Bortezomib, Mitoxantrone, Etoposide, and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the DLT, MTD, and the recommended Phase 2 dose of bortezomib in combination
with MEC in patients with relapsed/refractory AML.

SECONDARY OBJECTIVES:

I. To describe the non-dose limiting toxicities associated with bortezomib in combination
with MEC in patients with relapsed/refractory AML.

II. To describe any preliminary evidence of clinical activity of this combination (CR rate)
in relapsed/refractory AML.

III. To determine the median CD74 antigen expression in patients achieving a response versus
those patients not achieving a response.

OUTLINE:

This is a dose-escalation study of bortezomib.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8 and 11; and mitoxantrone IV,
etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6.
Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-5 weeks.

Inclusion

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care

- Female subject is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (ie., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study; female subject is not lactating

- Male subject agrees to use an acceptable method for contraception for the duration of
the study

- Relapsed or refractory AML (excluding acute promyelocytic leukemia), based on World
Health Organization Classification; all other subtypes of AML will be eligible;
refractory disease will be considered failure to respond to 2 cycles of induction
chemotherapy (7+3 and 5+2); any number of relapses will be eligible

- No evidence of leptomeningeal disease; a lumbar puncture does not need to be
performed unless there is clinical suspicion of leptomeningeal disease

- Previous treatment related toxicities must have resolved to Grade 1 (excluding
alopecia)

- Liver enzymes (AST and ALT) can not be greater than 2.5 times the upper limits of
normal (ULN), and total bilirubin =< 1.5 x ULN within 14 days of enrollment

- Renal function: Serum creatinine should be =< 1.5 x ULN within 14 days of enrollment

- No serious or poorly controlled medical conditions that could be exacerbated by
treatment or that would seriously complicate compliance with the protocol

- ECOG performance status 0-3

- No peripheral neuropathy >= Grade 2 within 14 days of trial enrollment

- Echocardiogram or MUGAs scan demonstrating an ejection fraction >= 45%

- Patients with secondary AML, and patients with a prior autologous and allogeneic bone
marrow transplant are eligible

- Patients with an allogeneic transplant must meet the following conditions: the
transplant must have been performed more than 90 days before registration to this
study, the patient must not have >= Grade 2 acute graft versus host disease (GvHD),
or either moderate or severe limited chronic GvHD, or extensive chronic GvHD of any
severity; the patient must be off all immunosuppression for at least 2 weeks

- No uncontrolled infections

- No history of hypersensitivity to boron or mannitol

- No known history of HIV or active hepatitis B or C

- No major surgery within 4 weeks prior to trial enrollment

Exclusion

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) 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 has to be documented by the investigator as not medically
relevant

- Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment

- Female subject is pregnant or breast-feeding; confirmation that the subject is not
pregnant must be established by a negative serum beta-human chorionic gonadotropin
(beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not
required for post-menopausal or surgically sterilized women

- Patient has received any standard or investigational therapy for their leukemia
within 14 days before enrollment (except for hydrea)

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

- Patients with prior malignancy are eligible; however, the patient must be in
remission from the prior malignancy and have completed all chemotherapy and
radiotherapy at least 6 months prior to registration and all treatment-related
toxicities must have resolved

- Leptomeningeal/ central nervous system involvement with AML; a lumbar puncture does
not need to be performed unless there is clinical suspicion

- Patients who have had prior pulmonary radiation

- Prohibited Concurrent Therapy: any investigational agent other than VELCADE; G-CSF
and GM-CSF are not allowed