A Phase I/II Trial of VR-CHOP in Lymphoma Patients

This study will assess whether adding bortezomib (Velcade) to R-CHOP (in a new combination
called VR-CHOP) can further improve outcomes in patients with indolent NHL who have not
previously received treatment.

Patients who are eligible to take part in the study will receive VR-CHOP at the doses of
Velcade and vincristine established in phase 1. Patients will receive VR-CHOP for up to 8
cycles of treatment (each of 21 days duration). During treatment, patients will be assessed
for their response to therapy and for possible side effects. All patients will go on to
receive maintenance therapy after completion of their initial treatment as designed by the
protocol.

Inclusion Criteria:

- Tissue diagnosis of a previously untreated, cluster of differentiation antigen 20+
(CD20+), B-cell non-Hodgkin lymphoma.

- For the Phase 1 trial: patients with any of the following diagnoses are
eligible:

- Follicular Lymphomas (Grade 1, 2, 3a, 3b)

- Small Lymphocytic Lymphoma

- Marginal Zone Lymphomas

- For the Phase 2 trial: patients with any of the following diagnoses are
eligible:

- Follicular Lymphomas (Grade 1, 2, 3a)

- Small Lymphocytic Lymphoma

- Marginal Zone Lymphomas

- Patients with follicular or other low-grade lymphoma must have an indication for
treatment based on modified Groupe d'Etude des Lymphomes Folliculaires (GELF)
criteria or a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥ 3.

- Indications for treatment based on modified GELF criteria include any one of the
following:

- B symptoms or other lymphoma-related symptoms

- Involvement of 3 nodal sites, each with a diameter of 3 cm

- Any nodal or extranodal tumor mass with a diameter of 7 cm

- Splenomegaly greater than 16 cm by CT scan.

- Pleural effusions or peritoneal ascites

- Cytopenias (leukocytes < 1.0 x 10 /L and/or platelets < 100 x 10/L)

- Leukemia (> 5.0 x 10 /L circulating malignant cells)

- Indications for treatment based on FLIPI criteria include any three of the
following:

- Age ≥ 60 years

- Ann Arbor stage III or IV

- Hemoglobin level < 120 g/L

- Number of nodal areas involved > 4

- Serum lactate dehydrogenase (LDH) level > normal

- Only chemotherapy-naïve subjects are eligible. Subjects may have received prednisone
(< 2 months of therapy) or radiation ≤ 2 sites of therapy.

- Voluntary written informed consent and Health Insurance Portability and
Accountability Act (HIPAA) Authorization 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 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.

- Female patients of child bearing potential must have a negative β-human chorionic
gonadotropin (β-hCG) test.

- Male subject agrees to use an acceptable method for contraception for the duration of
the study.

- ≥ 18 years of age at the time of registration.

- Patients must have adequate renal function as demonstrated by a serum creatinine <
1.5 mg/dl unless felt to be secondary to lymphoma.

- Must have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.5
the upper limit of normal and a total bilirubin ≤ 2.0 mg/dL unless secondary to
lymphoma.

- Must have a cardiac left ventricular ejection fraction ≥ 50%.

- At least 1 measurable tumor mass (greater than 1.5 cm in the longest dimension and
greater than 1.0 cm in the short axis).

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

Exclusion Criteria:

- Subject with primary or secondary central nervous system (CNS) lymphoma (current or
previously treated) will not be eligible.

- A history of unrelated (non-lymphomatous) neoplasm within the past 10 years other
than non-melanoma skin cancer or in-situ cervix cancer. Subjects with a prior
diagnosis of malignancy more than 10 years may be entered into the study at the
discretion of the Principal Investigator.

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

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

- Patient has hypersensitivity to boron or mannitol.

- Female subject is pregnant or breast-feeding. Chemotherapeutic agents are known to
have teratogenic effects on developing embryos and to cause chromosomal damage to
gametes. These agents also cause bone marrow suppression and can be excreted in milk.
Confirmation that the subject is not pregnant must be established by a negative serum
β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during
screening. Pregnancy testing is not required for post-menopausal or surgically
sterilized women.

- 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 ECG
abnormality at Screening has to be documented by the investigator as not medically
relevant.

- Patient has a platelet count of < 10 x 10¹⁰/L (unless due to bone marrow involvement
with lymphoma documented within 14 days before enrollment).

- Patient has an absolute neutrophil count of < 1.0 x 10⁹/L (unless due to bone marrow
involvement with lymphoma documented within 14 days before enrollment).

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

- Presence of antibodies to HIV.

- Subject unwilling to give informed consent.