Study of the Combination of Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Mantle Cell Lymphoma

The drug being tested in this study were combination of VcR-CAP and R-CHOP. Combination of
VcR-CAP and R-CHOP is being tested to treat people who had mantle cell lymphoma (MCL).

The study enrolled 487 patients. Participants were randomly assigned (by chance, like
flipping a coin) to one of the two treatment groups in a 1:1 ratio:

Treatment Group A (VcR-CAP) Treatment Group B (R-CHOP)

The study included a screening phase, a treatment phase, a short-term follow-up phase, and a
long-term follow-up phase. The screening phase was up to 28 days (56 days for bone marrow
evaluation) prior to randomization.

This multi-center trial was conducted worldwide. The total study duration from randomization
of the first patient until the last progression-free survival (PFS) event required for the
final analysis was expected to be approximately 42 months (24 months for enrollment and 18
months for follow-up) and survival follow-up every 12 weeks until death.

Inclusion Criteria:

- Male or female patients 18 years or older (the patient must be at least the legal age
limit to be able to give informed consent within the jurisdiction the study is taking
place)

- Diagnosis of mantle cell lymphoma MCL (Stage II, III or IV) as evidenced by lymph node
histology and either expression of cyclin D1 (in association with CD20 and CD5) or
evidence of t(11;14) translocation, such as by cytogenetics, fluorescent in situ
hybridization (FISH) or polymerase chain reaction (PCR). Patients with a diagnosis of
Stage I MCL will not be permitted to enter study.

- Paraffin embedded biopsy tissue block (preferably of lymph node origin) must be sent
to the central laboratory for confirmation of MCL diagnosis prior to randomization. In
China, a paraffin embedded lymph node biopsy tissue block must be sent for central
confirmation of sample adequacy, prior to randomization

- At least 1 measurable site of disease

- No prior therapies for MCL

- Not eligible for bone marrow transplantation as assessed by the treating physician
(e.g., age or the presence of co-morbid conditions that may have a negative impact on
the tolerability to transplantation).

- Eastern Cooperative Oncology Group ECOG status ≤2

- Absolute neutrophil count (ANC) ≥1500 cells/µL,

- Platelets ≥100,000 cells/µL or ≥75,000 cells/µL if thrombocytopenia is considered by
the investigator to be secondary to MCL (e.g., due to bone marrow infiltration or
sequestration from splenomegaly).

- Alanine transaminase ≤3 x upper limit of normal (ULN)

- Aspartate transaminase ≤3 x ULN

- Total bilirubin ≤1.5 x ULN,

- Calculated creatinine clearance ≥20 mL/min.

- Female patients must be post menopausal for at least 1 year (must not have had a
natural menses for at least 12 months), surgically sterile, or practicing an effective
method of birth control (e.g., prescription oral contraceptives, contraceptive
injections, intrauterine device, double-barrier method, contraceptive patch, male
partner sterilization) and have a negative serum βHCG or urine pregnancy test at
screening. They must also be prepared to continue birth control measures for at least
6 months after terminating treatment.

- Male patients must agree to use an acceptable method of contraception (for themselves
or female partners as listed above) for the duration of the study.

- All patients (or their legally acceptable representatives) must have signed an
informed consent document indicating that they understand the purpose of and
procedures required for the study and are willing to participate in the study.

- In order to participate in the pharmacogenomics component of this study, patients (or
their legally acceptable representative) must have signed the informed consent form
for pharmacogenomics research indicating willingness to participate in the
pharmacogenomics component of the study. Acquisition of tumor sample collections is
required for all patients (where available); all other sample collections are optional

Exclusion Criteria:

- Prior treatment with VELCADE

- Prior antineoplastic (including unconjugated therapeutic antibodies), experimental or
radiation therapy, radioimmunoconjugates or toxin immunoconjugates for the treatment
of MCL. In the event that a patient has received doxorubicin for the treatment of any
condition, other than MCL, the maximum dose and exposure received prior to entry into
this study should not exceed 150 mg/m2.

- short course (maximum of 10 days, not exceeding 100 mg/day) prednisone or equivalent
steroids are allowed to treat symptoms in patients with advanced disease who enter the
screening phase and are waiting to be randomized.

- Major surgery (at the discretion of the treating physician and in consultation with
the sponsor's medical monitor) within 2 weeks before randomization

- Peripheral neuropathy or neuropathic pain of Grade 2 or worse (as per the
investigators assessment)

- Diagnosed or treated for a malignancy other than MCL within 1 year of randomization,
or who were previously diagnosed with a malignancy other than MCL and have any
radiographic or biochemical marker evidence of malignancy. Patients with completely
resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ
malignancy are not excluded.

- Active systemic infection requiring treatment and patients with known diagnosis of
human immunodeficiency virus HIV or active hepatitis B (carriers of hepatitis B are
permitted to enter study)

- History of allergic reaction attributable to compounds containing boron, mannitol, or
hydroxybenzoates

- Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine
proteins or to any component of rituximab including polysorbate 80 and sodium citrate
dihydrate

- Female or male patients of child-bearing potential who will not use adequate
contraception during the course of the study.

- Serious medical (e.g., pericardial disease, cardiac failure [New York Heart
Association; NYHA Class III or IV, Attachment 12 or left ventricular ejection
fraction; LVEF <50%], active peptic ulceration, uncontrolled diabetes mellitus, or
acute diffuse infiltrative pulmonary disease), or psychiatric illness likely to
interfere with participation in this clinical study

- Concurrent treatment with another investigational agent.