Bortezomib (VELCADE), Cladribine and Rituximab (VCR) in Mantle Cell Lymphoma (PSHCI 10-011)

The phase I portion of the study is a standard dose-escalation schemed designed to determine
the maximum tolerated dose (MTD) of the combination of bortezomib, cladribine, and rituximab
therapy. The MTD is defined as the dose level in which ≤1 out of 6 patients have
dose-limiting toxicity (DLT). Three patients are enrolled on a dose level. If 0 out of 3
patients have DLT, then the next set of 3 patients are enrolled at the next highest dose
level. If ≥2 out of 3 patients have DLT, then the MTD will have been exceeded and dose
escalation will cease. Three additional patients will be enrolled at the next lowest dose
level if only 3 were treated previously at that level. If 1 out of 3 patients have DLT, then
the next set of 3 patients will be treated at the same dose level. If ≤1 out of 6 patients
treated at that dose level have DLT, then the next set of patients will be treated at the
next higher dose level. If ≥2 out of 6 patients treated at that dose level have DLT, then
the MTD will have been exceeded and dose escalation will cease. Three additional patients
will be treated at the next lowest dose level if only 3 were treated previously at that
level. This phase I study will use 3 dose levels of cladribine (3 mg/m2, 4 mg/m2, and 5
mg/m2), with 3 mg/m2 being the starting dose level. DLTs will be assessed at the completion
of the first 2 cycles of cladribine and rituximab.

Phase II Design: The phase II portion of the study is a two-arm, single-stage design with no
interim analysis. One arm will accrue newly diagnosed patients, and one arm will accrue
relapsed patients. In each arm, the progression-free survival rate at 2 years will be used
as the primary endpoint for determining whether the treatment is sufficiently active in each
arm. No comparisons will be made between the arms.

Inclusion Criteria:

- Females that are postmenopausal for at least 1 year before the screening visit,
surgically sterilized or if they are of childbearing potential agree to practice 2
effective methods of contraception from the time of signing the informed consent form
through 30 days after the last dose.

- Male subjects must 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 completely abstain from heterosexual intercourse.

- Patients with newly diagnosed and relapsed mantle cell lymphoma.

- ECOG performance status grade 3 or higher.

Exclusion Criteria:

- Patient has a platelet count of <50x10 9/L within 14 days before enrollment if not
related to disease.

- Patient has an absolute neutrophil count less than 100 within 14 days before
enrollment if not related to disease.

- Patient has a calculated or measured creatinine clearance of <20 mL/minute within 14
days before enrollment.

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

- Patient has > 1.5 x ULN total bilirubin.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association Class II or IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
conduction system abnormalities.

- Patient has hypersensitivity to bortezomib, boron or mannitol.

- Female subject is pregnant or breast-feeding.

- Patient has received other investigational drugs within 14 days before enrollment.

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

- Diagnosed or treated for another malignancy within 3 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.