Bortezomib, Rituximab and Combination Chemotherapy in Treating Participants With Mantle Cell Lymphoma

PRIMARY OBJECTIVES:

I. Determine the safety and the maximum tolerated dose (MTD) of bortezomib when added to the
combination of rituximab, methotrexate, and cytarabine alternating with bortezomib,
rituximab-hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone
(hyperCVAD) in patients with untreated aggressive mantle cell lymphoma. (Phase I) II.
Evaluate the time to failure (TTF) rate following therapy with bortezomib plus
rituximab-hyperCVAD alternating with bortezomib plus rituximab-high dose
methotrexate/cytarabine in patients between 18 and 79 years of age with untreated aggressive
mantle cell lymphoma. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate overall response rate, complete remission rate, overall survival, and duration of
remission. (Phase I) II. Evaluate overall response rate, overall survival, and duration of
remission. (Phase II) III. Evaluate toxicity of the combination regimen. (Phase II) IV.
Correlate outcome with pretreatment markers. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of bortezomib followed by a phase II study.

Participants receive Drug Combination I during courses 1, 3, 5, and 7 (if needed) and Drug
Combination II during courses 2, 4, 6, and 8 (if needed) in the absence of disease
progression or unacceptable toxicity.

Drug Combination I: Participants receive rituximab intravenously (IV) over 6 hours on day 1,
cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4, doxorubicin IV over 15-30
minutes on day 5, vincristine IV over 15-30 minutes on days 5 and 12, dexamethasone orally
(PO) or IV on days 2-5 and 12-15, and bortezomib IV over a few seconds after the first dose
of cyclophosphamide and immediately after vincristine and doxorubicin have been given on day
5.

Drug Combination II: Participants receive rituximab IV over 6 hours on day 1, methotrexate IV
over 24 hours on day 2, and cytarabine IV over 2 hours every 12 hours on days 3-4.

After completion of study treatment, participants are followed up every 3 months for 1 year,
every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Inclusion Criteria:

- Confirmed diagnosis of previously untreated nodular or diffuse mantle cell lymphoma
and their blastoid cytologic variant.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

- Serum bilirubin < 1.5 mg/dl and serum creatinine < 2.0 mg/dl within 14 days before
enrollment (unless higher levels are due to lymphoma).

- Platelet count > 100,000/mm^3 within 14 days before enrollment (unless due to
lymphoma).

- Absolute neutrophil count (ANC) > 1,000/mm^3 within 14 days before enrollment (unless
due to lymphoma).

- Cardiac ejection fraction >= 50% by echocardiogram (ECHO) or multigated acquisition
(MUGA).

- Patients must be willing to receive transfusions of blood products.

- Voluntary 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.

- Female subject is either post-menopausal for at least 1 year before the Screening
visit or surgically sterilized or if they are of childbearing potential, agree to
practice 2 effective methods of birth control, at the same time (i.e., a hormonal
contraceptive, intra-uterine device, diaphragm with spermicide, condom with
spermicide, or abstinence) from the time of signing the informed consent through 30
days after the last dose of study treatment, or agree to completely abstain from
heterosexual intercourse.

- Male subject, even if surgically sterilized (ie, status post vasectomy) agrees to
practice effective barrier contraception during the entire study treatment period and
through 30 days after the last dose of study treatment, or agree to completely abstain
from heterosexual intercourse.

Exclusion Criteria:

- Human immunodeficiency virus (HIV) infection.

- Central nervous system (CNS) involvement.

- Co-morbid medical or psychiatric illnesses that preclude treatment with intense dose
chemotherapy.

- Concurrent or previous malignancy with < 90% probability of survival at 5 years.

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

- 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
electrocardiography (ECG) abnormality at screening has to be documented by the
investigator as not medically relevant.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

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

- Participating 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.