteria and are not taking HAART with a potential for drug-drug
interactions are eligible

- Patients with advanced malignant solid tumors are excluded

- Patients with known impairment of gastrointestinal (GI) function or GI disease that
may significantly alter the absorption of sorafenib

- Patients who are taking concomitant medications that in the investigator's opinion are
strong inducers of the cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
enzymes and therefore likely to interact with the study agents, will not be eligible