Study of Bortezomib in Combination With Cyclophosphamide and Rituximab
Study of Bortezomib in Combination With Cyclophosphamide and Rituximab
The goal of this clinical research study is to learn if bortezomib when given in combination
 with cyclophosphamide and rituximab can help to control mantle cell lymphoma. The safety of
 this drug combination will also continue to be studied.
The Study Drugs:

 Bortezomib is designed to block a protein that plays a role in cell function and growth. This
 may cause cancer cells to die.

 Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may
 slow or stop their growth and spread throughout the body. This may cause the cancer cells to
 die.

 Rituximab is designed to attach to lymphoma cells, which may cause them to die.

 Study Drug Administration:

 If you are found to be eligible to take part in this study, you will receive all of the study
 drugs preferably through a central venous catheter (CVC) that will be left in place the
 entire time that you are receiving the study drugs. A CVC is a sterile flexible tube that
 will be placed into a large vein while you are under local anesthesia. You will sign a
 separate consent form for this procedure, which will describe the procedure and the risk in
 more detail.

 You will receive rituximab by vein over 6 hours on Day 1 of every 21-day study cycle.

 You will receive bortezomib by vein over 3 to 5 seconds, after you have received rituximab on
 Day 1 of every cycle. You will also receive bortezomib on Days 4, 8, and 11 of every cycle.

 You will receive cyclophosphamide by vein over 3 hours 2 times each day (6 hours total each
 day) on Days 2, 3, and 4 of every cycle. On these days, you will also receive mesna by vein
 non-stop. Mesna is a drug that protects the bladder from damage by chemotherapy drugs. It is
 used to decrease the risk of bleeding in the bladder.

 You will receive G-CSF (filgrastim - a drug that is used to help build your white blood cell
 counts and prevent infections) as an injection under the skin starting 24-36 hours after you
 receive bortezomib. You will receive filgrastim 1 time each day until your white blood cell
 counts recover.

 Study Visits:

 At each study visit, you will be asked about how you are feeling and about any other drugs
 that you may be taking.

 Throughout the study, blood (about 1 tablespoon each time) will be drawn 2-3 times a week for
 routine tests.

 Within 2 days before each cycle, the following tests and procedures will be performed:

 -  You will have a physical exam, including measurement of your weight and vital signs.

 -  You will complete the questionnaire about nervous system side effects.

 -  Your performance status will be recorded.

 -  Blood (about 2 tablespoons) will be drawn for routine tests.

 After every 2 cycles, the following tests and procedures will be performed:

 -  You will have a physical exam, including measurement of your weight and vital signs.

 -  Your performance status will be recorded.

 -  You will have a chest x-ray or CT scans to check the status of the disease. These scans
 may be of your head, neck, chest, stomach, and/or pelvis. The CT scan at Cycle 4 will
 only occur if the doctor thinks it is needed.

 -  Blood (about 5 teaspoons) will be drawn for routine tests.

 -  If your doctor thinks it is needed, you will have a bone marrow biopsy/aspirate to check
 the status of the disease.

 -  If your doctor thinks it is needed, you will have an ECHO or a multigated radionuclide
 angiography (MUGA) scan and/or an ECG.

 You will have an exam of the colon (colonoscopy) to check the status of the disease after
 Cycle 2. Biopsy samples (about 3-6) of the colon will be taken during this exam to check the
 status of the disease.

 After Cycles 2, 6, and/or 8, if your doctor thinks it is needed, you will have a positron
 emission tomography (PET) scan to check the status of the disease.

 After Cycle 6, you will be taken off study if the disease is in "complete remission" (if the
 disease has disappeared). Otherwise, you may receive 2 more cycles of study treatment.

 If you are receiving 2 more cycles, if colonoscopy was done after Cycle 2 and it showed
 lymphoma, you will have another colonoscopy after Cycle 6 and Cycle 8 to check the status of
 the disease. Biopsy samples (about 3-6) of the colon will be taken during this exam to check
 the status of the disease.

 Length of Study:

 You will receive the study drugs for up to 8 cycles (about 8 months). You will be taken off
 study early if the disease gets worse or intolerable side effects occur before Cycle 8, or if
 the disease is in complete remission after Cycle 6.

 End-of-Treatment Visit:

 After you have finished receiving the study drugs, the following tests and procedures will be
 performed:

 -  You will have a physical exam, including measurement of your weight and vital signs.

 -  You will complete the questionnaire about nervous system side effects.

 -  Your performance status will be recorded.

 -  You will have a chest x-ray or CT scans to check the status of the disease.

 -  Blood (about 5 teaspoons) will be drawn for routine tests.

 -  If your doctor thinks it is needed, you will have a bone marrow biopsy/aspirate to check
 the status of the disease.

 -  If your doctor thinks it is needed, you will have an ECHO or a MUGA scan and/or an ECG.

 Follow-Up Visits:

 After you have finished receiving the study drugs, you will have follow-up visits according
 to the following schedule:

 -  Every 3 months during Year 1 after treatment.

 -  Every 4 months during Year 2 after treatment

 -  Every 6 months during Years 3-4 after treatment.

 -  Every 12 months after Year 4 after treatment.

 At each of the follow-up visits, the following tests and procedures will be performed:

 -  You will have a complete physical exam, including measurement of your weight and vital
 signs.

 -  You will complete the questionnaire about nervous system side effects.

 -  Your medical history will be recorded

 -  Your performance status will be recorded.

 -  Blood (around 1 tablespoon) will be drawn for routine tests.

 -  You will have a chest x-ray to check the status of the disease.

 -  You will have CT scans of the head, neck, chest, abdomen, and pelvis to check the status
 of the disease.

 -  If the doctor thinks it is needed, you will have a bone marrow aspirate/biopsy to check
 the status of the disease.

 This is an investigational study. All of the drugs used in this study are FDA approved and
 commercially available for the treatment of various types of lymphoma. The use of this drug
 combination is investigational.

 Up to 46 patients will take part in this multicenter study. All will be enrolled at M. D.
 Anderson.
Inclusion Criteria:

 1. Confirmed diagnosis mantle cell lymphoma and its variants, excluding marginal zone and
 disease exclusively in the GI system. Patients should have measurable disease based on
 Cheson Criteria or Bone Marrow/tissue sample positive for mantle cell lymphoma. No
 prior therapy with a combination of bortezomib, cyclophosphamide and rituximab.

 2. Patients with performance status of 2 or less (Zubrod).

 3. Serum bilirubin <1.5 mg/dl and serum creatinine < 2.0 mg/dl unless due to lymphoma;
 absolute neutrophil count (ANC) >1000/mm^3 and platelets >100,000/mm^3 unless due to
 lymphoma.

 4. Cardiac ejection fraction 50% or greater.

 5. Ages 18 to 85.

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

 7. Signed consent form.

 8. Voluntary written 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.

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

 10. Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to
 1 of the following: 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.

 Exclusion Criteria:

 1. Human immunodeficiency virus (HIV) infection.

 2. Central nervous system (CNS) involvement.

 3. Patient has a platelet count of < 100 K (eg <30 x 10^9/L for studies with bortezomib
 alone) within 14 days before enrollment.

 4. Patient has an absolute neutrophil count of ANC (eg <1.0 x 10^9/L for studies with
 bortezomib alone)> within 14 days before enrollment.

 5. Patient has > 1.5 times Total Bilirubin

 6. Patient has a calculated or measured creatinine clearance of < 20 mL/minute creatinine
 clearance (eg <20 mL/minute for studies with bortezomib alone) > within 14 days before
 enrollment.

 7. Patient has >/= Grade 2 peripheral neuropathy within 14 days before enrollment.

 8. 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.

 9. Patient has hypersensitivity to bortezomib, boron or mannitol.

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

 11. Participation in clinical trials with other investigational agents not included in
 this trial, within 14 days the start of this trial and throughout the duration of this
 trial.

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

 13. 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.

 14. Concurrent or previous malignancy whose prognosis is poor (< 90% probability of
 survival at 5 years).