Bortezomib and Chemotherapy in Treating Participants With Lymphoid Malignancies Undergoing Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of Velcade
(bortezomib) in patients with lymphoid malignancies undergoing allogeneic peripheral blood
stem cell or bone marrow transplantation.

II. To determine the 1-year disease-free-survival (DFS) and the toxicity profile of Velcade
(bortezomib) in patients with lymphoid malignancies undergoing allogeneic peripheral blood
stem cell or bone marrow transplantation.

SECONDARY OBJECTIVES:

I. To compare the incidence of graft versus host disease (GVHD) with historical controls.

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

Participants receive carmustine intravenously (IV) over 1 hour on day -6, cytarabine IV over
1 hour twice daily (BID) on days -5 to -2, etoposide IV over 3 hours BID on days -5 to -2,
and melphalan IV over 30 minutes on day -1. Participants also receive rituximab IV on days
-13, -6, +1, and +8, and bortezomib IV over 1 minute on days -13, -6, -1, and +2.
Participants receiving a matched unrelated or mismatched donor transplant also receive
anti-thymocyte globulin IV over 4-6 hours on days -6 and -5. Participants then undergo
allogeneic hematopoietic stem cell transplantation over 30-45 minutes on day 0 and receive
filgrastim subcutaneously (SC) once daily (QD) starting on day +7 until blood counts return
to normal level. Participants receive tacrolimus IV starting on day -2 changing to orally
(PO) before leaving the hospital for 6-8 months after the transplant. Participants also
receive methotrexate IV over a few minutes on days +1, +3, and +6 and those receiving a
matched unrelated or mismatched donor transplant also receive methotrexate IV on day +11.

After completion of study treatment, participants are followed up at 1 month, every 3 months
for 1 year, and then every 6 months for 5 years.

Inclusion Criteria:

- Any histological subtype of CD20+ lymphoid malignancies or T-cell lymphoid
malignancies.

- Patients with CD20+ lymphoid malignancies in relapse after failing >= 1 prior regimen
of conventional treatment and not eligible for non-myeloablative transplant. Patients
with T-cell lymphoid malignancies can either be in relapse or newly diagnosed with
high risk features (such as high International Prognostic Index [IPI] of >= 2).

- Patients with prior non-myeloablative transplant are eligible if not from the same
donor.

- A fully-matched or one-antigen mismatched sibling or unrelated donor.

- Left ventricular ejection fraction (EF) >= 40% with no uncontrolled arrhythmias or
symptomatic heart disease.

- Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and
diffusion capacity of the lung for carbon monoxide (DLCO) >= 40%.

- Serum creatinine < 1.8 mg/dL.

- Serum bilirubin < 3 X upper limit of normal.

- Serum glutamate pyruvate transaminase (SGPT) < 3 X upper limit of normal.

- Voluntary signed, written Institutional Review Board (IRB)-approved 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.

- Men and women of reproductive potential must agree to follow accepted birth control
methods for the duration of the study. Female subject is either post-menopausal or
surgically sterilized or willing to use an acceptable method of birth control (i.e., a
hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with
spermicide, or abstinence) for the duration of the study. Male subject agrees to use
an acceptable method for contraception for the duration of the study.

Exclusion Criteria:

- Past history of anaphylaxis following exposure to rituximab or Velcade, boron or
mannitol.

- History of grade 3 or 4 National Cancer Institute (NCI) toxicity with prior Velcade
therapy.

- Patient with active central nervous system (CNS) disease.

- Pregnant (positive beta human chorionic gonadotropin [HCG] test in a woman with child
bearing potential defined as not post-menopausal for 12 months or no previous surgical
sterilization) or currently breast feeding. Pregnancy testing is not required for
post-menopausal or surgically sterilized women.

- Known infection with human immunodeficiency virus (HIV), human T-lymphotropic virus
(HTLV-I), hepatitis B, or hepatitis C.

- Patients with other malignancies diagnosed within 2 years prior to study day -13
(except skin squamous or basal cell carcinoma).

- Active uncontrolled bacterial, viral or fungal infections.

- Major surgical procedure or significant traumatic injury within 4 weeks prior to day
-13.

- Serious, non-healing wound, ulcer, or bone fracture.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 3 months prior to day -13.

- History of stroke within 6 months.

- Myocardial infarction within the past 6 months prior to study day 1, or has New York
Heart Association (NYHA) class III or IV heart failure or arrhythmia, unstable angina,
uncontrolled congestive heart failure or arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities. Prior to study entry, any
electrocardiography (ECG) abnormality at screening must be documented by investigator
as not medically relevant.

- Uncontrolled hypertension (>= 140/90).

- Uncontrolled chronic diarrhea.

- A prior allogeneic transplant from the same donor.

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

- Patient has received other investigational drugs within 3 weeks before enrollment.

- Active peripheral neuropathy greater or equal to grade 2.