Bortezomib and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVE:

Determine the response rate of bortezomib in combination with a chemotherapy backbone of
doxorubicin (doxorubicin hydrochloride), vincristine (vincristine sulfate), PEG-asparaginase
(pegaspargase), and dexamethasone in patients with relapsed/refractory acute lymphoblastic
leukemia.

SECONDARY OBJECTIVES:

- Estimate the rate of complete response (CR) and CR with incomplete platelet recovery
(CRp) on Day 29 after re-induction.

- Determine progression-free survival (PFS) at 2 years after re-induction.

- Determine failure-free survival (FFS) at 1 year after re-induction.

- Overall survival (OS) at 1 year after re-induction.

- Assess safety and tolerability of the study drug.

- Determine whether bortezomib induces reactive oxygen species (ROS) in circulating acute
lymphoblastic leukemia (ALL) blast cells.

OUTLINE:

Patients receive bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11; doxorubicin
hydrochloride intravenously (IV) on day 1; pegaspargase IV or intramuscularly (IM) on Days 5
and 22; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on
Days 1 to 14; cytarabine intrathecally (IT) on Day 1 and methotrexate intrathecally (IT) on
Day 15. Patients with central nervous system disease receive intrathecal treatment per
investigator's discretion.

Participants are followed up every 3 months for up to 2 years after completion of study
treatment.

INCLUSION CRITERIA

- Voluntary written informed consent

- Female subjects who:

- Are postmenopausal for at least 1 year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
form through 30 days after the last dose of bortezomib, or agree to completely
abstain from heterosexual intercourse

- Male subjects, even if surgically sterilized (ie, status post vasectomy) who:

- Agree to 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

- Agree to completely abstain from heterosexual intercourse

- • Relapsed or refractory B or T cell acute lymphoblastic leukemia that has progressed
following at least one prior therapy. Ph+ patients are eligible. Relapsed ALL is
defined in patients as the reappearance of leukemia cells in the peripheral blood or
bone marrow or appearance of extramedullary disease after a complete remission.
Refractory ALL is defined in patients as failure to achieve a complete remission after
induction therapy. Complete remission is defined by <5% leukemia cells in the bone
marrow with recovery of peripheral blood counts. Relapsed disease can be documented by
bone marrow biopsy (>5% cells in the bone marrow) or by flow cytometry in the
peripheral blood or biopsy of extramedullary disease.

- Has received at least 1 line of prior systemic therapy that may NOT have included
bortezomib (Velcade); patients who have undergone autologous/allogeneic stem cell
transplantation are eligible

- Transplant-eligible patients are eligible

- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

- No poorly-controlled intercurrent illness including, but not limited to, ongoing or
active infection, poorly controlled diabetes, symptomatic congestive heart failure, or
psychiatric illness that in the opinion of the investigator would limit compliance
with study requirements

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper
limit of normal (ULN)

- Total bilirubin ≤ 1.5 x (ULN unless elevation is deemed due to leukemia infiltration)

- Adequate renal function defined as creatinine clearance of ≥ 30 mL/minute by the
Cockcroft-Gault method

EXCLUSION CRITERIA

- > 1.5 x ULN total bilirubin

- ≥ Grade 2 peripheral neuropathy

- 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
electrocardiogram (ECG) abnormality at screening must be documented by the
investigator as not medically relevant

- Hypersensitivity to bortezomib, boron, or mannitol

- Pregnant or lactating

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

- Diagnosed or treated for another malignancy within 2 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 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

- Prior exposure ≥ 350 mg/m² of anthracycline (doxorubicin equivalent)

- Left ventricular ejection fraction < 40%